Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids

1Cancer is a complex group of multiple diseases characterized by inappropriately controlled cell proliferation and replication eventually resulting in disruption of normal physiology, metabolism, or structure. Benign tumors are self-limited and do not invade or metastasize, but in complex stages groups of cells display uncontrolled growth, invasion and metastasis. In the metastasis stage, cancer cells migrate from one organ (the original tumor site) to another organ of the body through the circulatory and lymphatic systems. Cancer occurs by a series of successive deleterious mutations that change cell functions. These mutations often cause aberrant proliferation.

2Cancer is a major global health care problem that continues to remain a leading cause of morbidity and mortality, with >277 different cancer types. According to estimates from the World Health Organization (WHO) in 2019, in 112 of 183 countries, cancer is the first or second major cause of death before the age of 70 and ranks third or fourth in a further 23 countries. In 2020, for all cancers, 19,292,789 new cases were estimated globally, with a total of 9,958,133 cancer deaths. According to global demographic trends, 420 million new cancer cases are expected annually by 2025.

3Over the past 20 years, cancer treatments have improved significantly, and more potent medications have better safety profiles and more precise molecular targeting. Drug resistance is a major challenge with cancer treatment. During clinical usage, almost all targeted anticancer medications encounter resistance. Numerous processes have been related to drug resistance, including genetic and/or epigenetic mutation, amplification, cancer stem cells (CSCs), efflux transporters, apoptotic dysregulation, and autophagy, among others.

4Cancer chemotherapy with single-agent or single mono functional ‘targeted’ drugs has limited rates of success due to resistance and lack of selectivity. To tackle this limitation, combination therapy (multi-component drugs to treat cancer), was developed. Three alternative combination strategies are used: (a) two or more medicines that operate on distinct sites simultaneously or concurrently; (b) multi-targeting or promiscuous drugs treatment; and (c) hybridization drugs.

5Tumor heterogeneity, drug-drug interactions, unpredictable pharmacokinetic (PK) safety profiles, and poor patient compliance presents a problem for cancer treatment despite the use of drug-combination medicines. Hence, improving drug selectivity while eliminating drug resistance has become crucial for the successful treatment of cancer patients.

6There are unique challenges to cancer care in the developing as well as developed countries. These include issues with healthcare financing, patient awareness, and treatment delivery.

7To improve the efficiency of using a two-drug cocktail, one approach involves so-called hybrid drugs. The hybridization of biologically active molecules is a new concept and a powerful tool in drug design and development, used to target a variety of diseases. It is a strategy of rational design of such ligands or prototypes based on the recognition of pharmacophoric sub-units that maintain pre-selected characteristics of the original templates.

8Hybrid drugs are also termed “single molecule multiple targets” or “multiple ligands”. Hybrid molecules imply that one molecule shows structural features of two “parent” molecules. Two parent biologically active molecules (pharmacophores) that independently act at two distinct pharmacological targets. Molecular hybrids designed in a manner to the maintain their activities by merging or blending of two or more bioactive compounds or their pharmacophoric subunits into in a new molecular structure with a dual mode of action. The presence of two or more pharmacophores in a single unit leads to a pharmacological potency greater than the sum of each individual moiety’s potencies.

9Additionally, it is important to note that hybrid drugs usually have high molecular mass and lipophilicity; they violate Lipinski’s and Veber’s rules. However, hybrid anticancer drugs have remarkable advantages over conventional anticancer drugs because they are designed to act on a different bio target or interact with numerous targets simultaneously, reducing the likelihood of drug-drug interactions, with reduced side effects and reduced propensity to elicit resistance relative to the parent drugs. These novel hybrid molecules have improved affinity, enhanced efficacy and improved safety.

10Nowadays, hybrid drugs have drawn interest in the purposeful and logical design of ligands functioning selectively on multiple targets, and this has been reflected by an increase in the number of relevant publications in the field. In this review, we have compiled recent findings from 2011 to 2021 on novel hybrid compounds for different drug classes that exhibit promising anticancer activities. This analysis highlights in vitro anticancer activity of synthesized anticancer hybrids on different cell lines.

11Hybrid drugs are categorized based on the manner in which they are connected to each other. The concept of design and preparation of hybrid molecules is achieved using two strategies, which are described as follows:

121. Combining drug pharmacophoric moieties with: (a) two pharmacophoric groups directly linked; (b) two pharmacophoric groups linked by a spacer.

13These approaches are achieved by: (i) the merging of two pharmacophoric groups from two different drugs acting through the same mechanism of action; (ii) the merging of pharmacophoric groups from two drugs acting through different mechanisms of action.

14This is the integration of multiple pharmacophores in a single molecule. In this scenario, the starting point is to choose two established pharmacophores with high selectivity for their respective targets and a proper linker is selected to connect these two pharmacophores. This strategy is used to design new anticancer hybrids and is based on the ability of a combination of pharmacophoric moieties on a new molecular structure to retain their affinity and activity for the biological targets (Figure 1).

152. Combining two or more entire drugs: the second approach combines two or more entire medications that can be connected either directly or indirectly using a spacer or linker. The following categories apply:

16(a) Directly linked hybrid drugs: each molecule is connected via a functional group. Notable examples are mostly enzymatically hydrolysable esters, and carbamateoramide.

17(b) Merged or overlapped hybrid drugs: these types of hybrid agents are obtained by overlapping structural motifs or pharmacophores of two drugs. These hybrid agents differ significantly in their structures compared to the drugs from which they were designed. The hybrid agents may retain the functional properties of either or both of the overlapping drugs.

18(c) Spacer linked hybrid drugs: the main purpose of using a linker or spacer is to provide a bridge to connect two drugs and modulate the release of individual drugs in vivo. These molecules can be classified as cleavable and non-cleavable.

19(1) Non-cleavable hybrid drugs: non-cleavable linkers are connected with non-hydrolysable chemical bonds to create chemically as well as enzymatically stable linkers. This strategy is also based on the ability of the different molecules to retain their biological activity, specificity and respective affinity for their biological targets.

20(2) Cleavable hybrid drugs: a cleavable linker is based on the release of two parental molecular structures under physiological or enzymatic conditions that prevail at the site of activity. The majority of cleavable conjugates have an ester linkage that plasma esterases can cleave to release two separate medicines with independent actions (Figure 1).

21The purpose of cleavable hybrid drugs is to either improve poor pharmacokinetic properties and slowly deliver the two therapeutic entities in the body (e.g., ester, amide or carbamate), or to improve the selectivity and the antineoplastic activity of the drugs and release the two drugs directly in the targeted tissues (e.g., phosphorylated DES (Diethylstilbestrol) prodrugs for prostate cancer).

22Hybrids drugs have been formed by connecting two drugs with the same mechanism of action or by connecting two drugs with different mechanisms of action. The aim of connecting two drugs is to target specific biological tissues.

23Quinazoline is a heterocyclic compound and potent bioactive scaffold that has been associated with anticonvulsant, anticancer, analgesic, sedative, anti-hypertensive, anti-inflammatory, anti-histaminic, antimicrobial, anti-viral and anti-tubercular properties. Quinazoline containing compounds were investigated for their inhibition of kinases, which are major explored targets of cancer medicine development.

24Cheng et al. (2015) synthesized and explored quinazoline based imidazole hybrids and evaluated their anticancer activity against Epidermal Growth Factor Receptor (EGFR) and HT-29 cells (in normoxic and hypoxic conditions). Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 1(a) showed excellent activity with an IC50 of 0.47 nM, 2.21 µM and 1.61 µM, respectively compared to the gefitinib control with an IC50 of 0.45 nM, 3.63 and 5.21 µM, respectively. The structure of quinazoline based imidazole hybrids is given in Figure 2. Table 1 shows in vitro antiproliferative activity against the human cancer cell line HT-29 and EGFR inhibitory activity (nM) of compounds 1(b–e).

25Zhang Y et al. (2017) synthesized and evaluated anticancer activity of quinazolinebased deoxynojirimycin hybrids against Epidermal Growth Factor Receptor (EGFR) and α-glucosidase. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 2(a) showed excellent activity with an IC50 1.79 nM and 0.39 µM, respectively (the control gefitinib had an (−IC50 of = 3.32 nM and >100 µM, respectively). The structure of a quinazoline-based deoxynojirimycin hybrid is given in Figure 3 and in vitro EGFR and α-glucosidase inhibitory activity of compounds 2(b–e) against human cancer cell lines is shown in Table 2.

26Quinazoline based urea hybrids were synthesized by Zhang et al. (2016) and evaluated for their ability to inhibit EGFR and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2). Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 3(a) showed excellent activity with an IC50 of 1.0 nM and 79 nM, respectively, when the control vandetanib had an IC50 of 11 nM and >15 nM, respectively. The structure of a quinazolinebased urea hybrid is given in Figure 4 and in vitro EGFR and VEGFR-2 inhibitory activity of compounds 3(b–e) against human cancer cell lines is shown in Table 3.

27Yadav et al. (2016) synthesized substituted quinazoline based aryl hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed excellent activity against different isoforms of PI3K, but compound 4(a) showed 3.7 times more potent activity against Phosphoinositide 3-Kinase(PI3K) α (IC50 = 0.201 μM) than γ isoform (IC50 = 0.75 μM), and was a selective inhibitor of MCF-7 cells (human breast adenocarcinoma) with GI50 7 μM. Compound 4(a) also did not show any cytotoxicity to normal human cells. It inhibited 37% and 62% triglyceride (TGI) at 25 mg/kg dose in Ehrlich solid tumor and Ehrlich ascites carcinoma tumor models, respectively, with a control of 5-flurouracil at 22 and 20 mg/kg dose with TGI inhibition 50 and 96%, respectively. The structure of quinazoline-based aryl hybrids is given in Figure 5 and the in vitro cytotoxicity of compounds 4(b–e) against human cancer cell lines is shown in Table 4.

28Ding et al. (2018) synthesized and reported aminoquinazoline-sulphonamide based hybrids and evaluated their anticancer activity. Most of these compounds showed dual inhibitory activity against EGFR and PI3K α. Compound 5(a) showed excellent activity with an IC50 of 2.4 and 317 nM, compared to controls gefitinib (IC50 2.4 nM) and dactolisib (IC50 16.4 nM). Compound 5(a) exhibited potent activity against a panel of cell lines including adenocarcinomic human alveolar basal epithelial cells (A549 IC50 = 8.23 µM), epithelial cells (BT549, IC50 = 1.02 µM), human colon cancer cells (HCT-116, IC50 = 5.60 µM), breast cancer cells (MCF-7, IC50 = 5.59 µM), human hepatic adenocarcinoma cells (SK-HEP-1, IC50 = 6.10 µM), and gastric carcinoma cells (SNU638, IC50 = 4.10 µM). For comparison, the controls gefitinib and dactolisib had IC50 doses of 8.27, 6.56, 5.98, 26.7, 10.1, and 7.56 µM or 0.62, 0.74, 0.84, 1.33, 1.82,and 1.24 µM in the same cell lines), respectively. The structure of aminoquinazoline-sulphonamide based hybrids is given in Figure 6 and in vitro cytotoxicity (IC50, μM) of compounds 5(b–e) against human cancer cell lines is shown in Table 5.

