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.

1. Introduction

Molecular hybridization (MH) is an established drug design method used by medicinal chemists to create and refine new lead compounds [1]. It is the rational combination of two or more pharmacophoric units with distinct modes of action into a single molecule [2,3]. MH is expected to increase the biological activity of newly created pharmacophores [4] through alterations to their pharmacokinetic profiles, modes of action, potency, selectivity, and biological activity [5].

Coumarins are a class of naturally occurring O-heterocyclic compounds with 2H-1-benzopyran-2-one as a core framework (Figure 1) [6,7] Coumarins are widely recognized for their pharmacological effects in both natural and synthetic forms. They possess antifungal, antibacterial, anti-inflammatory, antioxidant, anti-cholinesterase, antidiabetic, antineoplastic, anti-HIV, anticoagulant, and anticancer bioactivities (Figure 2) [8,9,10,11,12,13,14,15]. For instance, the naturally occurring coumarin Calanolide A (Figure 1), which was extracted from the species Calophyllum, showed interesting anti-HIV activity [16]. Warfarin is a synthetic anticoagulant drug that blocks the formation of blood clots [17]. Due to their important bioactivity, more research has recently focused on how coumarins might be combined with other chromophores to create new structural diversity with improved activity.

Chalcones (1,3-diaryl-2-propen-1-ones) (Figure 1) are made up of two aromatic rings linked by an α,β-unsaturated carbonyl group [18,19,20]. Researchers have expressed interest in the chalcone scaffold, and several studies have emphasized the significance of these molecules in the domains of pharmacology and chemistry [21]. Because of their significant antioxidant, antiviral, antidiabetic, anticancer, anti-inflammatory, antibacterial, antifungal, and antihyperlipidemic properties, chalcones, both natural and synthetic, are of great chemical and pharmacological interest (Figure 2) [22,23,24,25,26,27,28,29,30,31,32]. For example, Licochalcone A is a naturally occurring chalcone isolated from the roots of Glycyrrhiza species, specifically G. glabra and inflata. It possesses anti-inflammatory, anticancer and antioxidant properties (Figure 1) [33,34,35,36,37]. Several chalcone-based drugs have been licensed for use in therapeutic settings. For instance, sofalcone is used as an antiulcer and mucoprotective medication, while metochalcone is used as a choleretic drug (Figure 1) [38,39,40].

Triazoles are heterocyclic compounds with a basic framework comprising a five-membered ring containing three nitrogen atoms at positions 1,2,3- or 1,2,4 in the ring. (Figure 1). Because of their excellent chemical stability against oxidation, reduction, and hydrolysis, they have a wide range of medical applications [41,42,43,44]. Due to their wide range of biological significance, triazoles have been recognized as prominent pharmacophores for several commercial drugs (Figure 2) [45,46,47,48,49,50,51,52,53]. For example, tazobactam (Figure 1) is an antibacterial drug that treats infections in both adult and pediatric patients [54,55,56,57].

Coumarin derivatives are popular and attractive in the field of medicinal/organic chemistry [58,59,60,61,62,63,64,65,66,67,68]. Hence, several review papers on this topic have been published. For example, Adimule et al. (2022) arranged a recent advance in the one-pot synthesis of coumarin derivatives from different starting materials using metal nanoparticles as heterogeneous catalysts [7]. Song et al. (2020) released an update on coumarin derivatives with anticancer activities by underlining interactions between coumarin derivatives and diverse enzymes and receptors in cancer cells [11]. Additionally, the recent development of coumarin hybrids as antifungal agents was summarized by Hu et al. [14]. Furthermore, an overview of synthetic approaches and the biological activity of coumarin derivatives was provided by Annunziata et al. [67]. The present review focuses on coumarin hybrids. However, it starts with recent developments in coumarin chemistry to give the reader the necessary background and transition needed for the chemistry of coumarin hybrids. We attempt to summarize the synthesis strategies and biological activities of coumarin, coumarin–chalcone and coumarin–triazole hybrids. This review will be beneficial for synthetic and medicinal chemists aiming to develop these hybrids into lead drug compounds.

2. Synthesis of Coumarin, Coumarin–Chalcone Hybrids, and Coumarin–Triazole Hybrids

2.1. Synthesis of Coumarin Derivatives

Chen et al. (2014) synthesized several coumarin derivatives starting from dicarboxylic acids 1 (Scheme 1) [68]. Acid 1 was esterified to form ester 2, which underwent cyclization to form 2-carboalkoxcyclohexanone 3. The Pechmann reaction of 3 with resorcinol catalyzed by Bi(NO₃)₃ afforded compound 4, which was bromoalkylated to form 5. Compound 5 was reacted with various cyclic secondary amines to give amino-functionalized coumarins (6a–w) in medium-to-good yields.

Elbastawesy et al. (2015) constructed twelve novel coumarin derivates, starting from resorcinol 7 (Scheme 2) [69]. After subsequent cyclization, following an S_N2 reaction with ethyl chloroacetate and then amidation with hydrazine, compound 10 was obtained which, after further reactions, gave compound 11. From this important intermediate, coumarins 13a–l were obtained in good yields.

Rasool et al. (2016) converted 4-chlororesorcinol 14 via Pechmann condensation into coumarins 20a–o (Scheme 3) [70]. After Pechmann cyclization, an S_N2 reaction of 15 with ethyl 2-bromoacetate, and then amidation, compound 17 was obtained. The derivatization of 17 gave compound 18, which then underwent an S_N2 reaction to give coumarins 20a–o in medium-to-good yields.

Weng and Yuan (2018) successfully synthesized two types of coumarin (Scheme 4) [71]. 4-Hydroxycoumarin 21 was reacted with aromatic aldehydes via two different conditions to produce compounds 22a–d and 23a–d.

