Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids

Abstract

Cancer is a complex disease, and its treatment is a big challenge, with variable efficacy of conventional anticancer drugs. A two-drug cocktail hybrid approach is a potential strategy in recent drug discovery that involves the combination of two drug pharmacophores into a single molecule. The hybrid molecule acts through distinct modes of action on several targets at a given time with more efficacy and less susceptibility to resistance. Thus, there is a huge scope for using hybrid compounds to tackle the present difficulties in cancer medicine. Recent work has applied this technique to uncover some interesting molecules with substantial anticancer properties. In this study, we report data on numerous promising hybrid anti-proliferative/anti-tumor agents developed over the previous 10 years (2011-2021). It includes quinazoline, indole, carbazole, pyrimidine, quinoline, quinone, imidazole, selenium, platinum, hydroxamic acid, ferrocene, curcumin, triazole, benzimidazole, isatin, pyrrolo benzodiazepine (PBD), chalcone, coumarin, nitrogen mustard, pyrazole, and pyridine-based anticancer hybrids produced via molecular hybridization techniques. Overall, this review offers a clear indication of the potential benefits of merging pharmacophoric subunits from multiple different known chemical prototypes to produce more potent and precise hybrid compounds. This provides valuable knowledge for researchers working on complex diseases such as cancer.

Keywords: anticancer agents; cell lines; in vitro; molecular hybridization; pharmacophore.

Figure 1

Different methods of molecular hybridization. (A) Drug A and B are directly linked to each other; (B) brug A and B are merged with each other; (C) drug A and B are connected by a flexible spacer; (D) drug A and B are connected through a rigid spacer; (E) two pharmacophoric moieties are directly connected to each other; (F) two pharmacophoric moieties are connected by a flexible spacer; (G) two pharmacophoric moieties are connected by a rigid spacer.

Figure 2

Structure of quinazoline-based imidazole hybrids and the most promising compound 1a.

Figure 3

Structure of quinazoline-based deoxynojirimycin hybrids and the most promising compound 2a.

Figure 4

Structure of quinazoline-based urea hybrids and the most promising compound 3a.

Figure 5

Structure of quinazoline-based aryl hybrids and the most promising compound 4a.

Figure 6

Structure of aminoquinazoline-sulphonamide hybrids and the most promising compound 5a.

Figure 7

Structure of quinazoline-amino sulphonamide based hybrids and the most promising compound 6a.

Figure 8

Structure of quinazoline-artemisinin based hybrid 7.

Figure 9

Structure of quinazoline phenyl morpholine based hybrids and the most promising compound 8a.

Figure 10

FDA approved/clinical trial drugs with quinazoline hybrids.

Figure 11

Structure of indole with hydroxycinnamamide hybrid and the most promising compound 9a.

Figure 12

Structure of indole with hydroxycinnamamide hybrids and the most promising compound 10a.

Figure 13

Structure of indole with sulphonamide hybrids and the most promising compound 11a.

Figure 14

Structure of indole-triazole based hybrids and the most promising compound 12a.

Figure 15

Structure of indole-pyrimidine based hybrids and the most promising compound 13a.

Figure 16

Structure of indole-chalcone based hybrids and the most promising compound 14a.

Figure 17

Structure of indole-pyrole based hybrids and the most promising compound 15a.

Figure 18

Structure of indole-chalcone based hybrids and the most promising compound 16a.

Figure 19

Structure of indole-ospemifene-triazole based hybrids and the most promising compound 17a.

Figure 20

Structure of indole-ospemifene-triazole based hybrids and the most promising compound 18a.

Figure 21

FDA approved/clinical trial drugs with indole hybrids.

Figure 21

FDA approved/clinical trial drugs with indole hybrids.

Figure 22

Structure of carbazole-imidazole based hybrids and the most promising compound 19a.

Figure 23

A carbazole-piperazine hybrid (20).

Figure 24

Carbazole hybrids that are FDA approved/or under clinical trials.

Figure 25

A pyridine hybrid (21).

Figure 26

A pyrimidine-indazole based hybrid 22.

Figure 27

A pyrimidine-di-indazole based hybrid (23).

Figure 28

A pyrimidine hybrid (24).