29Continuing the work of Ding et al. (2018), Fan et al. synthesized amino quinazoline based hybrids and evaluated their anticancer activity. Most of these compounds showed inhibitory activity against PI3K. Compound 6(a) showed excellent activity towards PI3Kα with an IC50 13.6 nM in comparison to other isoforms of PI3K including PI3Kβ, PI3Kγ and PI3Kδ, which had IC50 of396.2, 117.5, and 101.8 nM. Compound 6(a) exibited potent activity against a panel of cell lines including HCT-116, SK-HEP1, MDA-MB-231 (epithelial, human breast cancer cells), SNU638, A549, and MCF-7 with IC50 values 0.16, 0.28, 0.28, 0.48, 1.32, and 3.24 µM. Control BEZ235 had IC50 values of 0.84, 1.82, 0.18, 1.24, 0.62, and 1.33 µM. The structure of quinazoline-amino sulphonamide based hybrid is given in Figure 7 and in vitro cytotoxicity (IC50, μM) of compounds 6(b–e) against human cancer cell lines is shown in Table 6.

30Frohlich et al. (2017) synthesized hybrids of quinazoline with artemisinin and evaluated their in vitro anticancer activity on CCRF-CEM (lymphoblastoid cell) and CEM/ADR5000 (leukemia cells). Most of the synthesized compounds showed potent anticancer activity; out of them, compound 7 (Figure 8) showed excellent activity with an EC50 of 2.8 and 0.6 µM. Control doxorubicin had an EC50 of 0.009 and 23.27 µM, respectively.

31Yang et al. (2018) synthesized quinazoline based hybrids and evaluated them for their Bromodomain-containing protein 4 (BRD4) inhibitory activity. SAR studies revealed that the phynylmorpholine along with the pyrazole skeleton showed potent activity against BRD4. Compound 8(a) showed potent activity against human AML cells (MV4-11) with an IC50 value of 1.10 µM (Kd 66 nM) when control BET760 had an IC50 0.80 µM (Kd 37 nM). The structure of quinazoline-phenyl morpholine based hybrids is given in Figure 9 and in vitro cytotoxicity of compounds 8(b–e) against human cancer cell lines is shown in Table 7.

32The hybrids of quinazoline have been evaluated in various clinical trials in recent years, with several of them showing promising results. In addition, the Food and Drug Administration (FDA) approved certain quinazoline-based enzyme inhibitors for the management of various malignancies. Dacomitinib, erlotinib, gefitinib, afatinib, and lapatinib are the quinazoline based hybrid drugs approved by the FDA for management of different types of cancers (Figure 10). Additionally, in Table 8, we have summarized quinazoline-based hybrid molecules under clinical trials for the treatment of different types of cancer.

33Indole is a remarkable and adaptable heterocycle that has been used to create important biological scaffolds in pharmaceutical research. Indole/indole derivatives have many reported therapeutic properties, such as anti-virals, anti-convulsants, antibacterials, anti-microbials, anticancer agents, anti-malarials, anti-inflammatories, anti-oxidants, and anti-diabetics. Different natural and synthesized indole motifs have demonstrated considerable anticancer potential. Such substances have been found to act on a variety of protein targets, including sirtuins, PIM (proviral integration site for Moloney murine leukemia virus) kinases, HDACs (histone deacetylases) and DNA topoisomerase.

34Zhang et al. (2013) synthesized hybrids of indole with hydroxycinnamamide, and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 9(a) exhibited excellent activity against various cell lines including human myeloid leukemia (U937), prostate adenocarcinoma (PC-3), A549, ovarian carcinoma (ES-2), MDA-MB-231, and HCT116 at IC50 1.8, 3.7, 4.4, 5.4, 3.1, and 5.5 µM, respectively with control suberoylanilide hydroxamic acid (SAHA) had IC50 values of 2.3, 9.9, 3.8, 12.7, 5.6, and 6.0 µM, respectively. Furthermore, compound 9(a) showed excellent HDAC (histone deacetylase) inhibitory activity against different isoforms of HDAC including HDAC1, HDAC2, HDAC3, and HDAC6 with IC50 values of 0.39, 1.42, 0.28, and 0.94 µM compared to control SAHA at IC50 values of 0.076, 0.256, 0.028, and 0.118 µM, respectively. The structure of indole with hydroxycinnamamide hybrids is shown in Figure 11 and in vitro cytotoxicity of compounds 9(b–e) against human cancer cell lines is shown in Table 9.

35Zhang et al. (2013) synthesized and explored hybrids of indole with hydroxycinnamamide, evaluating their anticancer activity against different cell lines. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 10(a) exhibited excellent activity against various cell lines including U937, K562 (myelogenous leukemia cells), HEL (human erythroleukemia cells), KG1(myeloid leukemia cells), HL60 (promyelocytic leukemia cells), MDA-MB-231, PC-3, MCF-7, HCT116, and A549 with IC50 values 0.16, 0.51, 0.19, 0.22, 1.69, 0.22, 0.46, 2.68, 0.52, and 2.74 µM, respectively. Furthermore, compound 10a showed excellent HDAC selectivity against different isoforms of HDAC including HDAC1, HDAC2, HDAC3, and HDAC6 with IC50 values 11.8, 498.1, 3.9, and 308.2 nM with control SAHA had IC50 values of 34.6, 184.7, 90.1, and 63.0 nM, respectively. The T structure of indole and hydroxycinnamamide hybrids is shown in Figure 12 and the in vitro cytotoxicity of compounds 10(b–e) against human cancer cell lines is shown in Table 10.

36Mehndiratta et al. (2014) synthesized hybrids of indole with sulphonamides, and evaluated their anticancer and anti-inflammatory activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 11(a) showed excellent activity against HeLa nuclear HDAC enzyme with an IC50 of 7.9 nM. The structure of indole and sulphonamide hybrids is shown in Figure 13 and the in vitro cytotoxicity of compounds 11(b–e) against human cancer cell lines is shown in Table 11.

37Panathur et al. (2013) synthesized indole based hybrids, and evaluated them for anticancer activity against three cancer cell lines including K562, MDA-MB 231 and LNCaP (androgen-sensitive human prostate adenocarcinoma cells). Most of the synthesized compounds showed potent anticancer activity; among them, 9 compounds showed excellent activity against MDA-MB 231, with three compounds inhibiting growth of LNCaP cell up to 50% at 10 µM. Furthermore, the lead molecule 12(a) showed SIRT1 (Sirtuin 1) inhibitory activity up to 70% with control finasteride (growth inhibition 56%) at 40 µM. The structure of indole-triazole based hybrids is given in Figure 14 and the in vitro cytotoxicity of compounds 12(b–e) against human cancer cell lines is shown in Table 12.

38Lee et al. (2014) synthesized indole based hybrids and evaluated their proto-oncogene serine/threonine-protein kinase (PIM) kinase selectivity against different forms of PIM kinase including PIM1, PIM2, and PIM3. Compound 13(a) showed excellent selectivity towards PIM1 with IC50 values of 0.058, 0.52, and 0.16 µM. Furthermore, the lead molecule 13(a) was tested against different cell lines, including MV-4-11 (acute myeloid leukemia cell), Jurkat (T lymphocyte cells), and K562, and was found to be very selective towards MV-4-11 in a cell viability assay. The lead molecule also showed binding interaction with Lys67 and Glu89 in the active site of PIM1 (ATP-binding). The structure of an indole-pyrimidine based hybrid is shown in Figure 15, and the in vitro cytotoxicity of compounds 13(b–e) against human cancer cell lines is shown in Table 13.

39Mirzaei et al. (2017) synthesized and explored indole-chalcone based hybrids and evaluated their anticancer activity against various cell lines including A549, MCF7, SKOV3 (human ovarian cancer cell), and NIH3T3 (embryonic fibroblast cells), finding IC50 values of 4.3, 100, 20.2, and 154.6 µg/mL with control etoposide IC50 of 7.8, 9.9, 8.5, and 118.0 µg/mL, respectively. Furthermore, the lead molecule 14(a) was subjected to a tubulin polymerization inhibitory assay, with results revealing that the lead molecule showed excellent inhibitory activity, having an IC50 of 17.8 µM with control colchicine, having an IC50 of 2.3 µM. The structure of indole-chalcone based hybrids is shown in Figure 16 and the in vitro cytotoxicity of compounds 14(b–e) against human cancer cell lines is shown in Table 14.

40Zhou et al. (2016) synthesized and explored hybrids of indole with pyrrole and evaluated their anticancer activity against various cell lines including HL-60, SMMC-7721 (hepatocarcinoma cells), A-549, MCF-7, and SW480 (colon carcinoma cell). Most of the synthesized compounds showed potent anticancer activity. Among them, compound 15(a) showed excellent activity having IC50 values of 1.27, 1.72, 2.68, 1.78, and 1.44 µM with control cisplatin (DDP) having IC50 values of 1.16, 8.08, 7.10, 10.45, and 8.88 µM, respectively. The structure of indole-pyrole based hybrids is shown in Figure 17 and the in vitro cytotoxicity of compounds 15(b–e) against human cancer cell lines is shown in Table 15.

41Kumar et al. (2014) synthesized indole based chalcone hybrids and evaluated their antiproliferative activity against A549, PC3 and PaCa2 (pancreatic cancer) cell lines. Among the synthesized derivatives, compound 16(a) showed potent activity having IC50 values of 2.4 and 0.8, 36.0 and 22.5, and >50 µM, respectively (with control mitomycin C having an (IC50 = of 0.45 µM against A549 at 24h). The structure of indole-chalcone based hybrids is shown in Figure 18 and the in vitro cytotoxicity of compounds 16(b–e) against human cancer cell lines is shown in Table 16.

42Kumar et al. (2018) synthesized and explored indole-ospemifene-triazole based hybrids and evaluated their anticancer activity against MCF-7 and MDA-MB-231. Most of the synthesized compounds showed good anticancer activity, compound 17(a) exhibited excellent activity at IC50 1.56 and 48.46 µM controls included ospemifene (IC50 55 and 50 µM), tamoxifen (IC50 3.5 and >100 µM), and plumbagin (IC50 75 and 4.4 µM). The structure of the indole-ospemifene-triazole based hybrid is shown in Figure 19 and the in vitro cytotoxicity of compounds 17(b–e) against human cancer cell lines is shown in Table 17.

43Kumar et al. (2018), and Sharma et al. (2019) synthesized indole-isatin based triazole hybrids and evaluated their anticancer activity. Among the synthesized compounds, compound 18(a) showed excellent activity against MCF-7 and MDA-MB-231 cell lines withIC50 values of 37.42 and >100 µM Control included plumbagin (IC50 3.5 4.4 µM), peganumine A (IC50 38.5 µM and not observed) and tamoxifen (IC50 50 and 75 µM), respectively. Furthermore, the biological activity was validated by docking studies. The structure of the indole-isatin-triazole based hybrid is shown in Figure 20, and the in vitro cytotoxicity (µM) of compounds 18(b–c) against human cancer cell lines is shown in Table 18.

44Dacinostat (LAQ824), an indole-based hybrid molecule, is approved for the management of breast and prostate cancer, whereas panobinostat (LBH-589) is a marketed medicine for numerous malignancies. Quisinostat (JNJ-26481585), a synthetic indole-hydroxamic acid molecule (hybrid) with putative antitumor action is an orally available 2nd generation molecule to inhibit HDAC. Cediranib is a tyrosine kinase inhibitor which affects the function and development of endothelial cells in human kidney tumors. Anlotinib (AL3818) is a potent kinase inhibitor with potential antitumor as well as antiproliferative efficacy currently in clinical trials. Figure 21, shows chemical structures of indole-based FDA approved/clinical trial drugs and Table 19 gives descriptions of them.