Fayed et al. (2019) synthesized coumarin derivatives through a one-pot reaction of compound 24, 4-methoxybenzaldehyde, and malononitrile to produce intermediate 25 which, upon hydrolysis using 60% H₂SO₄, gave compound 26 (Scheme 5) [72]. The subsequent cyclization of 26 with glacial acetic acid gave compound 27 in a 75% yield (Scheme 5).

Naik et al. (2019) synthesized four novel coumarin derivatives (Scheme 6) [73]. An S_N2 reaction between 4-hydroxycoumarin 21 and dibromoalkane gave intermediate 28 which, upon another S_N2 reaction with 29, provided coumarins 30a–d in medium yields.

Xu et al. (2020) converted carboxylic acid 31 into cinnamoyl chlorides 32 which, upon reaction with compound 21, gave coumarin derivatives 33a–i in medium yields (Scheme 7) [74].

Alshibl et al. (2020) synthesized coumarin derivates via Knoevenagel condensation between 34 and chlorosulfonic acid to produce coumarin sulfonyl chloride 35, which underwent an S_N2 reaction with p-substituted aniline 36 to give coumarin-3-sulfonamides 37a–d in medium-to-excellent yields (Scheme 8) [75].

In line with the development of coumarin derivatives, Wang et al. (2020) synthesized 3-substituted coumarin derivatives via a three-step synthetic route from substituted benzyl chlorides/bromides 38 (Scheme 9) [76]. The starting materials 38 were treated with mercaptoacetic acid in the presence of sodium hydroxide to give benzylmercaptoacetic acid 39 which, upon treatment with hydrogen peroxide, gave benzylsulfonylacetic acid 40. Finally, the target compounds 42a–d were synthesized via a Knoevenagel reaction between 40 and substituted salicylaldehydes 41 and were obtained in low-to-medium yields.

Abduljabbar and Hadi (2021) synthesized coumarin derivatives 45a–b via the acetic acid-catalyzed reaction between 3-acetyl coumarin 43 and hydrazides 44 (Scheme 10) [77].

Mzezewa et al. (2021) initiated the synthesis of 3,7-substituted coumarin with a Pechmann condensation of dihydroxybenzaldehyde 46 to give compound 47, which, upon esterification with 2-bromoethylbenzene, gave 48 (Scheme 11) [78]. The subsequent bromination of 48 with N-bromosuccinimide gave 49 which, upon reaction with propargylamine, gave coumarin 50.

Kokat and Jadhav (2022) constructed coumarin derivatives 54a–g (Scheme 12) [79]. The bromination of 3-acetyl coumarin 43 gave 51, which, upon cyclization with thiourea and then an S_N2 reaction on the amino group, gave 53. Finally, an S_N2 reaction between substituted anilines and compound 53 resulted in the formation of the target coumarins 54a–g in good yields.

Yadav et al. (2022) synthesized 4-anilinocoumarins in four steps (Scheme 13) [80]. At first, compound 55 was prepared via the reaction of aniline with 4-hydroxycoumarin 21. Next, 55 was treated with ethyl chloroacetate in the presence of KOH/K₂CO₃ to give the N-alkylated product 56. The reaction of this intermediate with hydrazine hydrate yielded the desired hydrazide compound 57, which, upon condensation with aromatic aldehydes 58, gave 4-anilinocoumarins 59a–j in good yields.

With the same purpose of developing coumarin derivatives, Zhou et al. (2022) converted 4-hydroxycoumarin 21 to nitro product 60 (Scheme 14) [81]. The subsequent reduction of the nitro group gave the amino compound 61, which underwent substitution with various acid chlorides to form the target compounds 62a–j in good yields.

Ghouse et al. (2023) synthesized 3-substituted coumarin derivatives, starting from salicylaldehyde 63 (Scheme 15) [82]. A reaction between salicylaldehyde 63 and diethyl malonate gave compound 64 which, upon hydrolysis with sodium hydroxide, yielded compound 65. The amidation of 65 with N-Boc piperazine in the presence of EDC·HCl, HOBt, and DIPEA gave 66. Deprotection of the Boc group using TFA led to the formation of compound 67. The reaction of 67 with various benzenesulfonylchlorides 68 yielded sulfonamides 69a–e in good yields. On the other hand, 67 underwent a reaction with phenylisothiocyanates 70 to give carbothioamides 71a–c in good yields.

To obtain coumarin derivatives 73a–c, Prathap and Lokanath (2018) performed a condensation between 3-acetyl coumarin 43 and substituted benzene sulfonyl hydrazides 72 (Scheme 16) [83].

2.2. Synthesis of Coumarin–Chalcone Molecular Hybrids

Several research groups successfully attempted the synthesis of coumarin–chalcone molecular hybrids using different approaches. The synthesis of the novel coumarin–chalcone hybrid 78 was accomplished by Amin et al. (2013) (Scheme 17) [84]. The synthesis of the precursor chalcone 76 started by converting 7-hydroxycoumarin 74 to acetylated coumarin 75, followed by acetylation/deacetylation to give 76. The methylation of 76 gave compound 77. The aldol condensation of 77 with various aromatic aldehydes gave coumarin–chalcone 78. These compounds can be further functionalized to 79a–r by reaction of 78 with 4-(un)-substituted phenylsulfonyl hydrazines.

Vazquez-Rodriguez et al. (2013) synthesized hydroxy-3-benzoylcoumarins by initially reacting salicylaldehyde 80 with ethyl 3,4-dimethoxybenzoylacetate 81 to form the Knoevenagel product methoxy-3-benzoylcoumarins 82, which, upon hydrolysis, gave the target hydroxyl-3-benzoylcoumarins 83a–e in medium-to-good yields (Scheme 18) [85].

Rodríguez (2015) synthesized coumarin–chalcone derivatives through a two-step process, starting with the preparation of 3-acetyl coumarin 43 via a Knoevenagel reaction. The final coumarins 85a–d were obtained through a Claisen–Schmidt condensation between 43 and aromatic aldehydes 84, giving good-to-excellent yields (Scheme 19) [86].