Figure 29

Pyrimidine-pyrazole based hybrid (25 and 26).

Figure 30

A Pyrimidine-pyrazole based hybrid (27).

Figure 31

A pyrimidine-triazole based hybrid (28).

Figure 32

Structure of sulfonamide-thiazole fused pyrimidine hybrids and the most promising compound 29a.

Figure 33

Structure of tri-substituted pyrimidine hybrids and the most promising compound 30a.

Figure 34

Structure of a pyrimidine-triazole based hybrids and the most promising compound 31a.

Figure 35

Structure of pyrimidine-triazole based hybrids and the most promising compound 32a.

Figure 36

Structure of pyrimidine-pyrazole based hybrids and the most promising compound 33a.

Figure 37

Structure of pyrimidine-pyrazole based hybrids and the most promising compound 34a.

Figure 38

Pyrimidine based FDA approved drugs.

Figure 39

Structure of quinoline-guanidine based hybrid 35.

Figure 40

Structure of tetrahydro-pyrimido-quinoline based hybrid 36.

Figure 41

Structure of quinoline hybrid amsacrine 37 and the most promising compound 37a.

Figure 42

Structure of quinoline-indole based hybrids and the most promising compound 38a.

Figure 43

Structure of quinoline based ursolic acid hybrids and the most promising compound 39a.

Figure 44

Structure of quinolone-based piperazine hybrids and the most promising compound 40a.

Figure 45

Quinoline-based gallium(III) hybrid (41).

Figure 46

FDA approved drugs with quinoline hybrids.

Figure 47

Structure of quinone-based chalcone hybrids and the most promising compound 42a.

Figure 48

Structure of quinone based pyran hybrids and the most promising compound 43a.

Figure 49

FDA approved drugs with Quinone hybrids.

Figure 50

Structure of imidazole-based benzofuran hybrid derivatives (44).

Figure 51

Structure of imidazole based benzofuran hybrid derivatives (45).

Figure 52

Structure of imidazole based triazole hybrid derivatives (46).

Figure 53

Structure of imidazole-based artemisinin hybrid derivatives (47).

Figure 54

Structure of imidazole based benzofuran hybrid derivative 48.

Figure 55

Imidazole based anticancer drugs that are FDA approved or in clinical trials.

Figure 56

Organoselenium hybrid derivatives (49).

Figure 57

Structure of selenium-based quinone triazole hybrid derivatives (50).

Figure 58

Structure of selenium based anilino quinazoline hybrid derivatives (51).

Figure 59

Structure of selenium based anilino quinazoline hybrid derivatives (52).

Figure 60

Structure of selenium-based diaryl imidazole hybrid derivatives (53).

Figure 61

Selenium based potent anticancer compounds.

Figure 62

Structure of Platinum−acridine hybrid derivatives (54).

Figure 63

Platinum hybrid derivatives (55–60).

Figure 64

Structure of Platinum (iv) dihydro-2-quinolone hybrid derivatives (61).

Figure 65

Structure of naproxen platinum (IV) hybrid derivatives.

Figure 66

Structure of Camptothecin-linked platinum hybrid derivatives (67–69).

Figure 67

Structure of hydroxamic acid with artemisinin hybrid derivatives (70).

Figure 68

Structure of hydroxamate-β-carboline based hybrid derivatives (71).

Figure 69

Structure of hydroxamic acid based chalcone derivatives (72).

Figure 70

Structure of hydroxamic acid based 4-aminoquinazolin derivatives (73).

Figure 71

Structure of hydroxamic acid based indoline derivatives (74).

Figure 72

Structure of ferrocene-indole derivatives (75).

Figure 73

Structure of ferrocene containing a pyrazolyl derivative (76).

Figure 74

Structure of ferrocenyl-chalcone amide derivative (77).

Figure 75

Structure of ferrocene-coumarin moiety derivative (78).

Figure 76

Structure of ferrocene-chalcogeno (sugar) triazole conjugate derivatives (79).

Figure 77

Structure of curcumin-quinolone derivatives (80).

Figure 78

Structure of curcumin-sulfonamide derivatives (81).

Figure 79

Structure of curcumin-pyrazole derivative (82).