45Carbazole is a key scaffold found in a wide range of physiologically potent chemicals, including natural and synthetic analogues. Anticancer, antifungal, antibacterial, anti-HIV, anti-inflammatory, anti-protozoan, anti-psychotic, antidiabetic and anticonvulsant properties are found in molecules with r chemically modified carbazole moiety. The first carbazole compounds, celiptium and ellipticine, targeted topoisomerase II and cytochrome P450, respectively, and are used to combat cancer (metastatic breast cancer). An investigation of the carbazole nucleus for the production of novel structural scaffolds has led to the development of a number of available anti-tumor hybrids.

46Liu et al. (2015) synthesized and evaluated the anticancer activity of carbazole derivatives against various cell lines including HL-60, SMMC-7721, A549, MCF-7 and SW480. Among the synthesized carbazole derivatives, compound 19(a) showed potent activity with IC50 values of 0.51, 2.38, 3.12, 1.40, and 2.48 µM, where control cisplatin (DDP) hadIC50 values of 1.32, 6.24, 11.83, 15.17, and 12.95 µM, respectively. Compound 19(a) showed cell cycle arrest in SMMC-7721 cells. The structure of carbazole-imidazole based hybrids is shown in Figure 22 and the in vitro cytotoxicity of compounds 20(b–e) against human cancer cell lines is shown in Table 20.

47Mongre et al. (2019) synthesized a potent novel hybrid (20) of carbazole and piperazine and evaluated its anticancer activity against various cell lines including A549, NCI-H1299 (non-small cell lung carcinoma cells), HT-29, MCF-7, Hela (cervical carcinoma), and U2OS (osteosarcoma cells). The IC50 values in these cell lined were 1.779, 2.270, 2.20, 2.637, 3.072 and 2.739 µM, respectively. The molecule also showed potent cell cycle arresting activity at concentrations of 0.5, 1.0 and 2.0 µM by affecting G2/M cell cycle transition. Hybrid (20) also inhibited tumor progression in a xenograft model (BALB/c-nu nude mouse) at a dose of 3 mg/kg body weight without any toxicity. A carbzole-piperazine hybrid is depicted in Figure 23.

48Some well-known carbazole-based hybrids with potential anticancer effects have been published. Some carbazole-based hybrids are FDA approved medications or in clinical studies for cancer treatment. Alectinib was licensed by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2015 for the management of anaplastic lymphoma kinase-positive progressive non-small cell lung cancer (NSCLC). Midostaurin is a carbazole hybrid that was approved by the FDA and the European Medicines Agency (EMA) in 2017. It is used to treat recently diagnosed advanced systemic mastocytosis and acute myeloid leukemia.

49Currently, four hybrids of carbzole are being tested in clinical studies including becatecarin and edotecarin, which have been proven to intercalate DNA and maintain the DNA-topo I complex, and are currently in Phase II and Phase III clinical studies, respectively. CEP-2563 is a strong inhibitor of platelet derived growth factor (PDGF) and tyrosine kinase that is now in a Phase I clinical development for medullary thyroid cancer. UCN-01 is now being tested in a Phase II clinical study for breast cancer, lymphoma, and pancreatic by acting upon protein kinases. The structure of FDA approved/clinical trials drugs with carbazole hybrids is given in Figure 24 and their current status is shown in Table 21.

50The basic structure of RNA, DNA, and nucleic acids is the heterocyclic pyrimidine ring. Pyrimidine and its conjugated counterparts possess antiviral, antibacterial, anticancer, analgesic, anti-inflammatory, antimalarial and antioxidant activities. Anticancer action is the most often described therapeutic property of pyrimidine because it interacts with a variety of targets, as well as receptors to cause cell death. Multiple studies on the anticancer efficacy of pyrimidine compounds, as well as their therapeutic use, have supported their position as a prospective drug development nucleus.

51Combs et al. (2015) synthesized and patented aminopyrimidine hybrids and evaluated their P13K enzyme as well as cell proliferation inhibitory potential in 96-well plates using scintillation counting. Compound 21 (Figure 25) showed potent activity with IC50 < 20 nM.

52Boloor et al. (2012) synthesized and patented pyrimidine-indazole based hybrids as VEGFR2 inhibitors. Compound 22 showed potent activity with an IC50 < 50 μM. Furthermore, the lead compound 22 (Figure 26) was evaluated in an endothilian cell proliferation assay where it displayed activity withIC50s of 1-200 nM.

53Hogberg et al. (2012) developed and patented indole based pyrimidine hybrids and evaluated their anticancer activity as tubulin inhibitors. Among the synthesized compounds, compound 23 (Figure 27) showed potent activity on CCRFCEM (T lymphoblastoid cells) with an EC50 value of 0.015 µM.

54Mao et al. (2012) synthesized and patented pyrimidine-pyrazole based hybrid molecules and evaluated their anticancer activity against H1993 cells. The synthesized compounds did not show desirable activity on representative cell line. Furthermore, potent compound 24 (Figure 28) was subjected to enzymatic assay on cMet protein and displayed excellent activity, having an IC50 in the nM range.

55Tanaka et al. (2012) synthesized and patented pyrimidine-pyrazole based hybrid molecules and evaluated their anticancer activity as Fyn inhibitors. Among the synthesized compounds, compound 25 (Figure 29) showed excellent activity with an IC50 of 3 nM. Furthermore, 26 (Figure 29) showed excellent activity on carbonyl reductase 1 with an IC50 of 28 nM.

56Liang et al. (2013) synthesized and patented pyrimidine-pyrazole based hybrid molecules, and evaluated their anticancer activity as mammalian target of rapamycin mTOR inhibitors. Compound 27 (Figure 30) showed potent activity on A549 and U-87MG (glioma cells) with an IC50 < 1 µM.

57Dorsch et al. (2013) synthesized and patented pyrimidine-triazole based hybrids and evaluated their anticancer activity as general control non-derepressible 2 (GCN2) inhibitors of U20S human cells. Among the synthesized hybrids, the compound 28 (Figure 31) showed excellent activity with IC50 ≤ 0.3µM.

58El-Sayed et al. (2011) synthesized sulfonamide-thiazole fused pyrimidine derivatives, and evaluated their anticancer activity in amethyl green/DNA displacement assay. Among the synthesized compounds, compound 29a showed potent activity with an IC50 of 40 µg/mL and high DNA binding affinity. Furthermore, in vivo studies showed that the compound 29a increased the % lifespan of mice by 42.86% over standard fluorouracil. The structure of sulfonamide-thiazole fused pyrimidine derivatives is shown in Figure 32 and the in vitro cytotoxicity of compounds 29(b–e) against human cancer cell lines is shown in Table 22.

59Shao et al. (2013) synthesized tri-substituted pyrimidine based hybrid derivatives, and evaluated their anticancer activity as cyclin-dependent kinase (CDK) inhibitors. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 30a showed potent kinase inhibition against CDK9T1, CDK1B, CDK2A, CDK7H withKi of 14, 262, 316, and 163 nM, and cell toxicity activity against HCT-116, and MCF-7 cell lines with IC50 value of 0.79, and 0.64 µM, respectively. Furthermore, compound 30a showed potent activity of Mal-1 and caspase-3 inhibition by down regulation of apoptotic protein. The structure of substituted pyrimidine derivatives is shown in Figure 33 and the in vitro cytotoxicity of compounds 30(b–e) against human cancer cell lines is shown in Table 23.

60Fares et al. (2014) synthesized pyrimidine-based triazole hybrid derivatives and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 31(a) showed excellent activity against various cell lines including MCF-7, human hepatoma carcinoma cells (HEPG2), A-549, and (PC-3) with IC50 of 37.96, 56.65, 0.41, and 0.36 µM. Furthermore, compound 31a was screened in a CDK4 and CDK6 inhibition assay and compound showed 0 and 2% inhibition at 1 µM, 5 and 1% inhibition at 10 µM and 21 and 17% inhibition at 100 µM with control staurosporine having 93 and 90% inhibition at 1 µM. The structure of pyrimidine-triazole based hybrid derivatives is shown in Figure 34 and the in vitro cytotoxicity (µM) of compounds 31(b–e) against human cancer cell lines is shown in Table 24.

61Kurumurthy et al. (2019) synthesized pyrimidine based triazole hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 32(a) showed excellent activity against various cell lines including U937, THP-1 and Colo205 cells having IC50 values of 6.20, 11.27, and 15.01µg/mL with control etoposide having IC50 values of 17.94, 2.16, 7.24, and 1.26 µg/mL, respectively. The structure of pyrimidine-triazole based hybrid derivatives is shown in Figure 35 and the in vitro cytotoxicity of compounds 32(b–e) against human cancer cell lines is shown in Table 25.

62Nagendra et al. (2014) synthesized pyrimidine based pyrazole hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 33(a) showed excellent activity against various cell lines including A549, MCF7, DU145 (prostate cancer cell) and HeLa with IC50 values of 4.2, 37.2, 5.8, and 34.3 µM and control 5-FU having IC50 values of 1.3, 1.4, 1.5, and 1.3 µM, respectively. The structure of pyrimidine-pyrazole based hybrid derivatives is shown in Figure 36 and the in vitro cytotoxicity (µM) of compounds 33(b–e) against human cancer cell lines is shown in Table 26.

63Huang et al. (2012) synthesized pyrimidine based pyrazole hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 34(a) showed excellent activity against various cell lines including NCI-H226 (human lung squamous carcinoma cells), NPC-TW01 (nasopharyngeal carcinoma), and Jurkat having GI50 29, 30, and 54 µM, respectively. The structure of pyrimidine-pyrazole based hybrid derivatives is shown in Figure 37, and the in vitro cytotoxicity of compounds 34(b–e) against human cancer cell lines is shown in Table 27.

64Ceritinib, palbociclib, and ibrutinib are three hybrids which contain pyrimidine scaffold that have received US-FDA approval for their antitumor effects against non-small cell lung cancer, advanced breast cancer and leukemia, respectively. Pyrimidine-based FDA approved drugs are depicted in Figure 38 and their details are shown in Table 28.

65Quinoline has been identified as a major scaffold with huge therapeutic potential, including antibacterial, anti-viral, anti-helmintic, anti-malarial and anti-prozoal activities. Due to its derivatives having demonstrated outstanding effects against cancerous cells via various mechanisms, the quinoline nucleus has played a crucial role in the research and development of chemotherapeutic agents. Camptothecin is a natural anticancer agent with the capacity to obstruct DNA topoisomerase.

66Sidoryk et al. (2015), synthesized quinoline based guanidine hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 35 showed excellent activity against BALB/3T3, A549, MCF-7, LoVo, and KB cell lines (Table 29). Furthermore, compound 35 (Figure 39) showed excellent activity in a DNA displacement assay and potent activity in G2/M phase of the cell cycle.

67Gedawy et al. (2015) synthesized tetrahydro-pyrimido-quinoline based hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 36 (Figure 40) showed excellent activity against HCT-116, and MCF-7 (Table 30).

68Sanchez et al. (2011) synthesized quinoline-based thiazole hybrids based on the structure of m-Amsacrine (37, Figure 41), and evaluated their anticancer activity against cancerous (K-562) and non-cancerous (PMBCs) cells. Compound 37a showed excellent activity with IC50 values of 28.7 and 7.82 µM, respectively, compared to a control of Paclitaxel (IC50 0.25 µM). Mechanistically, compound 36(a) induced appototic cell death via caspase activation with an IC50 of 7.8 µM.