Vazquez-Rodriguez et al. (2015) synthesized coumarin–chalcone derivatives by reacting salicylaldehyde 86 with substituted ethyl benzoylacetate 87 via a Knoevenagel reaction to give derivatives 88a–h (Scheme 20) [87]. In the preparation of amino-substituted derivatives, the same strategy was applied to obtain nitro-substituted 3-benzoyl coumarin precursors, which were further processed without purification using SnCl₂·2H₂O. The target compounds 88a–h were obtained with moderate-to-excellent yields.

Patil et al. (2019) synthesized coumarin–chalcone derivatives by reacting salicylaldehyde 63 with ethyl acetoacetate to give compound 43 which, upon reaction with aromatic aldehydes 89, gave the α,β-unsaturated carbonyl compounds 90a–b in moderate yields (Scheme 21) [88].

Kurt et al. (2020) synthesized new coumarin–chalcone derivatives (Scheme 22) [89] through Claisen–Schmidt condensation between 3-acetyl coumarin 43 and p-nitrobenzaldehyde to give the desired compound 91, which was then subjected to reduction reaction to give compound 92. Coumarin–chalcone-substituted urea derivatives 93a–k were obtained in moderate-to-good overall yields by reacting 92 with various isocyanates.

Emam et al. (2021) prepared coumarin–chalcone derivatives via the synthesis route outlined in Scheme 23 [90]. The process involved the Claisen–Schmidt condensation of 3-acetyl coumarin 43 with aryloxybenzaldehydes 94 or dialkylaminobenzaldehydes 96 to give the desired chalcones 95a–c and 97a–c.

Konidala et al. (2021) synthesized coumarin–clubbed chalcone hybrids as outlined in Scheme 24 [91]. Initially, the acid-catalyzed Biginelli reaction of salicylaldehyde 63 with pentane-2,4-dione and urea/thiourea 98 yielded a dihydropyrimidine derivative 99. Subsequently, the Pechmann condensation of compound 99 with malonic acid formed compound 100. Finally, the base-catalyzed Claisen–Schmidt condensation of compound 100 with various aromatic aldehydes gave the target compounds 101a–z in medium-to-good yields.

Coumarin–chalcone derivatives were successfully synthesized by Hu et al. (2022) via the reaction of salicylaldehyde 63 with ethyl acetoacetate to give 3-acetyl coumarin 43; then, subsequent aldol condensation with various aldehydes gave coumarin–chalcone derivatives 102a–v in moderate-to-good yields (Scheme 25) [92].

2.3. Synthesis of Coumarin–Triazole Molecular Hybrids

Coumarin–triazole syntheses were reported from various starting materials. Pavić et al. (2021) synthesized coumarin–triazole hybrids, by initially chlorinating substituted 4-hydroxy coumarin 103 (Scheme 26) [93]. The obtained 4-chloro coumarin 104 was then converted to azides 105. The azide–alkyne cycloaddition was used to produce the target products 107a–d in moderate yields by reacting the azides 105 with the harmine-based terminal alkynes 106.

Shaikh et al. (2016) have described the synthesis of a series of new coumarin–triazole derivatives 112a–h from resorcinol 7 (Scheme 27) [94]. Compound 109 was synthesized through the Pechmann condensation between compound 108 and diethyl malonate. The treatment of compound 109 with propargyl bromide resulted in compound 110. Finally, the reaction of benzyl azide 111 and coumarin-based alkyne 110 via click chemistry produced the corresponding coumarin compounds containing 1,4-disubstituted-1,2,3-triazoles 112a–h in excellent yields.

Shaikh et al. (2016) described a protocol for the synthesis of a series of coumarin–triazoles 115a–f and 118a–e from benzyl azides and coumarin-based alkynes via click chemistry (Scheme 28) [95]. The reaction between compounds 8 (or 21) and propargyl bromide produced compounds 113 or 116, respectively. Then, the reaction between 113 and benzyl azide 114 as well as the reaction of coumarin-based alkynes 116 with 117 gave the corresponding coumarin-based 1,4-disubstituted-1,2,3-triazole derivatives 115a–f or 118a–e, respectively, in excellent yields.

Sinha et al. (2016) developed a new class of coumarin–triazoles through the application of the 1,3-dipolar cycloaddition of azides and alkynes (Scheme 29) [96]. Initially, 3-acetamido coumarin analogs 121 were synthesized using salicylaldehydes 119 and N-acetyl glycine 120 under microwave conditions. The subsequent, reaction of compound 121 with sodium nitrite followed by sodium azide gave the desired 3-azido coumarin derivatives 122. Next, a click reaction between cyclooctyne 123 and 3-azido coumarins 122 gave compounds 124a–f in excellent yields.

The synthesis of the target triazolyl coumarin derivatives by Al-Wahaibi et al. (2018) utilized 2-(coumarin-4-yl) acetic acid 125, which was prepared by reacting citric acid with phenol in sulfuric acid (Scheme 30) [97]. Compound 125 was then reacted with thiocarbohydrazide 126 to produce compound 127. The reaction of aminotriazole 127 with various aromatic aldehydes 128 using acetic acid as a catalyst gave the arylideneamino derivatives 129a–c in medium yields. The reaction of compound 127 with carbon disulfide in pyridine gave the mercapto derivative 130. The mercapto derivative 130 was then reacted with iodomethane to produce the methylthio analogue 131. The reaction of 131 with various primary aromatic amines 132 gave the desired 6-arylamino compounds 133a–c in good yields.

Kumar et al. (2018) successfully synthesized coumarin derivatives containing a 1,2,3-triazole ring (Scheme 31) [98]. The chemistry began by reacting 5-substituted-2-mercapto-1,3,4-oxadiazole 134 with propargyl bromide to give the compound 135, which was used for the click chemistry. Compound 135 underwent a 1,3-dipolar cycloaddition with 4-azido methyl coumarins 136 or 138 to yield compounds 137a–e and 139a–c, respectively, in good yields.

