Recent Trends in the Synthesis and Bioactivity of Coumarin, Coumarin-Chalcone, and Coumarin-Triazole Molecular Hybrids

Abstract

Molecular hybridization represents a new approach in drug discovery in which specific chromophores are strategically combined to create novel drugs with enhanced therapeutic effects. This innovative strategy leverages the strengths of individual chromophores to address complex biological challenges, synergize beneficial properties, optimize pharmacokinetics, and overcome limitations associated with single-agent therapies. Coumarins are documented to possess several bioactivities and have therefore been targeted for combination with other active moieties to create molecular hybrids. This review summarizes recent (2013-2023) trends in the synthesis of coumarins, as well as coumarin-chalcone and coumarin-triazole molecular hybrids. To cover the wide aspects of this area, we have included differently substituted coumarins, chalcones, 1,2,3- and 1,2,4-triazoles in this review and considered the point of fusion/attachment with coumarin to show the diversity of these hybrids. The reported syntheses mainly relied on well-established chemistry without the need for strict reaction conditions and usually produced high yields. Additionally, we discussed the bioactivities of the reported compounds, including antioxidative, antimicrobial, anticancer, antidiabetic, and anti-cholinesterase activities and commented on their IC₅₀ where possible. Promising bioactivity results have been obtained so far. It is noted that mechanistic studies are infrequently found in the published work, which was also mentioned in this review to give the reader a better understanding. This review aims to provide valuable information to enable further developments in this field.

Keywords: biological activity; chalcone; coumarin; molecular hybridization; triazole.

Figure 1

Structures of coumarin, chalcone and triazole and their derivatives.

Figure 2

Significant biological activities of coumarin, chalcone and triazole derivatives.

Scheme 1

Synthesis of coumarins 6a–w from dicarboxylic acid 1 [68].

Scheme 2

Synthesis of coumarins 13a–l from resorcinol 7 [69].

Scheme 3

Synthesis of coumarins 20a–o from 4-chlororesorcinol 14 [70].

Scheme 4

Synthesis of coumarins 22a–d and 23a–d from 4-hydroxycoumarin 22 [71].

Scheme 5

Synthesis of coumarin 27 from acetyl-2H-chromen-2-one 24 [72].

Scheme 6

Synthesis of coumarins 30a–d from 4-hydroxy coumarin 21 [73].

Scheme 7

Synthesis of coumarins 33a–g from substituted carboxylic acid 31 [74].

Scheme 8

Synthesis of coumarins 37a–d from 4-hydroxy-6-substituted coumarin 34 [75].

Scheme 9

Synthesis of coumarins 42a–d from substituted benzylchlorides 38 [76].

Scheme 10

Synthesis of coumarins 45a–b from 3-acetyl coumarin 43 [77].

Scheme 11

Synthesis of coumarin 50 from dihydroxybenzaldehyde 46 [78].

Scheme 12

Synthesis of coumarins 54a–g from 3-acetyl coumarin 43 [79].

Scheme 13

Synthesis of coumarins 59a–j from 4-hydroxy coumarin 21 [80].

Scheme 14

Synthesis of coumarins 62a–j from 4-hydroxy coumarin 21 [81].

Scheme 15

Synthesis of coumarins 69a–e and 71a–c from salicylaldehyde 63 [82].

Scheme 16

Synthesis of coumarins 73a–c from 3-acetyl coumarin 43 [83].

Scheme 17

Synthesis of coumarin–chalcones 78 from 7-hydroxy coumarin 74 [84].

Scheme 18

Synthesis of coumarin–chalcones 83a–e from substituted salicylaldehyde 80 [85].

Scheme 19

Synthesis of coumarin–chalcones 85a–d from 3-acetyl coumarin 43 [86].

Scheme 20

Synthesis of coumarin–chalcones 88a–h from substituted salicylaldehyde 86 [87].

Scheme 21

Synthesis of coumarin–chalcones 90a–b from salicylaldehyde 63 [88].

Scheme 22

Synthesis of coumarin–chalcones 93a–k from 3-acetyl coumarin 43 [89].

Scheme 23

Synthesis of coumarin–chalcones 95a–c and 97a–c from 3-acetyl coumarin 43 [90].

Scheme 24

Synthesis of coumarin–chalcones 101a–z from salicylaldehyde 63 [91].

Scheme 25

Synthesis of coumarin–chalcones 102a–v from salicylaldehyde 63 [92].

Scheme 26

Synthesis of coumarin–triazoles 107a–d from 103 [93].

Scheme 27

Synthesis of coumarin–triazoles 112a–h from resorcinol 7 [94].

Scheme 28

Synthesis of coumarin–triazoles 115a–f and 118a–e from 8 and 21 [95].

Scheme 29

Synthesis of coumarin–triazoles 124a–f from substituted salicylaldehyde 119 [96].

Scheme 30

Synthesis of coumarin–triazoles 129a–c and 133a–c from 125 [97].

Scheme 31

Synthesis of coumarin–triazoles 137a–e and 139a–c from 134 [98].

Scheme 32

Synthesis of coumarin–triazole 142 [99].

Scheme 33

Synthesis of coumarin–triazoles 147a–k and 149a–k from orcinol 143 [100].

Scheme 34

Synthesis of coumarin–triazoles 151a–v from 7-hydroxy-4-methyl coumarin 8 [101].

Scheme 35

Synthesis of coumarin–triazoles 157 from salicylic aldehydes 152 [102].

Scheme 36

Synthesis of coumarin–triazoles 163a–c from compound 159 [103].

Scheme 37

Synthesis of coumarin–triazoles 167a–i from substituted salicylaldehyde 164 [104].

Scheme 38

Synthesis of coumarin–triazoles 169 from 7-hydroxy-4-methyl coumarin 8 [105].

Scheme 39

Synthesis of coumarin–triazoles 174a–e from aromatic anilines 170 [106].

Scheme 40

Synthesis of coumarin–triazole 179a–e from substituted salicylaldehyde 175 [107].

Scheme 41

Synthesis of coumarin–triazoles 181/183 from salicylaldehyde 63 [108].

Scheme 42

Synthesis of coumarin–triazole 189 from β-d-glucopyranoside 184 [109].

Scheme 43

Synthesis of coumarin–triazole 192 from 191 [110].

Scheme 44

Synthesis of coumarin–triazoles 196a–d from 8-acetyl-coumarin 193 [111].

Scheme 45

Synthesis of coumarin–triazole–chalcones 201a–e from aromatic aldehydes and ketones [112].

Figure 3

Coumarin-based compounds as antioxidants.

Figure 4

Coumarin-based compounds as antimicrobial agents.

Figure 5

More examples of coumarin-based compounds as antimicrobial agents.

Figure 6

Coumarin-based compounds as anticancer agents.

Figure 7

More examples of coumarin-based compounds as anticancer agents.

Figure 8

Coumarin-based compounds as antidiabetic agents.

Figure 9

Coumarin-based compounds as anti-cholinesterase.

Figure 10

Coumarin-based compounds as anti-inflammatory agents.

Figure 11

Other bioactivities of coumarin-based compounds.