69Luniewski et al. (2012) synthesized quinoline based indole hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 38(a) showed excellent activity against KB, A-549, MCF-7, Hs294T, and BALB/3T3 cell lines having IC50 values of 0.15, 0.24, 0.38, 0.62, and 0.31 µM with control 5,11-dimethyl-5H-indolo [2,3-b]quinoline (DIMIQ) at IC50 values 1.14, 2.19, 1.50, 9.70, and 5.70 µM, respectively. Furthermore, compound 38a showed excellent topo II inhibitory activity at concentration of 0.05 µM with control DIMIQ (Conc. 0.5 µM), m-AMSA (Conc. 0.05 µM), and daunorubicind (Conc. 0.5 µM) and cell cycle inhibitory activity at a concentration of 0.10 µM with control DIMIQ (Conc. 1.02 µM). Additionally, it showed positive inhibitory results in the G2M phase of the cell cycle. The structure of quinoline-indole based hybrid derivatives is given in Figure 42 and the in vitro cytotoxicity of compounds 38(b–e) against human cancer cell lines is shown in Table 31.

70Jin et al. (2019) synthesized quinoline-based ursolic acid hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 39(a) showed excellent activity against MDA-MB-231, HeLa, SMMC-7721, and QSG-7701 (hepatocyte cell line) at IC50 0.12, 0.08, 0.34, and 10.76 µM with control Etoposide with IC50 values of 5.26, 2.98, 3.48, and 28.75 µM, respectively. Furthermore, compound 39(a) showed excellent activity apoptosis-inducing activity in on HeLa cell lines (for 48 h). The structure of quinolinebased ursolic acid hybrids derivatives is shown in Figure 43, and the in vitro cytotoxicity (µM) of compounds 39(b–e) against human cancer cell lines is shown in Table 32.

71Solomon et al. (2019) synthesized quinoline based sulphonamide/piperazine hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 40(a) showed excellent activity against MB231, MB468, MCF7, 184B5 (normal mammary tissue), and MCF10A cell lines, having GI50 values of 3.4, 0.7, 2.3, 9.0, and 12.3 µM. Control chloroquine, had GI50 values of 22.5, 28.6, 38.4, 76.1, and 81.26 µM and Cisplatin having GI50 value 23.7, 31.0, 25.8, 25.5, and 51.51µM, respectively. Furthermore, compound 40(a) showed cell cycle interruption at the meta phase, and also increased the liposamal volume in cancerous cells which led to cell death. The structure of quinoline based piperazine hybrids is given in Figure 44 and the in vitro cytotoxicity (µM) of compounds 40(b–e) against human cancer cell lines is shown in Table 33.

72Kumar et al. (2014) synthesized quinoline-based gallium(III) hybrids and evaluated their anticancer activity. Synthesized hybrid 41 showed potent activity against HCT-116, Caco-2 (human colon cancer cell), HT-29, and CCD-18C (colonic fibroblasts), having IC50 values of 14.26, 19.56, 19.66, and 28.28 µM, respectively. Control etoposide had comparative values of 38.10, 32.90, 35.10, and 58.90 µM, respectively. Furthermore, hybrid 41 was evaluated for anti-malarial activity, showing more potent activity than lumefantrine on the 3D7 strain of Plasmodium falciparum. A quinoline-based gallium(III) hybrid is depicted in Figure 45.

73Quinoline containing drugs that have received FDA approval include lenvatinib, cabozantinib, and bosutinib which are protein kinase inhibitors and are used to cure medullary thyroid cancer and chronic myelogenous leukemia accordingly. FDA approved drugs with quinoline hybrids are depicted in Figure 46 and their details are shown in Table 34.

74Quinones are found in all living beings; particularly animals, plant and microbes. Through serving as crucial links in the cell nucleus respiratory cycle, they play a vital role in the power generation of such species. Numerous distinct medicinal uses of quinones have been noted, such as antiviral, antithrombotic, antiplatelet, antibacterial, antifungal, anti-inflammatory, and antiallergic properties.

75Markovic et al. (2015) synthesized quinone based chalcone hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 42(a) showed excellent activity against HeLa, LS174 (colorectal cancer cells), A549, and MRC-5 (multipotent stem cells) with IC50 values of 2.73, 6.44, 28.84, and 48.76, respectively. Furthermore, compound 42(a) showed caspase based apoptosis in G2/M and S phase of cell division. The structure of quinone-based chalcone hybrids derivatives is given in Figure 47 and the in vitro cytotoxicity of compounds 42(b–e) against human cancer cell lines is shown in Table 35.

76Jiang et al. (2015) synthesized quinone based pyran hybrids and evaluated their anticancer activity. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 43(a) showed excellent activity against KB (throat cancer cells), KB/VCR (colon cancer cells), A549, and HL60, with IC50 values 4.05, 1.28, 0.62, and 1.73 µg/mL. A control vincristine had IC50 values of 0.46, 0.26, and 12.09 µg/mL (for KB, KB/VCR, A549), respectively, and adriamycin had an IC50 value 0.02 µg/mL (HL60). The structure of quinone-based pyran hybrid derivatives is given in Figure 48 and the in vitro cytotoxicity (µg/mL) of compounds 43(b–e) against human cancer cell lines is shown in Table 36.

77Doxorubicin, daunorubicin, and mitoxantrone drugs are used to treat several types of cancer. These drugs are shown in Figure 49.

78The imidazole derivatives have recently gained a lot of interest and are already present in many existing treatments. Imidazole was first synthesized in 1858 using glyoxal and formaldehyde by Heinrich Debus. Various medicinal properties of imidazole based hybrid molecules have been reported; especially as antitumor, anti-diabetic, anti-HIV, anti-protozoal, anti-mycobacterial, anti-inflammatory, analgesic, and anti-protozoal agents.

79Xiao-Dong Yang et al. (2012) synthesized different derivatives of novel hybrid compounds between 2-phenylbenzofuran and imidazole. Myeloid liver carcinoma (SMMC-7721), colon carcinoma (SW480), breast carcinoma (MCF-7), lung carcinoma (A549) and leukemia (HL-60) cell lines were used for in vitro study of the cytotoxic effects of synthesized hybrids with cisplatin (DPP) as the standard drug. Five derivatives showed more potent cytotoxic activity than standard DPP. The structure of imidazole based benzofuran hybrid derivatives are given in Figure 50 and the in vitro cytotoxic activities of hybrid compounds 44(a–e) (IC50, µM) are listed in Table 37.

80Wen Chen et al. (2013) synthesized numerous derivatives of novel hybrid 2-phenyl-3-alkylbenzofuran and imidazole compounds. Myeloid liver carcinoma (SMMC-7721), colon carcinoma (SW480), breast carcinoma (MCF-7), lung carcinoma (A549) and leukemia (HL-60) cell lines were used for in vitro cytotoxic testing of synthesized hybrids, with DPP as the standard drug. They found that five derivatives showed more potent cytotoxic activity than standard DPP. The structure of imidazole based benzofuran hybrid derivatives is given in Figure 51 and the in vitro cytotoxic activities of hybrid compounds 45(a–e) (IC50, µM) are listed in Table 38.

81Al-blewi et al. (2013) synthesized numerous derivatives of novel imidazole-1,2,3-triazole hybrids. The synthesized compounds were screened for their anticancer activity against three different types of cancer, namely human colon carcinoma (Caco2 and HCT116), human cervical carcinoma (HeLa) and human breast adenocarcinoma (MCF-7) cancer cells-, using doxorubicin as a standard drug. They found that these derivatives showed potent more cytotoxic activity than standard doxorubicin. The structure of imidazole based triazole hybrid derivatives is given in Figure 52 and in vitro cytotoxic activities of hybrid compounds 46(a–e) are listed in Table 39.

82Yanping Hu et al. (2019) designed and synthesized a series of artemisinin-imidazole hybrids derivatives with multidrug resistance (MDR) reversal activity. All hybrids were screened in vitro for anticancer activities against four human cancer cell lines, human breast cancer (MCF-7), human non-small-cell lung (A549), (HEPG-2), breast cancer (MDA-MB-231) and normal human hepatic cells (L02). Adriamycin was used as reference drug. They found that most of the synthesized compounds showed higher anticancer activities than artemisinin. The structure of imidazole based artemisinin hybrid derivatives is given in Figure 53 and the in vitro cytotoxic activities of hybrid compounds 47(a–e) are listed in Table 40.

83Wen-Jian Song et al. (2012) designed and synthesized a series of novel hybrid compounds of 2-substituted benzofuran and imidazole. In vitro anticancer activity of synthesized hybrids against a panel of human tumor cell lines i.e., ovarian carcinoma cell line (Skov-3), leukemia (HL-60) and breast carcinoma (MCF-7) was evaluated. They found that the hybrid compounds were more selective than standard DPP. The structure of imidazole based benzofuran hybrid derivatives is given in Figure 54 and the in vitro cytotoxic activities of hybrid compounds 48(a–e) are listed in Table 41.

84Different imidazole-based anticancer hybrid drugs that are FDA approved/or under clinical trials are shown in (Figure 55), and their chemical structures brand/company name and targets are in Table 42.

85Selenium (Se) is a unique trace element. Se directly or indirectly exerts antioxidant functions in the human body. However, during recent years, researchers reported that Se containing compounds exhibit superior anticancer effects, with high efficacy and selectivity. It has been reported that a variety of organic selenium compounds, including selenoesters, selenocyanates, methylseleninic acid, isoselenocyanates, diselenides, and endocyclic selenium, have anticancer properties.

86Organic Se compounds have lower systemic effects, fewer side effects, and strong anti-tumor action. They also have a greater ability to inhibit metastasis. Several novel organic Se compounds have been synthesized in order to further improve the selectivity, specificity and efficacy and to lower the toxicity.

87Xianran He et al. (2020) synthesized organoselenium (SeCF3) derivatives as potential anticancer agents. The anticancer activity of the synthesized compounds was assessed using human cancer cell lines, human colon adenocarcinoma cells (SW480), human cervical cancer cells (HeLa), human lung carcinoma cells (A549), human breast adenocarcinoma cells (MCF-7). The in vitro biological evaluation was conducted at 24, 48 and 72 h intervals, and it was found that the organoselenium hybrid compounds were more selective than standard Fluorouracil (5FU). The structure of organoselenium hybrid derivatives is given in Figure 56 and the in vitro cytotoxic activities of hybrid compounds 49(a–c) are listed in Table 43.

88Guilherme A. Jardim et al. (2017) synthesized selenium-containing quinone-based 1,2,3-triazoles with potential antitumor activity via rhodium-catalyzed C-H bond activation and click reactions. All compounds were evaluated against five types of cancer cell lines: human promyelocytic leukemia cells (HL-60), human colon carcinoma cells (HCT-116), human glioblastoma cells (SF295), human lung cells (NCIH-460) and human prostate cancer cells (PC3), using paclitaxel as a positive control. L929 cells were also used to test the cytotoxic potential of the naphthoquinoidal derivatives in non-tumor cells. Overall, these compounds represented promising new lead derivatives with potential antitumor activity. The structure of selenium based quinone triazole hybrids is given in Figure 57 and in vitro cytotoxic activities of hybrid compounds 50(a–e) are listed in Table 44.