Nouraie et al. (2019) successfully synthesized coumarin-1,2,3-triazole hybrids in excellent yields (Scheme 32) [99]. For example, the reaction of 5-bromo-2-(prop-2-yn-1-yloxy)benzaldehyde 140 and 3-azido coumarin 141 gave compound 142 in a 92% yield.

Coumarin-1,2,3-triazole hybrids bearing a benzenesulfonate moiety have been successfully synthesized by Krishna et al. (2018) (Scheme 33) [100]. The Pechmann cyclization of orcinol 143 with ethyl 4-chloroacetoacetate gave compound 144. Compound 144 was then reacted with propargyl amine, resulting in N-propargyl coumarin 145. The subsequent treatment of coumarin 145 with benzene sulfonyl chloride produced the benzene sulfonate coumarin 148. The 1,3-dipolar cycloaddition of the resultant acetylenic compounds 145 and 148 with substituted aromatic azides under click chemistry yielded compounds 147a–k and 149a–k, respectively, in good-to-excellent yields.

Yadav et al. (2018) synthesized a series of novel coumarin–triazoles 151a–v by employing click chemistry on 7-hydroxy-4-methyl coumarin 8 (Scheme 34) [101]. Initially, compound 8 was alkylated using propargyl bromide to produce coumarin alkynes 113. The alkynes 113 underwent a cycloaddition reaction with azides 150 to yield a series of 1,4-substituted triazoles 151a–v in moderate yields.

Yilmaz and Faiz (2018) successfully synthesized 3-(1H-benzotriazol-1-ylcarbonyl)-2H-chromen-2-ones 157 from salicyl aldehydes 152 (Scheme 35) [102]. Coumarin-3-carboxylic acids 154 were obtained from the reaction of salicyl aldehydes 152 and Meldrum’s acid 153 with pyridine as a catalyst. Then, compounds 154 were reacted with 1-H-benzotriazole 155 to afford compounds 157. Coumarin triazole 157 can also be further functionalized to 158a–o by reaction with hydrazide 156.

The synthesis of 1,2,3-triazole-containing coumarin bearing Zn(II) and Mg(II) phthalocyanines was successfully carried out by Özdemir et al. (2020) (Scheme 36) [103]. The synthesis began by reacting 7-hydroxy-3-(3,4-dicyanophenoxyphenyl)coumarin 159 with propargyl bromide to produce coumarin alkynes 160. The 1,2,3-triazoles 162 were synthesized through the copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of 2-(azidoethyl)benzene 160 with terminal ethynyl-bearing phthalonitriles 161. The metallophthalocyanines 163a–c were obtained through the cyclotetramerization of triazole-coumarin phthalonitriles 162 in the presence of metal salts in 2-dimethylaminoethanol (DMAE) as a solvent.

The synthesis of coumarin-tethered 1,2,3-triazoles by Channabasappa et al. (2021) involved a multi-step route (Scheme 37) [104]. Compound 165 was prepared from substituted salicylaldehyde 164 and ethyl 3-oxobutanoate. The aryl azides 166 were reacted with substituted compounds 165, yielding compounds 167a–i in moderate yields.

The synthesis of coumarin-linked amino acids via triazole was accomplished by De Sousa et al. (2021) (Scheme 38) [105]. Compound 8 was propargylated to afford 113. Reaction of 113 with azido ethyl ester of tryptophan via azide-alkyne cycloaddition gave coumarin triazole 168, which was hydrolyzed to yield coumarin-linked triazole amino acid analog 169.

A series of new coumarin-1,2,3-triazole hybrids were also synthesized by Vagish et al. (2021) (Scheme 39) [106]. Initially, aniline 170 underwent diazotization followed by azidation to give azido 171. Key intermediate 172 was prepared via enolate-mediated triazole synthesis from 171 using acetylacetone. Finally, the target coumarin 1,2,3-triazole conjugates 174a–e were synthesized by the reaction of 172 with compound 173 under different conditions.

In a multi-step route, a series of coumarin–triazole hybrids were successfully synthesized by Basappa et al. (2020) (Scheme 40) [107]. The reaction between substituted salicylaldehydes 175 and diethylmalonate gave compound 176 which, upon reaction with hydrazine hydrate, gave hydrazides 177. The reaction of 177 with carbon disulfide resulted in the formation of the intermediate dithiocarbazate salts 178. The in-situ reaction of 178 with hydrazine hydrate produced the target compounds 179a–e in medium-to-good yields.

The synthesis of new coumarin derivatives containing aminobenzotriazole moiety was successfully carried out by Al-Shuaeeb (2023) (Scheme 41) [108]. A reaction between salicylaldehyde 63 and diethyl malonate gave compound 64 which, upon hydrolysis, yielded coumarin 3-carboxylic acid 65. Coupling using dicyclohexylcarbodiimide (DCC) was employed to connect coumarin 3-carboxylic acid 65 with 2-aminobenzotriazole 180, resulting in the formation of compounds 181 in good yield. Moreover, reaction of compound 65 with 2-amino-5-mercapto-1,3,4-thiadiazole 182 gave derivative 183 in good yield.

Adam and Zimam (2023) successfully synthesized new coumarin-1,2,3–triazole glucoside hybrids (Scheme 42) [109]. β-D-glucopyranoside 184 was reacted with acetic anhydride in the presence of pyridine to produce compound 185, which was then reacted with 1,2-dibromoethane to yield compound 186. Subsequently, compound 186 was reacted with sodium azide to produce azidosugar 187. The reaction of compound 187 with propargyl 4-hydroxy coumarin 116 occurred under click chemistry conditions to create 1,2,3–triazole glycoside 188. The acetylated glycoside 188 underwent a deprotection reaction to afford triazole glycoside 189 with free hydroxyl groups.