Figure 80

Structure of curcumin-pyrimidine derivatives (83).

Figure 81

Structure of curcumin-isatin derivatives (84).

Figure 82

Structure of triazole-pyrimidine derivatives (85).

Figure 83

Structure of triazole–myrrhanore C derivatives (86).

Figure 84

Structure of triazole-isoxazole derivatives (87).

Figure 85

Structure of triazole-dithiocarbamate derivatives (88).

Figure 86

Structure of triazole-thiazole derivative (89).

Figure 87

Structure of benzimidazole-pyrazole derivatives (90).

Figure 88

Structure of benzimidazole-pyrimidine derivatives (91).

Figure 89

Structure of benzimidazole–thiazolidinedione derivatives (92).

Figure 90

Structure of benzimidazole-quinazoline derivatives (93).

Figure 91

Structure of benzimidazole-β-Carboline derivatives (94).

Figure 92

Structure of isatin-based benzoazine derivatives (95).

Figure 93

Structure of isatin-dihydropyrazole derivatives (96).

Figure 94

Structure of isatin-pyridine derivatives [97(a–c), 98, and 99 (a–c)].

Figure 95

Structure of isatin-based coumarin derivatives (100).

Figure 96

Structure of isatin-indole derivatives (101).

Figure 97

Structure of isatin-benzoic acid derivatives (102).

Figure 98

Structure of isatin-thiazolo benzimidazole derivatives (103,104).

Figure 99

The isatin moiety as FDA-approved anticancer drug.

Figure 100

Structure of pyrrolo-benzodiazepine hybrids and the most promising compound 105a.

Figure 101

Structure of pyrrolo-benzodiazepine-based benzoindolone derivative (106).

Figure 102

Structure of pyrrolo-benzodiazepine-dione derivatives [107(a–c),108(a–c)].

Figure 103

Structure of triazole-pyrrolo-benzodiazepines derivative [109(a–c),110(a–c)].

Figure 104

Pyrrolo-benzodiazapine containing FDA approved anticancer drug.

Figure 105

Naturally occurring phytoconstituents containing chalcone.

Figure 106

Structure of chalcone-based phenothiazine hybrids and the most promising compound 111a.

Figure 107

Structure of chalcone-based benzoxadiazole hybrids and the most promising compound 112a.

Figure 108

Structure of chalcone-based triazolo-quinoxaline hybrids and the most promising compound 113a.

Figure 109

Structure of chalcone based melatonin hybrids and the most promising compound 114a.

Figure 110

Structure of chalcone-based quinoxalin hybrids and the most promising compound 115e.

Figure 111

Structure of coumarin-benzimidazole derivatives 116(a–e).

Figure 112

Structure of coumarin containing 1,2,3-triazole derivatives 117(a–e).

Figure 113

Structure of coumarin containing chalcone derivative [118(a–c),119(a–c)].

Figure 114

Structure of coumarin-based uracil derivatives 120(a–e).

Figure 115

Structure of coumarin-based furoxin derivatives 121(a–e).

Figure 116

Structure of nitrogen mustard contain oridonin derivatives 122(a–d).

Figure 117

Structure of nitrogen mustard-containing thiazole derivatives 123(a–e).

Figure 118

Structure of nitrogen mustard-containing triazine derivatives 124(a–d).

Figure 119

Structure of androstane oxime-nitrogen mustard hybrids [125(a-b),126(a-b)].

Figure 120

Structure of pyrazole-based indole derivatives 127(a–e).

Figure 121

Structure of benzofuran-pyrazole-based derivatives 128(a–d).

Figure 122

Structure of quinazoline-pyrazole-based derivatives (129–131) and pyrazole derivative (132–133).

Figure 123

Structure of pyrazoline-pyrazole-based derivatives 134(a–e).

Figure 124

Structure of pyrazole acrylic acid-based oxadiazole derivatives 135(a–c).

Figure 125

Structure of biquinoline-pyridine hybrid derivative 136(a–e).

Figure 126

Structure of isatin-pyridine derivative [137,138(a–d)].

Figure 127

Structure of pyrazolo [3,4] pyridine derivatives [139(a–d),140(a–d)].