89An B et al. (2018) synthesized selenium-containing 4-anilinoquinazoline hybrids and evaluated them as tubulin polymerization inhibitors. All the synthesized compounds were screened against a panel of six human tumor cell lines, human colon cancer cells (RKO), HEPG2, breast adenocarcinoma (MCF-7), human epithelial cervical cancer cells (HeLa), human colon cancer cells (HCT116), and human gastric cancer cells (MGC803). An antiproliferative activity assay showed that most of compounds inhibited human cancer cells at low nano-molar concentrations. These compounds disturbed microtubule dynamics, lowered mitochondrial membrane potential, and stopped Hela cells in the G2/M phase, ultimately leading to apoptosis. The structure of selenium based anilino quinazoline hybrids is given in Figure 58 and the in vitro cytotoxic activities of hybrid compounds 51(a–e) are listed in Table 45.

90Hairong Tang et al. (2021) synthesized novel selenium-containing chiral 1,4-diarylazetidin-2-ones and biologically evaluated for antitumor activities. All the newly synthesized selenium-containing compounds were screened for their antiproliferative activity against four human cancer cell lines, human epithelial cervical cancer cells (HeLa), human hepatoma cells (HUH-7), ovarian carcinoma cells (Skov-3) and human ovarian cancer cells (A2780), using paclitaxel as the positive control. The structure of Selenium based arylazetidin hybrids is shown in Figure 59 and the in vitro cytotoxic activities of hybrid compounds 51(a–d) are listed in Table 46.

91Sheng Huang et al. (2021) designed and synthesized fourteen novel selenium N-heterocyclic carbene (Se-NHC) compounds derived from 4,5-diarylimidazole and evaluated their antiproliferative activity towards ovarian cancer cells (A2780) and normal ovarian epithelial cells (IOSE80). Most of them were more effective towards ovarian cancer cells (A2780) than HepG2 hepatocellular carcinoma (HCC) cells. In addition, compound 53 displayed more than two-fold higher cytotoxicity to A2780 cells than to normal ovarian epithelial cells (IOSE80). Further research demonstrated that these inhibitors generated reactive oxygen species (ROS), harmed mitochondrial membrane potential (MMP), stopped cells from entering G0/G1 phase, and ultimately promoted apoptosis in the A2780 cells. The structure of selenium-based diarylimidazole hybrids is shown in Figure 60 and the in vitro cytotoxic activities of hybrid compounds 53(a–e) are listed in Table 47.

92Different selenium-based potent anticancer drugs their chemical structure (Figure 61), mode of action and doses are shown in Table 48.

93Platinum (Pt) medicines are still among the most often used anticancer treatments after more than 40 years of use. It is not unexpected that new research into changes in DNA repair pathways provides a reasonable explanation for Pt medicines’ efficacy since they primarily target DNA. The first platinum drug, cisplatin, was discovered by Barnett Rosenberg in 1960 and received FDA approval in 1978 for the treatment of advanced ovarian, bladder and testicular cancer. Oxaliplatin and carboplatin are also platinum containing clinical drugs. Despite the widespread use of platinum medicines in cancer treatment regimens, there are several associated drawbacks. It is associated with severe side effects such as nephrotoxicity, neurotoxicity, and ototoxicity. Additionally, using platinum medications has a number of adverse effects that range in intensity from mild to toxic (at high doses). In an attempt to circumvent these problems, a large number of platinum complexes have been prepared and tested for anticancer activity.

94A. Graham et al. (2012) synthesized platinum−acridine hybrid anticancer agents. In vitro cytotoxicity activity was evaluated on different cell lines, ovarian cancer (OVCAR-3), breast cancer (MCF-7, MDA-MB231), pancreatic (PANC1) and non-small cell lung cancer cells (NCI-H460) using cisplatin as the positive control. The structure of Platinum−acridine hybrids is given in Figure 62 and in vitro cytotoxic activities of hybrid compounds 54(a–e) are listed in Table 49.

95Jian Zhao et al. (2012) designed and synthesized six novel platinum (II) complexes 1−6 bearing different furoxan moieties as nitric oxide (NO) donors. The furoxan groups were introduced to the platinum complexes to release NO, which may have synergisticaction with the platinum-based moieties on the tumor cells. It was found that all compounds exhibited higher cytotoxicity against human cancer cell lines HCT-116 and SGC-7901 compared to standard carboplatin, and oxaliplatin. The structure of platinum hybrids is shown in Figure 63 and the in vitro cytotoxic activities of hybrid compounds (55–60) are listed in Table 50.

96Liu Z et al. (2021) prepared dihydro-2-quinolone (DHQLO) platinum (IV) compounds. Cytotoxic profiles of DHQLO platinum (IV) complexes were tested against five carcinoma cell lines including, ovarian cancer (SKOV-3), human cervical cancer cell (HeLa), human lung cancer (A549), murine colon cancer (CT-26), a cisplatin resistant cell line (A549R), and one normal human embryonic kidney cell line (293T). The antitumor activities of DHQLO platinum (IV) compounds were tested using the MTT assay with cisplatin and oxaliplatin as reference drugs. Cells were treated with drugs at different concentrations for 48 h, and the results were given as IC50 values. The structure of Platinum (iv) dihydro-2-quinolone hybrids is given in Figure 64 and the in vitro cytotoxic activities of hybrid compounds 61(a–e) are listed in Table 51.

97Yan Chen et al. (2020) synthesized naproxen platinum(IV) hybrids (62−66, Figure 65) that inhibited, matrix metalloproteinases and caused DNA damage. The antitumor activities of naproxen platinum(IV) compounds (62−66) were tested against four tumor cell lines including human lung cancer (A549), human ovarian cancer (SKOV-3), murine colon cancer (CT-26) and a cisplatin resistant cell line (A549R).A human normal liver cell LO-2 was also evaluated. The results are given in Table 52. It was observed that compounds 62–66 displayed moderate to effective antitumor activities against the tested tumor cell lines.

98Raffaella Cincinelli et al. (2013) designed and synthesized camptothecin-linked platinum anticancer agents. Biological activity was tested on different cell lines, including non-small cell lung cancer (H460), osteosarcoma (U2OS), cell carcinoma cells (A431), and ovarian carcinoma (IGROV-1, A2780). These compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. A general reduced potency with respect to TPT was observed in ovarian carcinoma IGROV-1 and A2780 cell lines. The structure of camptothecin-linked platinum anticancer hybrids is given in Figure 66 and the in vitro cytotoxic activities of hybrid compounds (67–69) are listed in Table 53.

99Different platinum-based potent anticancer drugs their chemical structure, specific cancer types and current status are shown in Table 54.

100Xing Yan et al. (2016) synthesized hybrids of hydroxamic acid with artemisinin and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds showed potent anticancer activity. Among them, compound 70(a) exhibited excellent activity against various cell lines including HepG2, MCF-7 and HL-60 (human leukemia cell) with IC50 values of 2.50, 2.62, and 1.28 µM, respectively, and control suberoylanilide hydroxamic acid (SAHA) IC50 values of 0.31, 1.90, and 0.18 µM, respectively. Furthermore, they synthesized 14 compounds. Amongst them, only two compounds 70(a), and 70(b), showed excellent HDAC (histone deacetylases) selectivity with IC50 values of 29.31 and 22.7 µM, respectively. The structure of a hydroxamic acid artemisinin hybrid is shown in Figure 67 and the in vitro cytotoxic activities of hybrid compounds 70(a–c) are listed in Table 55.

101Yong Ling et al. (2018) synthesized hydroxamate-β-carboline based novel hybrids and evaluated their antiproliferative activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 71(a) exhibited potent activity against panel of cell lines including HCT116 (human colon cancer cell), SUMM-7721(human hepatocellular carcinoma cells), HepG2, MCF-7and Huh-7(human hepatocellular carcinoma cells) with IC50 values of 0.82, 1.06, 0.65, 2.25 and 1.52 µM, respectively, and control SAHA IC50 values of 5.53, 5.61, 6.27, 4.48 and 4.95 µM, respectively. The structure of novel hydroxamate-β-carboline based derivatives is given in Figure 68 and the in vitro cytotoxic activities of hybrid compounds 71(a–d) are listed in Table 56.

102M.F.A. Mohamed et al. (2017) synthesized hybrids of hydroxamic acid and chalcone derivatives and evaluate their antiproliferative activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, 72(a) exhibited potent activity against cancer cell lines including HEPG2, MCF-7 and HcF-116 (human colon cancer cell), having IC50 values of 0.62, 2.05 and 2.92 µM, respectively and control, SAHA having IC50 values of 3.33, 2.18 and 1.23, respectively. The structure of hydroxamic acid based chalcone derivatives is given in Figure 69 and the in vitro cytotoxic activities of hybrid compounds 72(a–d) are listed in Table 57.

103Chao ding et al. (2017) synthesized and investigated novel 6-(1,2,3-triazol-4-yl) 4-aminoquinazolin derivatives possessing a hydroxamic acid moiety for antiproliferative activity against two cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, 73(a) exhibited potent activity against cell lines including A549 and BT-474 (human breast cancer cells) with IC50 values of 0.51 and 3.63 µM, respectively. Controls were lapatinib (IC50: 1.740.28 and 0.100.02) and SAHA (IC50: 2.57 and 2.67). The structure of hydroxamic acid based 4-aminoquinazolin derivatives is given in Figure 70 and the in vitro cytotoxic activities of hybrid compounds 73(a–d) (IC50, µM) are listed in Table 58.

104D.T.M. Dung et al. (2017) synthesized hybrids of indoline-based N-hydroxy propenamides and evaluated their antiproliferative activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 74(a) exhibited potent actively against three different cell lines including SW620 (colon cancer), Aspe-1(prostate cancer) and PC-3 at with IC50 values 3.05, 6.83 and 7.30 (µM), respectively with control SAHA having IC50 values of 1.44, 7.04, 5.30 (µM), respectively. The structure of hydroxamic acid based indoline derivatives is given in Figure 71 and the in vitro cytotoxic activities of hybrid compounds 74(a–d) are listed in Table 59.

105Hydroxamic acid based hybrids that are FDA approved or under clinical trial, and, their chemical structure and current status are listed in Table 60.

106Quirante et al. (2011) synthesized ferrocene-indole based hybrids (Figure 72) and evaluated their cytotoxic activity against A549 cells using 5-fluorouracil (5-FU) as a positive control. They synthesized 14 molecules, and 12 showed cytotoxic activity at IC50 values below 100 µM, where 5-FU had an IC50 value of <5 µM. Among these molecules, ferrocene-indole hybrid 75(a) showed the strongest cytotoxic activity with an IC50 value of 5 µM. Cytotoxic activities of hybrid compounds 75(a–d) are listed in Table 61.

107Xian-Feng Huang et al. (2014) synthesized novel hybrids of ferrocene containing pyrazolyl moieties and evaluated their anti-proliferative activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 76(c) exhibited potent activity against three different cell lines; A549 (human lung cancer cell), Hep G2 (human liver cancer cell) and MDA-MB-45 (human breast cancer cell) with IC50 values of 4.44, 20.82, and 4.89 (µM), respectively. Control 5-Fluro Uracil had IC50 values of 16.2, 17.6, 2.80 and cisplatin 0.87, 0.74 and 1.14, respectively. The structure of ferrocene derivatives containing pyrazolyl moiety is given in Figure 73 and in vitro cytotoxic activities of hybrid compounds 76(a–d) are listed in Table 62.