In 2023, Omar et al. synthesized a novel coumarin–triazole hybrid by reacting 4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol 190 with an equimolar amount of 4-(chloromethyl)-6,7-dimethyl-2H-chromen-2-one 191 to give coumarin–triazole 192 in 75% yield (Scheme 43) [110].

A series of coumarin−triazole hybrid syntheses conducted by Sharma and Bharate (2023) relied on the propargylation of 8-acetyl-coumarin 193 with propargyl bromide to give compound 194 (Scheme 44) [111]. The click reaction of the propargyl 194 with benzyl bromide 195 in the presence of sodium azide yielded the corresponding coumarin−triazole hybrids 196a–d in medium yields.

Pingaew et al. (2014) synthesized novel coumarin–triazole–chalcone hybrids in three steps (Scheme 45) [112]. Initially, chalcones 199 were synthesized using the Claisen–Schmidt condensation of various aromatic aldehydes 197 with amino acetophenones 198. Subsequently, the diazotation–azidation of the aminochalcones 199 afforded the corresponding azidochalcones 200. The azide–alkyne dipolar cycloaddition is the key route to the synthesis of 1,2,3-triazole linkage. Finally, the azides 200 readily underwent cycloaddition with alkynes 116 to afford the novel desired hybrid molecules 201a–e in medium-to-good yields.

3. Bioactivity of Coumarins, Coumarin–Chalcones, and Coumarin–Triazoles

3.1. Antioxidant Activity

Alshibl et al. (2020) synthesized coumarin derivates and examined their antioxidation activity using a DPPH assay (Scheme 8, Figure 3) [75]. Compound 37c exhibited the highest antioxidant activity, with an IC₅₀ value of 14.51 ± 1.827 μg/mL.

The capacity of hydroxy-3-benzoylcoumarins to scavenge peroxyl radicals was studied using the ORAC method [85]. ORAC assesses the ability of antioxidants (or their complex mixtures) to inhibit the bleaching of a target molecule (probe) induced by peroxyl radicals. The results from the ORAC method showed that compound 83e (Scheme 18, Figure 3) had the best values among the synthesized compounds. The ORAC-FL value was 8.51 ± 0.32, the ORAC-PGR value was 1.17 ± 0.10, and the hydroxy radical scavenging value was 90.9 ± 8.2% for compound 83e.

The method of screening the antioxidant activity of coumarin–clubbed chalcone hybrids developed by Konidala et al. (2021) was examined using an in vitro DPPH assay (Scheme 24, Figure 3) [91]. The results indicated that compound 101v showed the most potent antioxidant activity, with 77.92% scavenging activity (100 μg/mL).

The coumarin–triazole derivatives developed by Shaikh et al. were also evaluated for antioxidant activity using in vitro DPPH assay. Compound 112a (Scheme 27, Figure 3) was found to be the most potent candidate, with an IC₅₀ value of 15.20 μg/mL [94].

Coumarin–triazole 118e (Scheme 28, Figure 3), assessed using an in vitro DPPH radical scavenging assay, showed an IC₅₀ of 11.28 μg/mL [95].

The potential antioxidant activity of several coumarin hydrazides was also investigated using the cupric ion reducing antioxidant capacity (CUPRAC) method. All studied compounds reduced cupric ions, and the highest activity was observed for compound 158j, with 1.82 ± 0.08 mg TEAC/mg compound (Scheme 35, Figure 3) [102].

3.2. Antimicrobial Activity

Rasool et al. (2016) reported several coumarin hybrids as potential antimicrobial agents. Compound 20k (Scheme 3, Figure 4) was found to be the most potent candidate, with promising MIC values for Gram-negative bacteria (S. typhi = 8.84 ± 2.00 μg/mL; E. coli = 10.94 ± 1.25 μg/mL; P. aeruginosa = 12.00 ± 1.33 μg/mL) and Gram-positive bacteria (B. subtilis = 12.96 ± 1.82 μg/mL; S. aureus = 12.14 ± 1.48 μg/mL) [70].

Naik et al. (2019) synthesized novel coumarin derivatives, and the best antimicrobial activity was shown by compound 30d (Scheme 6, Figure 4), with promising MIC values against Gram-positive bacteria (E. coli = 14 μg/mL; P. aeruginosa = 15 μg/mL) and Gram-negative bacteria (B. subtilis = 14 μg/mL; S. aureus = 10 μg/mL) [73].

Additionally, Alshibl et al. (2020) successfully synthesized and tested coumarin derivates and found compound 37d (Scheme 8, Figure 4) to possess the highest IZ at a concentration of 125 μg/mL. The antimicrobial activity, expressed as the diameter (mm) of inhibition zones, for Gram-positive bacteria was S. aureus = 30 mm, B. subtilis = 29 mm, and B. megaterium = 29 mm; for Gram-negative bacteria, the antimicrobial activity was E. coli = 31 mm and P. aeruginosa = 31 mm, and for fungi it was S. cerevisiae = 32 mm and C. albicans = 30 mm [75].

Abduljabbar and Hadi (2021) constructed several coumarin derivatives and tested their antimicrobial activity using the disc-well-diffusion method [77]. The highest activity was demonstrated by compound 45b (Scheme 10, Figure 4), which showed the highest IZs at a concentration of 1000 μg/mL (P. aeruginosa = 22 mm and E. coli = 14 mm).

Other coumarin derivatives were assessed in vitro using the cup plate method for the MIC [79]. Compound 54a (Scheme 12, Figure 4) exhibited the best activity, with promising MIC values for Gram-negative bacteria (E. coli = 40 μg/mL; P. aeruginosa = 30 μg/mL), for Gram-positive bacteria (B. subtilis = 30 μg/mL; S. aureus = 20 μg/mL), and for fungi (A. niger = 30 μg/mL; C. albicans = 40 μg/mL).