108Frans J. Smit et al. (2016) synthesized hybrids of ferrocenyl-chalcone amide, and evaluate their antitumor activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 77(a) exhibited potent activity against three different cell lines, including Tk-10 (renal) UACC-62 (melanoma), and, MCF-7 at IC50 2.4, 3.0 and 2.5 μM, respectively. Control parthenolide (PTD)-had IC50 values of 6.4, 15.0 and 5.8, respectively. The structure of ferrocenyl-chalcone amide derivatives are shown in Figure 74 and the in vitro cytotoxic activities of hybrid compounds 77(a–d) are listed in Table 63.

109J.N. Wei et al. (2019) synthesized novel hybrids of ferrocene-coumarin moiety and evaluate their antiproliferative activity against six different human cancer cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 78(a) exhibited potent activity against six different cell lines: BIU-87 (Human Bladder Cancer cell), SGC-790 (human cancer gastric cells), EC9706 and ECa1090 (human esophageal cancer cells), MCF-7 (human breast adenocarcinoma cells) and Jurkat (human leukemia cell) with IC50 values 1.09, 10.61, 25.89, 36.38, 12.10 and 53.01 (µM), respectively. Control adriamycin had IC50 values of 6.09, 5.44, 8.56, 6.52, 7.95, 4.50 µM, respectively. The structure of ferrocene-coumarin derivatives is given in Figure 75 and the in vitro cytotoxic activities of hybrid compounds 78(a–d) are listed in Table 64.

110S. Panaka et al. (2016) synthesized hybrids of ferrocenyl chalcogeno (sugar) triazole conjugates and evaluated their antitumor activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 79(a) exhibited potent activity against five different cell lines including A549 (human lung cancer cell), MDA-MB-231 (human breast cancer cell), MCF-7 (human breast adenocarcinoma cell), HeLa (immortal human cell) and HEK-293T (normal non-tumorigenic human embryonic kidney) at IC50 values 2.9, 3.35, 5.58 and 11.6 (μM), respectively. A control, doxorubicin, had IC50 values of 0.36, 0.47, 0.98 and 0.89, respectively. The structure of ferrocenyl-chalcogeno (sugar) triazole conjugates is given in Figure 76 and the in vitro cytotoxic activities of hybrid compounds 79(a–d) (IC50, µM) are listed in Table 65.

111Saiharish Raghavan et al. (2015) synthesized hybrids of curcumin and quinolone and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 80(a) exhibited potent activity against four different cell lines including A549 (human lung cancer cell), MCF-7 (human breast adenocarcinoma cell), SKOV3 (ovarian cancer cell line) and H460 (human lung cancer cell) at IC50 values 23.9, 36.2,12.8, 21.75, respectively. The structure of curcumin-quinolone derivatives is given in Figure 77 and in vitro cytotoxic activities of hybrid compounds 80(a–d) are listed in Table 66.

112G. Banuppriya et al. (2018) synthesized hybrids of curcumin and sulfonamides and evaluated their anticancer activity against two cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 81(a) exhibited potent activity against two different cell lines including A549 (human lung cancer cell) and AGS (human gastric adenocarcinoma cell) at IC50 values 1.29 and 10.16 (µM), respectively with control Curcumin at IC50 values 25.33 and 20.76, respectively. The structure of curcumin-sulfonamide derivatives is given in Figure 78 and in vitro cytotoxic activities of hybrid compounds 81(a–d) are listed in Table 67.

113H.R. Puneeth et al. (2016) synthesized hybrids of curcumin-pyrazole and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 82(a) exhibited potent activity against four different cell lines including HeLa (human cervical cell), MCF-7 (human breast adenocarcinoma cell), K562 (human immortalized myelogenous leukemia cell) and HEK293T (normal non-tumorigenic human embryonic kidney) at IC50 values 45.54, 34.99, 25.55 and >1000 (µM), respectively with control Paclitaxel at IC50 values 11.61, 9.12, 8.43 and 1.43 (µM), respectively. The structure of curcumin-pyrazole derivatives is given in Figure 79 and in vitro cytotoxic activities of hybrid compounds 82(a–c) (IC50, µM) are listed in Table 68.

114Peiju Qui et al. (2013) synthesized hybrids of curcumin, pyrimidine and urea and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 83(a) exhibited potent activity against two different cell lines including HT29 (human colon adenocarcinoma cell) and HCT116 (human colon cancer cell) at IC50 values 7.10.4 and 6.21.2 (µM), respectively with control 5-fluorouracil at IC50 11.61, 9.12, 8.43 and 1.43 (µM), respectively. The structure of curcumin pyrimidine derivatives is given in Figure 80 and in vitro cytotoxic activities of hybrid compounds 83(a–c) (IC50, µM) are listed in Table 69.

115Sahil Sharma et al. (2015) synthesized hybrids of curcumin and isatin and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 84(a) exhibited potent activity against four different cell lines including THP-1 (Leukemia), COLO-205 (Colon), HCT-(116) and PC-3 (Prostate) at IC50 values of 2.87, 4.15, 1.12 and 5.67 (µM), respectively. The structure of curcumin-isatin derivatives is given in Figure 81 and in vitro cytotoxic activities of hybrid compounds 84(a–c) are listed in Table 70.

116Li Ying et al. (2015) synthesized hybrids of triazole, pyrimidine and urea and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 85(a) exhibited potent activity against four different cell lines including EC-109 (squamous cell carcinoma cells), MCF-7 (human breast adenocarcinoma cells), MGC-803 (immortal human cells) and B16-F10 (murine melanoma cells) at IC50 2.96, 3.11, 3.60 and 4.55 (µM), respectively and with control 5-fluorouracil an IC50 of 11.61, 9.12, 8.43 and 1.43 (µM), respectively. The structure of triazole-pyrimidine derivatives is given in Figure 82 and in vitro cytotoxic activities of hybrid compounds 85(a–d) are listed in Table 71.

117Madasu Chandrashekhar et al. (2016) synthesized hybrids of triazole–myrrhanore Cand evaluated their anticancer activity against different cell lines. Most of synthesized compounds displayed potent anticancer activity. Among them, compound 86(a) exhibited good anticancer activity against different cell lines including A549 (human lung cancer cell), Hela (human cervical cell), MCF-7 (human breast adenocarcinoma cell), DU-I45 (human prostate cancer cell) and HepG2 (human hepatocellular carcinoma cell) at IC50 06.16, 07.76, 09.59, 08.83 and 09.52 (µM), respectively, with control doxorubicin 2.81, 2.57, 1.13, 1.41 and 3.01 (µM), respectively. The structure of triazole–myrrhanore C derivatives is given in Figure 83 and in vitro cytotoxic activities of hybrid compounds 86(a–c) (IC50, µM) are listed in Table 72.

118Zahra Najafi et al. (2015) synthesized hybrids of triazole and isoxazole and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 87(a) exhibited potent activity against two different cell lines including MCF-7 and T47D (breast cancer cell line) at IC50 > 100 and 27.7 µM, respectively with control etoposide at IC50 7.5 and 7.9, respectively (µM). The structure of triazole-isoxazole derivatives is given in Figure 84 and in vitro cytotoxic activities of hybrid compounds 87(a-b) (IC50, µM) are listed in Table 73.

119Y.C. Duan et al. (2013) synthesized hybrids of 1,2,3-triazole and dithiocarbamate and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 88(a) exhibited potent activity against four different cell lines including MGC-803 (immortal human cell), MCF-7 (human breast adenocarcinoma cells), PC-3 (human pancreatic cancer cell) and EC-109 (squamous cell carcinoma cell) at IC50 0.73, 5.67, 11.61 and 2.44 µM, respectively with control 5-fluorouracil at IC50 7.01, 7.54, 27.07 and 3.34 µM, respectively. The structure of triazole-dithiocarbamate derivatives is shown in Figure 85 and in vitro cytotoxic activities of hybrid compounds 88(a–c) (IC50, µM) are listed in Table 74.

120R.M. Kumbhare et al. (2015) synthesized hybrids of triazole thiazole and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 89(a) exhibited potent activity against four different cell lines including MCF-7 (human breast cancer), A549 (human lung cancer), A375 (human melanoma cancer), and MCF-10A (normal breast epithelial cells) with IC50 values of 2.12, 5.48, 4.7 and 29.33 µM, respectively. Control doxorubicin had comparative IC50 0.12, 3.13, 7.2 and 24.0 µM and paclitaxel at IC50 2.58, 4.9, 8.0, 38.0 µM, respectively. The structure of triazole based thiazole derivatives is given in Figure 86 and in vitro cytotoxic activities of hybrid compounds 89(a–c) are listed in Table 75.

121R. Sivaramakarthikeyan et al. (2020) synthesized hybrids of benzimidazole and pyrazole and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 90(a) exhibited potent activity against three different cell lines including SW1990 (human pancreatic adenocarcinoma cell), AsPC1 (human pancreatic tumor cell), MRCS (marginal reticular cells) with IC50 values of 30.9, 32.8, 80.0 µM, respectively and control gemicitabine at IC50 values of 35.09, 39.27 and 54.17 µM, respectively. The structure of benzimidazole-pyrazole derivatives is given in Figure 87 and in vitro cytotoxic activities of hybrid compounds 90(a–c) (IC50, µM) are listed in Table 76.

122Kun Pena Shao et al. (2014) synthesized hybrids of benzimidazole–pyrimidine and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 91a exhibited potent activity against three different cell lines including MCF-7 (human breast adenocarcinoma cells), MGC-803 (immortal human cells), EC-9706 (esophagus squamous cell carcinoma) and SMMC-7721 (human hepatocellular carcinoma cells) with IC50 values of 1.43, 1.33, 3.33, 20.50 (µM), respectively with control 5-Fluorouracil had IC50 values 7.12, 3.45, 8.07 and 15.08 (µM), respectively. The structure of benzimidazole-pyrimidine derivatives is given in Figure 88 and in vitro cytotoxic activities of hybrid compounds 91(a–c) (IC50, µM) are listed in Table 77.

123Pankaj Sharma et al. (2016) synthesized hybrids of benzimidazole and thiazolidinedione and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 92a exhibited potent activity against five different cell lines including PC-3, DU-145 (prostate cancer), MDA MB-231 (breast cancer), A549 (lung cancer) and MCF10A (normal breast epithelial cells) with IC50 values of 39.87, 31.41, 29.18, 11.46 and >100 (µM), respectively with control 5-Fluorouracil had IC50 values of 45.32, 40.58, 35.98, 30.47 (µM), respectively. The structure of benzimidazole-pyrimidine derivatives is given in Figure 89 and in vitro cytotoxic activities of hybrid compounds 92(a–c) are listed in Table 78.

124Lei Shi et al. (2014) synthesized benzimidazole-quinazoline hybrids and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 93a exhibited potent activity against two different cell lines including Hep-G2 (human liver carcinoma cells) and MCF-7 (human breast adenocarcinoma cell) at IC50 8.7 and 1.5 (µM), respectively. Control golvatinib had IC50 values of 65.5 and 49.6 µM, respectively. The structure of benzimidazole-quinazoline derivatives is given in Figure 90 and in vitro cytotoxic activities of hybrid compounds 93(a–c) are listed in Table 79.

125Reddymasu Sireesha et al. (2021) synthesized hybrids of benzimidazole and β-carboline and evaluated their anticancer activity against different cell lines. Most of the synthesized compounds displayed potent anticancer activity. Among them, compound 94a exhibited potent activity against four different cell lines, including MCF-7 (human breast cancer cell line), A549 (a human lung cancer cell line), Colo-205 (a human colon cancer cell line) and A2780 (a human ovarian cancer cell line) with IC50 values of 0.22, 1.55, 1.68 and 1.16 (µM), respectively, with the control etoposide having IC50 values of 2.11, 3.08, 0.13 and 1.31 (µM), respectively. The structure of benzimidazole–β-carboline derivatives is given in Figure 91 and in vitro cytotoxic activities of hybrid compounds 94(a–c) are listed in Table 80.