The antimicrobial activity of novel 4-anilinocoumarin derivatives was also investigated using the zone inhibition assay/well-diffusion assay [80]. Compound 59h (Scheme 13, Figure 4) showed good activity for Gram-negative bacteria (E. coli = 3.755 ± 0.091 mm; P. aeruginosa = 5.66 ± 0.014 mm) and Gram-positive bacteria (B. subtilis = 5.335 ± 0.021 mm; S. aureus = 6.595 ± 0.021 mm).

The antimicrobial activity screening of coumarin–chalcone hybrids developed by Vazquez-Rodriguez et al. (2015) was examined in vitro for T. maritimum strains [87]. All T. marirtimum strains were highly sensitive to compound 88g (Scheme 20, Figure 4). The MIC and MBC were evaluated in eight of the T. maritimum with the following results: NCIMB 2154—MIC = 62.5 μM, MBC = 62.5 μM; Tm Chile—MIC = 62.5 μM, MBC = 62.5 μM; LP2R—MIC = 62.5 μM, MBC = 125 μM; JIP 31/99—MIC = 15.6 μM, MBC = 15.6 μM; LL01 8.3.8.—MIC = 0.1 μM, MBC = 0.1 μM; LL01 8.3.1—MIC = 0.1 μM, MBC = 0.1 μM; Dba4a—MIC = 0.5 μM, MBC = 1.9 μM; and 3.35—MIC = 1.0 μM, MBC = 1.9 μM.

The coumarin–clubbed chalcone hybrids developed by Konidala et al. (2021) [91] were also evaluated in vitro using the well-diffusion method. Compound 101a (Scheme 24, Figure 5) was the most potent, with an MIC value of 10 μM against a Gram-positive bacterium (Staphylococcus aureus), an MIC value of 8 μM against a Gram-negative bacterium (Escherichia coli), and an antifungal activity MIC value of 10 μM against Aspergillus niger.

Shaikh et al. (2016) synthesized a series of new coumarin–triazole derivatives and tested their antimicrobial activity [94]. Compound 112f (Scheme 27, Figure 5) displayed significant antifungal activity (in comparison to the standard antifungal drug miconazole), with the following MIC values: Candida albicans = 12.5 μg/mL, Fusarium oxysporum = 50 μg/mL, Aspergillus flavus = 50 μg/mL, Aspergillus niger = 25 μg/mL, and Cryptococcus neoformans = 100 μg/mL.

The antimicrobial activity of a series of novel coumarin–triazole hybrids was also investigated. Compound 115d (Scheme 28, Figure 5) exhibited the best activity, with the following MIC values for fungi: Aspergillus Niger = 4 μg/mL, Penicillium Chrysogenum = 4 μg/mL, and Curvularia Lunata = 8 μg/mL. When compound 115d was docked into the active site of the cytochrome P450 lanosterol 14α-demethylase of C. albicans using VLifeMDS 4.3 software, it showed the lowest interaction energy of −72.29 kcal/mol [95].

Shaikh et al. (2016) also successfully synthesized and tested the antimicrobial activity of coumarin–triazole derivates [95]. Compound 118a (Scheme 28, Figure 5) showed excellent inhibitory activity, with MIC values of 8 μg/mL, 4 μg/mL, 4 μg/mL, 2 μg/mL, 2 μg/mL, and 2 μg/mL against Staphylococcus aureus, Micrococcus luteus, Bacillus cereus, Escherichia coli, Pseudomonas fluorescens, and Flavobacterium devorans, respectively.

1,2,3-Triazole 167b (Scheme 37, Figure 5) showed potent inhibition, with MIC values against S. aureus (12.5 ± 0.45 μg/mL), E. coli (25.0 ± 1.20 μg/mL), P. aeruginosa (12.5 ± 0.90 μg/mL), A. niger (25.0 ± 0.65 μg/mL), A. flavus (25. ± 0.65 μg/mL), and C. albicans (12.5 ± 0.60 μg/mL) [104].

The antimicrobial activity of coumarin derivatives containing aminobenzotriazole and triazole moieties indicated compounds 181 and 183 (Scheme 41, Figure 5), with the highest IZs at a concentration of 50 μg/mL. The antimicrobial activity of compounds 181 and 183, expressed as the diameter (mm) of the inhibition zone, is as follows: Gram-positive (Staphylococcus aureus = 15 and 16 mm; Streptococcus aureus = 12 and 14 mm), Gram-negative (Proteus spp. = 7 and 9 mm), and fungi (Aspergillus spp. = 19 and 9 mm; Candida spp. = 22 and 7 mm) [108].

3.3. Anticancer Activity

Weng and Yuan (2017) successfully synthesized and tested two types of coumarin derivatives against a human lung cancer cell line [71]. Among the investigated compounds, compounds 22c and 23c (Scheme 4, Figure 6) exhibited the most potent growth inhibition, with compound 22c showing IC₅₀ values of SK-LU-1 = 20 μM, SPC-A-1 = 20 μM, and 95D = 23 μM and compound 23c showing IC₅₀ values of SK-LU-1 = 20 μM, SPC-A-1 = 21 μM, and 95D = 25 μM.

Fayed et al. (2019) examined the anticancer activity of several coumarin derivatives using an MTT assay. Compound 27 (Scheme 5, Figure 6) displayed significant anticancer activity, with IC₅₀ values of MCF-7 = 2.42 μM, HCT-116 = 6.11 μM, HepG-2 = 13.32 μM, and A549 = 17.21 μM. Docking studies showed that compound 27 fits in the binding pocket of caspase-3, and the binding energy was −6.224 kcal/mol [72].

The coumarin derivatives tested by Zhou et al. (2022) [81] showed compound 62i (Scheme 14, Figure 6) to exhibit the best in vitro activity against lung cancer cell motility via an analysis of invasion assay cells treated with 15 μM of the compound. The values of the Relative Invaded Number (RIN) for each lung cancer cell are as follows: A549 = 0.8, H460 = 0.8, H1650 = 0.75, and H1975 = 0.78.

Ghouse et al. (2023) synthesized 3-substituted coumarin derivatives and examined their anticancer activity using their CA inhibitory potential against the isoforms hCA I, II, IX, and XII [82]. The results showed that compounds 69d and 71b (Scheme 15, Figure 6) exhibited the best K_i values. Compound 69d showed hCA I, K_i > 100 μM; hCA II, K_i > 100 μM; hCA IX, K_i = 5.56 μM; hCA XII, K_i = 9.8 μM, and compound 71b showed hCA I, K_i > 100 μM; hCA II, K_i > 100 μM; hCA IX, K_i = 9.2 μM; and hCA XII, K_i = 8.0 μM. In silico studies revealed key interaction residues of the molecule 71b and confirmed the binding mode and stability of ligand interactions within the binding pockets of the enzymes hCA IX and hCA XII, which were overexpressed in hypoxic cancer cells.

The anticancer activity of coumarin–chalcone hybrids tested by Amin et al. (2013) [84] against a human colon cancer cell line (HCT-116) showed compound 79o (Scheme 16, Figure 6) to exhibit excellent anticancer activity, with an IC₅₀ of 0.01 μM. The investigation was extended for the inhibition of PI3K (P110α/p85α), and the IC₅₀ value was found to be 50.78 μM.

Compound 93k (Scheme 22, Figure 6) also exhibited strong activity, with IC₅₀ values against H4IIE (IC₅₀ = 1.62 ± 0.57 μM), HepG2 (IC₅₀ = 8.212 ± 1.14 μM), and CHO (IC₅₀ = 21.490 ± 3.22 μM) [89].

Pavić et al. (2021) tested novel coumarin–chalcone hybrids in vitro against human cancer cell lines. Compound 107b (Scheme 26, Figure 7) was the most active, with IC₅₀ values of HepG-2 = 19.5 ± 1.5 μM; SW620 = 20.8 ± 0.4 μM; HCT116 = 4.7 ± 0.6 μM; MCF-7 = 6.9 ± 0.7 μM; and Hek293T > 50 μM [93].

A new class of coumarin–triazole compounds developed by Sinha et al. (2016) were evaluated for anticancer activity via an MTT bioassay. Compound 124d (Scheme 29, Figure 7) showed the highest potency and selectivity in all the tested cancer cell lines, with IC₅₀ values of HeLa = 17.5 ± 1.22 μM, MCF-7 = 9.83 ± 0.69 μM, and MRC-5 = 185.22 ± 1.65 μM [96].

Similarly, a series of coumarin–triazole derivatives were synthesized and evaluated as anticancer agents against a human colorectal cancer cell line by Al-Wahaibi et al. (2018) [97]. The compounds 129c and 133c (Scheme 30, Figure 7) exhibited marked cytotoxic activity, with IC₅₀ values of 4.363 μM and 2.656 μM, respectively.

Among several compounds developed by Vagish et al. (2021), coumarin–chalcone 174c (Scheme 39, Figure 7) was found to show higher potency against the PC-3, DU-145, and COX-2 cell lines with IC₅₀ values of 10.538 ± 0.3 μM, 9.845 ± 0.6 μM, and 32.450 ± 0.18 μM, respectively [106].

The anticancer activity of coumarin–1,2,3–triazole–glucoside hybrids was evaluated against liver cancer using an MTT assay liver cancer [109]. The highest activity was demonstrated by compound 189 (Scheme 42, Figure 7) with an IC₅₀ value of 106.81 μg/mL.

Among the chalcone–coumarin hybrids developed by Pingaew et al. (2014), compound 201b (Scheme 45, Figure 6) possessed the highest anticancer activity against HuCCA-1, HepG2, A549, and MOLT-3, with IC₅₀ values of 11.13 ± 0.40 μM, 15.70 ± 2.00 μM, 31.40 ± 1.00 μM, and 5.16 ± 0.69 μM, respectively [112]. Molecular docking was also performed to investigate the binding of the ligands to potential targets. The highest binding energy was found to be −9.6 kcal/mol.

3.4. Antidiabetic Activity

Among the coumarin derivatives developed by Xu et al. (2020), compound 33b (Scheme 7, Figure 8) showed the strongest α-glucosidase inhibition with an IC₅₀ value of 12.98 μM [74].

Among the coumarin–chalcone derivatives developed by Hu et al. (2022) as α-glucosidase inhibitors, compound 102t (Scheme 25, Figure 8) displayed the highest IC₅₀ value of 24.09 ± 2.36 μM [92].

Coumarin-tethered 1,2,3-triazole analogues developed by Vagish et al. (2021) showed variable in vitro α-amylase inhibition activities [106]. Compound 174g (Scheme 39, Figure 8) showed potent α-amylase inhibition with an IC₅₀ value of 4.11 μM. The molecular docking of compound 174g using α-amylase showed docking score of −5.60 kcal/mol.

The antidiabetic activity screening of coumarin–triazole hybrids developed by Basappa et al. (2020) revealed compound 179c (Scheme 40, Figure 8) to exhibit potent inhibition of α-amylase with an IC₅₀ value of 5.43 μM. [107].

3.5. Anti-Cholinesterase Activity

Mzezewa et al. (2021) examined 3,7-substituted coumarin derivatives as inhibitors of monoamine oxidase (MAO) and cholinesterase enzymes [78]. Compound 50 (Scheme 11, Figure 9) inhibited MAO-A (IC₅₀ = 3.86 μM), MAO-B (IC₅₀ = 0.029 μM), AChE (IC₅₀ = 108 μM), and BuChE (IC₅₀ = 105 μM). In silico studies using the SwissADME tool predicted that compound 50 could have acceptable pharmacokinetic and drug-likeness properties.

The coumarin–triazole hybrids developed by De Sousa et al. (2021) were also evaluated for anti-cholinesterase activity via the inhibition of acetylcholinesterase [105]. Compound 169 (Scheme 38, Figure 9) showed an inhibitory activity of 17.25 ± 1.56% at 50 μmol/L.