126Benzimidazole based hybrids that are FDA approved/under clinical trials and their current status are given in Table 81.

127In humans and other mammals, isatin is an endogenous compound that has a variety of pharmacological properties, including anticancer activity. Human health is facing several difficulties in the modern medical period, especially with regard to human cancers. As a result, new therapies that selectively target tumor cells will unavoidably be added to the therapeutic arsenal for these cancers.

128AZIZ et al. (2021) synthesized different sets of isatin-based benzoazine hybrids, i.e., isatin quinoxaline quinazoline and phthalazines hybrids. All the synthesized hybrids were evaluated in vitro for their antiproliferative activity against three human cancer cell lines, namely breast cancer (ZR-75), human colon cancer (HT-29) and lung cancer (A-549). The structure of isatin-based benzoazine derivatives is given in Figure 92 and in vitro cytotoxic activities of hybrid compounds 95(a–c) are listed in Table 82.

129Meleddu et al. (2017) synthesized isatin-dihydropyrazole derivatives and then evaluated their capability to inhibit tumor cell growth against nine human cancer cell lines, namely A549 (lung carcinoma), IGR39 (melanoma), U87 (glioblastoma), MDA-MB-231 (breast cancer), MCF-7 (breast adenocarcinoma), and BT474 (invasive ductal carcinoma), H1299 (non-small cell lung carcinoma), BxPC-3 (pancreatic adenocarcinoma), SKOV-3 (ovarian cancer) and human foreskin fibroblasts. Sunitinib was the standard drug taken for evaluation of anticancer activity. The structure of dihydropyrazole isatin based hybrids is given in Figure 93 and the in vitro cytotoxicity of hybrid compounds 96(a–d) against human cancer cell lines is shown in Table 83.

130Wagdy et al. (2015) synthesized isatin-pyridine derivatives and tested their anti-proliferative activity against three human tumor cancer cell lines, i.e., hepatocellular carcinoma (HEPG2), lung cancer (A549), and breast cancer (MCF-7) using a sulforhodamine B (SRB) colorimetric assay. Doxorubicin has been used as a reference cytotoxic compound. The structure of pyridine isatin based hybrids is given in Figure 94 and in vitro cytotoxicity of compounds 97(a–c), or 98, 99(a–c) against human cancer cell lines is shown in Table 84.

131Singh et al. (2015) synthesized isatin-coumarin hybrids which contain triazole as a linker, and investigated their in vitro cytotoxicity activity against four human cancer cell lines (COLO-205, THP-1, HCT-116 and PC-3) using sulforhodamine B19. The cells were given 48 h to multiply in the presence of a test substance. COLO-205, THP-1 and HCT-116 (three of the four cancer cell lines tested) were sensitive to the synthesized hybrids, and the THP-1 cancer cell line was the most susceptible to these hybrids, whereas PC-3 was found to be resistant. The structure of isatin-based coumarin hybrids is given in Figure 95 and in vitro cytotoxicity of compounds 100(a–d) against human cancer cell lines is shown in Table 85.

132Wabli et al. (2017) synthesized isatin-indole derivatives and evaluated their antiproliferative activity on three cell lines: ZR-75 (human breast), HT-29 (colon) and A-549 (lung). Compound 101(d) had an average IC50 value of 1.17 μM against the tested human cancer cell lines, making it the most active compound, with a potency approximately seven times greater than that of sunitinib. The structure of isatin-based indole hybrids is given in Figure 96 and in vitro cytotoxicity IC50 (µM) of compounds 101(a–d) against human cancer cell lines is shown in Table 86.

133Panga et al. (2020) synthesized isatin-benzoic acid conjugates and tested their in vitro cytotoxic activity against MCF-7 and HeLa cell lines. All the synthesized isatin-benzoic acid conjugates showed moderate to strong cytotoxicity against both HeLa and MCF-7 cell lines with IC50 values ranging from 4.02 to 17.83 μM and 17.14 to 24.6 μM, respectively. Among all synthesized compounds, 102(b) showed maximum activity on both cell lines. The structure of isatin-based benzoic acid hybrids is given in Figure 97 and in vitro cytotoxicity of compounds 102(a–d) against human cancer cell lines is shown in Table 87.

134Eldehna et al. (2016) synthesized isatin-thiazolo benzimidazole hybrids and evaluated their anti-proliferative efficacy against MCF-7 and MDA-MB-231 breast cancer cell lines by using sulforhodamine B colorimetric (SRB) assay. Staurosporine was utilized as a positive control, and the results were shown as IC50 values. Compounds 103(a) and 104(a) had maximum anticancer activity towards the tested cell lines. The structure of isatin-based thiazolo-benzimidazole hybrids is shown in Figure 98, and the in vitro cytotoxicity IC50 (µM) of compounds 103(a–c), 104(a–c) against human cancer cell lines is shown in Table 88.

135Isatin containing FDA-approved hybrids are depicted in Figure 99.

136Pyrrolo-benzodiazepines (PBD) are naturally found in many actinomycetes species. PBD block transcription factors and promote DNA replication by binding covalently to DNA, and thus inhibits cell growth.

137Bose et al. (2012) synthesized hybrids of pyrrole and benzodiazepine and tested cytotoxic activities of the synthesized compounds was in vitro against five tumor cell lines: THP-1 (human acute monocytic leukemia), U-937 (human histiocytic lymphoma), HL-60 (human promyelocytic leukemia), Jurkat (human T-cell leukemia) and A-549 (lung carcinoma). Among the synthesized compounds, 105(a) was the most potent. The structure of pyrrolo-benzodiazepine hybrids is given in Figure 100 and the in vitro cytotoxicity IC50 of compounds 105(a–c) against human cancer cell lines is shown in Table 89.

138Kamal et al. (2012) synthesized pyrrolo-benzodiazepine conjugated with benzo indolone derivatives. The synthesized derivatives were assessed for their anticancer activity in human cancer cell lines of the lung, skin, colon and prostrate by using the MTT assay. These new conjugates exhibited encouraging anticancer activity, with IC50 values ranging from 1.05 to 36.49 µM. Doxorubicin and DC81, the positive controls, displayed IC50 values in the range of 0.03–2.51 µM and 0.86–1.65 µM, respectively. Compound 106(d) had the maximum anticancer activity. The structure of pyrrolo-benzodiazepine-based benzoindolone hybrids is given in Figure 101 and in vitro cytotoxicity of compounds 106(a–d) against human cancer cell lines is shown in Table 90.

139Li et al. (2021) synthesized new pyrrolo [2,1-c] [1,4] benzodiazepine-3,11-dione (PBD) derivatives and evaluated their HDAC6 inhibitory effect. When R = H, the activity of the linker with the benzene ring was moderate. However, when the linker was extended by one methylene, the compound’s activity drastically dropped (107a vs. 107b). The structure of pyrrolo-benzodiazepine-dione hybrids is given in Figure 102 and the in vitro IC50 of compounds [107(a–c),108(a–c)] against HDAC6 enzyme is shown in Table 91.

140Chen et al. (2013) synthesized a new series of PBD-triazole hybrids and their cytotoxicity was investigated on various mouse and human cells, taking tubastatin A as a positive control. Cis-hybrids (109a–c) were much more cytotoxic than trans isomers (110a–c) in sensitive melanoma (A375). Compound 109a exhibited a higher inhibitory activity compared to that of other agents on A375 cells. The structure of triazole pyrrolo-benzodiazepine hybrids is given in Figure 103 and the in vitro cytotoxicity of compounds [109(a–c), 110(a–c)] against cancer cell lines is shown in Table 92.

141FDA approved drugs containing pyrrolo-benzodiazepines include tomaymycin, sibiromycin and neothramycin, which are depicted in Figure 104.

142Chalcone compounds are one of the most important fundamental categories of natural products as they are abundant within tea leaves, fruits and vegetables, fruits, and are of great interest because of their pharmacological effectiveness in treating many diseases. Some of the naturally occurring chalcones are depicted in Figure 105.

143One of the most significant bioactive substances with a chalcone structure (isoliquiritigenin) was isolated from liquorice roots. Butein, a physiologically active flavonoid found in Rhus verniciflua (Stokes’ bark), has been shown to have strong anticancer effects on a variety of cancer types.

144Chalcone-based hybrid compounds have the potential to improve selectivity and anticancer activity while also overcoming drug resistance. Therefore, combining the chalcone moiety with additional anticancer pharmacophores is a promising strategy for creating new anticancer drugs. In recent times, a number of chalcone hybrids have been prepared and evaluated for their cytotoxic activity; some of them are found to have remarkable activity both in vitro and in vivo.

145Zahrani et al. (2020) synthesized chalcone-based phenothiazine derivatives and evaluated their cytotoxic activity against two carcinoma cell lines (human breast cancer cell line MCF-7 and human hepatocellular carcinoma HEPG-2 cells) compared with anticancer standard drugs cisplatin and doxorubicin under the similar conditions following the MTT (methylthiazol-tetrazolium) colorimetric assay. 111(a) and 111(b) were the most effective compounds with IC50 values of 7.14 µg/mL and 7.6 g/mL, respectively. The structure of chalcone based phenothiazine hybrids is shown in Figure 106 and the in vitro cytotoxicity of compounds 111(a–d) against cancer cell lines is shown in Table 93.

146Shivapriya et al. (2021) produced chalcone benzoxadiazole hybrids and evaluated their cytotoxic activity against the human epidermal carcinoma (KB) cell line using MTT assay. Chalcone-benzoxadiazole hybrids were prepared through the Claisen–Schmidt condensation reaction. The structure of chalcone-based benzoxadiazole hybrids is given in Figure 107 and the in vitro cytotoxicity of compounds 112(a–d) against cancer cell lines is shown in Table 94.

147Alswah (2017) et al., designed and synthesized a series of triazolo-quinoxaline-chalcone derivatives 113a–d, and evaluated their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116) and human hepatocellular carcinoma (HEPG-2) using the MTT assay method with doxorubicin as a reference drug. The initial results showed that some of the chalcones exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, with IC50 values found to be in the 1.65 to 34.28 µM range. Compound 113(a) showed maximum cytotoxic activity towards given cell lines. The structure of chalcone-based triazolo-quinoxaline hybrids is given in Figure 108 and the in vitro cytotoxicity of synthesized hybrids against cancer cell lines are shown in Table 95.

148Yepes et al. (2021) synthesized a new series of hybrid molecules by inclusion of two scaffolds: chalcone and melatonin. To achieve this goal, biologically active chalcone was attached via a non-hydrolizable thioalkyloxy linker to the corresponding melatonin bioisostere scaffold. The anticancer activity of the synthesized hybrids was evaluated against an in vitro model of colorectal cancer. In this study, two cell lines were used, i.e., the non-malignant (CHO-K1) and human colon adenocarcinoma cells (SW480). The reference drug used was 5-FU. Compound 114(a) maximum activity. The structure of chalcone based melatonin hybrids is given in Figure 109 and in vitro cytotoxicity of compounds 114(a–d) against cancer cell lines is shown in Table 96.

149Ma et al. (2021) synthesized chalcone-based quinoxalin as anti-cancer hybrids. All of the synthesized compounds (115a–e) were tested in vitro for their anticancer activities against, PC12, BPH-1 and MCF-7 cells using the MTT assay. With IC50 values in the micro molar range (9.1–98.7 mM) against all tested cancer cells, all synthesized compounds demonstrated moderate to good antiproliferative activity and compound 115(e) showed maximum cytotoxic activity. The structure of chalcone-based quinoxalin hybrids is given in Figure 110 and the in vitro cytotoxicity of compounds 115(a–e) against cancer cell lines is shown in Table 97.

150The coumarin scaffold (2H-1-benzopyran-2-one) is extensive in nature, and it’s derivatives exhibit various antibacterial, antifungal, antimalarial, and anticancer pharmacological properties.

151Kamaldeep Paul et al. (2013) synthesized coumarin-benzimidazole hybrids. The synthesized compounds showed potent activity against leukemia cancer cells (CCRF-CEM, HL-60(TB), K-562, RPMI-8226), colon cancer cells (HCT-116, HCT-15), melanoma cancer cells (LOX IMVI, UACC-257) and breast cancer cells (MCF7, T-47D). The compounds containing substitution (NR1R2) were the most potent with inhibition of most of the cell lines. The compound with ethanolamine as a substituent (NR1R2) at position 7 of the coumarin-benzimidazole scaffold, was the most potent synthesized compound. The structure of coumarin-benzimidazole hybrids is given in Figure 111 and the in vitro % growth inhibition of compounds 116(a–e) against cancer cell lines is shown in Table 98.

152R. An et al. synthesized amide containing 1,2,3-triazole hybrids, which showed moderate to excellent activity against MDB-MB 231 cell lines under both normoxic and hypoxic conditions. The structure of coumarin-triazole hybrids is given in Figure 112 and the in vitro IC50 of compounds 117 (a–e) against cancer cell lines are shown in Table 99.

153H.A. Elshemy et al., (2017) synthesized coumarin-chalcone hybrids having anticancer activity against HEPG2, leukemia, and WI-38 cell lines. All coumarin-chalcone hybrids had potent activity against HEPG2 and K562, and weak activity against WI-38 cell. Among the coumarin-chalcone hybrids, 4-methoxyphenyl chalcone 118(a) was more potent than 3,4-dimethoxyphenyl chalcone 118(b), which showed higher activity than chalcone with 3,4,5-trimethoxyphenyl moiety 118(c).

154In the coumarin-acrylohydrazide series, compound 119(c) showed the highest activity against a leukemia cell line (k562) while compound (119a and 119b) showed potent activity against the HEPG2 cell line and moderate activity against the WI-38 cell line. The structure of coumarin containing chalcone hybrids is shown in Figure 113 and the in vitro IC50 (µM) of compounds [118(a–c),119(a–c)] against cancer cell lines is shown in Table 100.

155Mohit Sanduja et al. (2020) synthesized uracil-coumarin-based compounds as potent anticancer hybrid compounds. The uracil-coumarin hybrid compounds inhibited the MCF-7 cancer cell proliferation more effectively compared to standard 5-FU. The most potent compound 120b (GI50 = 1.55µM) contained A with fluorine atom as R with two carbon chain lengths between triazole and coumarin moieties. The structure of coumarin containing uracil hybrids is given in Figure 114, and in vitro GI50 (µM) of compounds 120(a–e) against cancer cell lines is shown in Table 101.

156Zhuo zing et al., (2018) synthesized novel coumarin-based furoxin hybrids which had potent activity against Hela cell proliferation. The compound 121(e) had the highest antiproliferative activity and was more potent than standard, doxorubicin. The structure of coumarin containing furoxin hybrids is given in Figure 115 and the in vitro IC50 of compounds 121(a–e) against cancer cell lines is shown in Table 102.

157Shengtao Xu et al. (2014) synthesized natural oridonin bearing nitrogen mustard hybrid as potential anticancer compound. The hybrid showed activity against the multidrug resistant cell lines SW620/AD300 and NCL-H460/MX20. Compound 122(b) induced apoptosis and affected cell cycle progression in human hepatoma (Bel-7402) cells. The structure of nitrogen mustard contain oridonin hybrids is given in Figure 116 and the in vitro IC50 of compounds 122(a–d) against the cancer cell line (Bel-7402) is shown in Table 103.

158Laczkowski et al. (2016) synthesized nitrogen mustard-based thiazole hybrid drugs that showed antiproliferative activity against human cancer cell lines MV4-11, A549, MCF-7 and HCT-116. Among the all derivatives, 123(a–e) was most potent and exhibited activity against human leukemia (MV4-11) cells. The compounds 123(b) and 123(e) had potent activity against MCF-7 and HCT116. The structure of nitrogen mustard contain thiazole hybrids is given in Figure 117 and the in vitro IC50 of compounds 123(a–e) against cancer cell lines is shown in Table 104.

159Kolesinska et al. (2012) synthesized hybrids containing a nitrogen mustard-triazine scaffold as potent anticancer compounds. These were prepared by rearrangement of mono, bis and tris-(1,3,5-triazin-2-yl)-1,4-diazacyclo [2.2.2] octanium chlorides leading to the formation of 2-chloroethylamino fragments attached to 1,3,5-triazine via one, two or three piperazine, respectively. Their cytotoxicity and alkylating activity depended on substituents on the triazine ring and nitrogen mustard. Among the above mentioned compounds, 124(b) and 124(d) were the most potent. The structure of nitrogen mustard-containing triazine hybrids is shown in Figure 118 and the in vitro IC50 of compounds 124(a–d) against cancer cell lines is shown in Table 105.

160Acharya et al. (2017) synthesized androstene oxime-nitrogen mustard hybrids and nitrogen mustard conjugates of various steroidal oximes. The conjugation was achieved by oxime-ester linkage. The 17-E-steroidal oxime benzoic acid mustard ester, 3β acetoxy-17E-[p-(N,N-bis(2-chloroethyl)amino]benzoyloxiamino-androst-5ene 125(a) showed the highest growth inhibition on IGROV (ovarian cancer cells) with a GI50 of 0.937 µg/mL. The structure of androstene oxime-nitrogen mustard hybrids is shown in Figure 119 and the in vitro GI50 (µg/mL) of compounds (125(a-b),126(a-b)) against cancer cell lines is shown in Table 106.

161Hassan et al. (2021) synthesized indole-pyrazole hybrids as anticancer agents. The newly synthesized hybrids were screened for their cytotoxicity activities in vitro against four human cancer types, i.e., colorectal (HCT-116), breast carcinoma (MCF-7), liver carcinoma (HepG2) and lung carcinoma (A549). Among all indole-pyrazole hybrids, 126a and 126b showed excellent anticancer activity against the HepG2 cancer cell line with an IC50 of 6.1 and 7.9 µM, respectively. The structure of the pyrazole-based indole hybrid is given in Figure 120 and the in vitro IC50 of compounds 127(a–e) against cancer cell lines are shown in Table 107.

162Somaia et al. (2015) synthesized benzofuran-pyrazole-based hybrids as anticancer drugs. The newly synthesized compounds showed remarkable growth inhibitory activity against leukemia (CCRF-CEM), A549 (lung carcinoma), and HCT-116 (colorectal carcinoma) cells. Compound 128c showed good src inhibition activity at 10 µM and was found to be most potent compound. The structure of benzofuran-pyrazole hybrids is given in Figure 121 and in vitro IC50 of compounds 128(a–d) against cancer cell lines is shown in Table 108.

163Abdelaal et al. (2021) synthesized quinazoline-pyrazole hybrids as potential antiproliferative agents. The newly synthesized compounds showed activity against hepatocellular carcinoma (liver) HEPG2, mammary gland (breast) MCF-7 and colon cancer HCT-116 cells. The structure of quinazoline-pyrazole hybrids is given in Figure 122 and the in vitro IC50 of compounds (129–133) against cancer cell lines is shown in Table 109.

164Washim Akhtar et al. (2021) synthesized 15 novel pyrazoline-pyrazole hybrids, all of which showed activity in the MTT growth inhibition assay against five cancer cells lines: MCF-7, A549, SiHa, COLO205 and HePG2 cells. Compound 134 (b) was found to active against A549, SiHa, COLO205 and HePG2 cell lines with IC50 values of 4.94, 4.54, 4.98 and 2.09 µM, respectively, and was non-toxic against normal cells. The structure of pyrazoline-pyrazole hybrids is given in Figure 123 and in vitro IC50 of compounds 134(a–e) against cancer cell lines is shown in Table 110.

165Garima Verma et al. (2018) synthesized pyrazole acrylic acid-based oxadiazole and amide hybrids as anticancer and antimalarial agents. The anticancer activity of newly synthesized compounds was measured using the sulforhodamine B assay. Compounds 135(a–c) demonstrated promising results against all tested cell lines. The non-cyclized compounds (amide derivatives) favored anticancer activity. The structure of pyrazole acrylic acid based oxadiazole hybrids is shown in Figure 124 and the in vitro IC50 of compounds 135(a–c) against cancer cell lines is shown in Table 111.

166Chetan B. Sangani et al. (2014) synthesized biquinoline-pyridine hybrids as potential EGFR and HER-2 kinase inhibitors by base catalyzed cyclocondensation through one potent multicomponent reaction. All the synthesized compounds were tested against A549 (adenocarcinomic human alveolar basal epithelial) and Hep G2 (liver cancer) cell lines. Enzyme inhibitory activity was measured against HER-2. Compound 136(d) was found to be most potent compound. The structure of biquinoline-pyridine hybrids is given in Figure 125 and the in vitro IC50 of compounds 136(a–e) against cancer cell lines is shown in Table 112.

167W.M. Eldehna et al. (2015) synthesized isatin-pyridine hybrids as potential antiproliferative agents. They showed antiproliferative activity against hepatocellular carcinoma (HEPG2), lung cancer (A549) and breast cancer (MCF-7) cell lines. Compound 137 showed the most potent activity against HEPG2 with an IC50 of 2.5 µM, while compound 138(c) was the most potent compound against A549 and MCF-7 cell line with IC50 values of 10.8 and 6.3 µM, respectively. The structure of isatin-pyridine hybrids is shown in Figure 126 and the in vitro IC50 of compounds [137,138(a–d)] against cancer cell lines is shown in Table 113.

168E.K. Hamza et al. (2020) synthesized pyrazolo pyridine hybrids as potential anticancer agents. The activity of the newly synthesized compounds was evaluated in vitro against two human cancer cell lines (HCT116 and MCF-7). Compounds 139(a–d) showed activity against HCT116 and compounds 140(a–d) showed activity against MCF-7 cancer cell lines. The structure of pyrazolo pyridine hybrids is shown in Figure 127 and the in vitro IC50 (µM) of compounds [139(a–d),140(a–d)] against cancer cell lines is shown in Table 114.

169For a very long time, medicinal chemists from all over the world have been trying to develop new and effective cancer treatments. Combination therapy and hybrid chemotherapeutics haves become more common, because a complex disease such as cancer cannot be properly treated with a single drug. This study presents rational approaches behind the design of anticancer agents employing molecular hybridization. This method has potential because it combines two moieties to create new molecular scaffolds. Molecular hybridization offers a wide range of applications since it can produce compounds with distinct and/or multiple modes of action and minimal side effects. The few examples included in this article are not intended to be an exhaustive collection of anticancer hybrids, but to provide a quick explanation of the idea and its potential uses for researchers working in this field.