The coumarin–triazole hybrids developed by Sharma and Bharate (2023) [111] were screened for their inhibition of ChEs and BACE-1. The most active compound, 196b (Scheme 44, Figure 9), inhibited acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase-1 (BACE-1) with IC₅₀ values of 2.57, 3.26, and 10.65 μM, respectively.

3.6. Anti-Inflammatory Activity

Alshibl et al. (2020) developed coumarin derivatives and examined their anti-inflammatory activity [75]. Compound 37c (Scheme 8, Figure 10) showed a proteinase-inhibitory activity of 41.69 ± 2.83%. It also showed 9.45% inhibition (at 2.5 mg/kg) for a prophylactic anti-inflammatory effect on formaldehyde-induced rat paw edema. It exhibited IC₅₀ values of 15.40 μM for COX-1 and 11.90 μM for COX-2. Molecular docking predicted binding affinity between compound 37c and human COX-2 isozyme at −7.3 kcal/mol.

Coumarin derivatives such as compound 42d (Scheme 9, Figure 10) suppressed the release of TNF-α and exhibited favorable inhibitory activity at a concentration of 10 μM against COX-1 (38.84 ± 5.17% inhibition) and COX-2 (35.71 ± 4.01% inhibition) [76]. Furthermore, at a dose of 20 mg/kg, compound 42d effectively reduced ear swelling with 41.43% inhibition.

Coumarin–triazole derivatives assessed in vitro by estimating the pro-inflammatory cytokine TNF-α in an LPS-stimulated U937 cell line showed compound 147d (Scheme 33, Figure 10) to significantly inhibit TNF-α at a 10 μM concentration, with 62.03 ± 0.28% inhibition and an IC₅₀ value of 8.01 ± 0.03 μM [100].

3.7. Miscellaneous Activity

Chen et al. (2014) synthesized new coumarin derivatives as potential atypical antipsychotics [68]. Compound 6u (Scheme 1, Figure 11) showed a high affinity for the dopamine D₂ and D₃ receptors and serotonin 5-HT_1A and 5-HT_2A receptors, with low affinity for the H₁ receptor (D₂, K_i = 12.7 nM; D₃, K_i = 13.6 nM; 5-HT_1A, K_i = 7.8 nM; 5-HT_2A, K_i = 2.2 nM; H₁, K_i = 1825.3 nM).

Coumarin–chalcone derivatives developed by Rodríguez (2015) were tested against the epimastigote, trypomastigote, and amastigote stages of the T. cruzi parasite [86]. The results indicated that compound 85d (Scheme 19, Figure 11) was the most potent trypanocidal agent, with IC₅₀ values at different parasite stages as follows: Epimastigote = 46.8 ± 3.7 μM; Trypomastigote = 2.6 ± 0.2 μM; and Amastigote = 2.9 ± 0.1 μM. The IC₅₀ values in mammalian cell lines were as follows: RAW 264.7 = 6.1 ± 0.5 μM; VERO = 56.8 ± 5.4 μM.

The potential antitubercular activity of coumarin–triazole derivatives was investigated against MTB H37Ra (ATCC 25177) by Shaikh et al. (2016) [95]. Compound 115f (Scheme 28, Figure 11) exhibited interesting and highly promising antitubercular activity (MIC = 1.80 μg/mL). Compound 115f was reported to inhibit the DprE1 enzyme of MTB and has the most active binding mode in the active site of the DprE1 enzyme.

N. Yadav et al. (2018) successfully synthesized a series of novel coumarin–triazole derivatives as antiplasmodials [101]. The compounds were evaluated for in vitro antiplasmodial activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7). Compound 151i (Scheme 34, Figure 11) was found to be the most active, with an IC₅₀ value of 0.763 ± 0.0124 μg/mL.

A series of novel coumarin hydrazides were investigated against porcine pancreatic lipase by Yilmaz and Faiz (2018) [102]. Compound 158n (Scheme 35, Figure 11) showed the highest activity among the synthesized compounds, with 46.31 ± 3.55% pancreatic lipase inhibition at 10 μM.

Pingaew et al. (2014) developed chalcone–coumarin hybrids and evaluated their antimalarial activity against Plasmodium falciparum [112]. Compound 201d (Scheme 45, Figure 11) proved to be the most potent compound (IC₅₀ = 1.60 μM). The results of an in-silico study with falcipain-2, a cysteine protease from P. falciparum, showed a binding energy of −8.1 kcal/mol.

4. Conclusions and Prospective

Herein, we reviewed recent trends (2013–2023) in the synthesis and bioactivity of coumarin, coumarin–chalcone molecular hybrids, and coumarin–triazole molecular hybrids. The chemistry to synthesize these compounds was enabled by several established reactions including Pechmann condensation, Claisen–Schmidt condensation, and azide–alkyne cycloaddition reactions. The synthesized compounds showed diversity in their structures in terms of substituent types, substitution pattern, and the fusion/attachment point to coumarin. The reactions proceeded in a few steps under mild conditions and usually gave good-to-excellent yields. A wide range of bioactivities including antioxidant, antimicrobial, anticancer, antidiabetic, and anti-cholinesterase activities were also reviewed. Although some structure–activity studies (SAR) have been presented in some cases, extensive SARs are lacking in the literature. Additionally, though significant progress was made in synthesis and bioactivity screening, the mechanism of action remains to be investigated in detail. Several questions need to be addressed: do the hybrids interact with the known receptors of one or both chromophores or do they target new receptors? How does the synergistic effect take place? An understanding of this mechanism is critical for optimizing the structures of the hybrids to deliver optimum synergistic effects. The development of molecular hybrids continues to be an active and dynamic field with potential future prospects in medicinal chemistry and health science. It is our hope that these compounds will be useful for the treatment of various diseases.