Coumarin Triazoles as Potential Antimicrobial Agents

Currently, in hospitals and community health centers, microbial infections are highly common diseases and are a leading cause of death worldwide. Antibiotics are generally used to fight microbial infections; however, because of the abuse of antibiotics, microbes have become increasingly more resistant to most of them. Therefore, medicinal chemists are constantly searching for new or improved alternatives to combat microbial infections. Coumarin triazole derivatives displayed a variety of therapeutic applications, such as antimicrobial, antioxidant, and anticancer activities. This review summarizes the advances of coumarin triazole derivatives as potential antimicrobial agents covering articles published from 2006 to 2022.


Introduction
In the modern drug discovery era, the design and development of new antimicrobial drugs are receiving great attention from the research community due to the emergence of multidrug-resistant strains (MDRs) in recent years [1][2][3][4]. MDRs pose a serious health threat to the global population and are frequently associated with increased healthcare costs and prolonged hospital stays [5]. Even though recent advances have improved our understanding of the pathogenesis of antimicrobial infection, scientists have become increasingly focused on discovering novel, more effective, and safe drug Candidates to overcome MDRs. In recent years our research lab has been actively involved in the design and development of new bioactive molecules to tackle MDR strains [6][7][8][9][10][11][12][13][14].
Coumarin pharmacophore has been considered the most ideal small-molecule scaffold for the development of new drugs because of its drug-like properties and, more significantly, its association with innumerable pharmacological activities. Coumarin pharmacophore is part of several clinically used drug Candidates, including some well-known antibiotic drugs ( Figure 1A). Our lab recently comprehensively reviewed the medicinal applications of pharmacologically important coumarins [15,16].
Triazole, also recognized as pyrrodiazole, is a five-membered nitrogen heterocycle with two carbon and three nitrogen atoms. Triazole exists in two isomeric forms-1,2,3-triazole (II) and 1,2,4-triazole (III)-based on the positions of the nitrogen atoms in the five-membered ring system ( Figure 2). Triazole analogs have greatly attracted biologists and chemists alike due to their wide applications in medicinal chemistry with numerous biological activities [17][18][19][20]. Triazole moiety is part of several clinically used drugs for the treatment of various illnesses such as cancer, diabetes, etc. Some notable antimicrobial drugs have been listed in Figure 1B. treatment of various illnesses such as cancer, diabetes, etc. Some notable antimicrobial drugs have been listed in Figure 1B. The combination of two or more clinical drugs to achieve higher efficacy and greater clinical benefits is becoming the new normal in clinical trials. Thus, combinatorial therapies are becoming a very important part of the clinical trial process to achieve success in patient well-being. Keeping this in mind, drug discovery researchers are planning to combine two or more drug functionalities in a single molecule to obtain synergistic effects or to enhance the particular pharmacological effects of drug Candidates. Considering the pharmacological importance of both coumarins and triazoles, medicinal chemists have worked to develop new small-molecule drugs by combining coumarin (I) and triazole moieties (II or III) to generate more effective drugs (IV and V) ( Figure 2).  The combination of two or more clinical drugs to achieve higher efficacy and greater clinical benefits is becoming the new normal in clinical trials. Thus, combinatorial therapies are becoming a very important part of the clinical trial process to achieve success in patient well-being. Keeping this in mind, drug discovery researchers are planning to combine two or more drug functionalities in a single molecule to obtain synergistic effects or to enhance the particular pharmacological effects of drug Candidates. Considering the pharmacological importance of both coumarins and triazoles, medicinal chemists have worked to develop new small-molecule drugs by combining coumarin (I) and triazole moieties (II or III) to generate more effective drugs (IV and V) ( Figure 2). The combination of two or more clinical drugs to achieve higher efficacy and greater clinical benefits is becoming the new normal in clinical trials. Thus, combinatorial therapies are becoming a very important part of the clinical trial process to achieve success in patient well-being. Keeping this in mind, drug discovery researchers are planning to combine two or more drug functionalities in a single molecule to obtain synergistic effects or to enhance the particular pharmacological effects of drug Candidates. Considering the pharmacological importance of both coumarins and triazoles, medicinal chemists have worked to develop new small-molecule drugs by combining coumarin (I) and triazole moieties (II or III) to generate more effective drugs (IV and V) ( Figure 2).
From the literature, we observed increased antimicrobial activities by the insertion of a triazole ring into the various organic core molecules. Most of the existing antimicrobial drugs hold triazole pharmacophore in their elemental structures, which proves the antimicrobial Antibiotics 2023, 12, 160 3 of 29 potencies of the triazole template so that it expresses significant antimicrobial activity. From the in silico studies, it is evident that the enzyme forms hydrogen bonding interactions with the triazole ring along with coumarin moiety. Since both lactone (coumarin) and triazole are bioactive pharmacophores, the new hybrid molecule with these two bioactive species will be with increased effects evaluated in comparison to the parent drug.
The present article covers the antimicrobial activities of the combined coumarin and triazole analogs published to date and serves to further advance the drug design and development process of coumarin-bearing triazoles as possible new drug Candidates to overcome the effects of the MDR strains.

Antibacterial and Antifungal Activities of Coumarin Triazole Derivatives
In 2006, M. Cacic et al. reported the first example of a C4-triazole-substituted coumarin 1 ( Figure 3) together with its antibacterial activity [21]. Examination of the antimicrobial activity of 1 indicated high antimicrobial activity against S. pneumoniae, and it was slightly less active against P. aeruginosa, B. subtilis, B. cereus, and S. panama. The authors did not report the exact values of antimicrobial activity data and concluded their results with a generalized viewpoint. Furthermore, they noted that the research was in progress. A year later, Jayashree et al. reported the synthesis, characterization, and antimicrobial activity of twelve C-3-substituted triazolo-thiadiazinyl coumarin derivatives 2a-l from salicylaldehyde as a starting material ( Figure 3) (Table 1) [22]. The antibacterial screening demonstrated that compounds 2a, 2b, and 2c had a comparable activity with the standard antibiotics (amoxicillin and gentamycin) against two species of Gram-positive bacteria (B. subtilis and S. aureus) and three species of Gram-negative bacteria (E. coli, K. pneumoniae, and P. aeruginosa). Overall, aryl substitution has improved the antimicrobial activity compared to their corresponding heteroaryl analogs. Compound 2a displayed a 38 mm zone of inhibition (ZoI) toward B. subtilis, 35 mm (K. pneumoniae), and 32 mm (S. aureus and E. coli). Their most active compound, 2b, exhibited the ZoI toward S. aureus (43 mm), B. subtilis, K. pneumoniae, P. aeruginosa (42 mm), and E. coli (40 mm).
In 2011, the synthesis and in vitro antimicrobial evaluation of two series of coumarinmono-and bis-triazoles derivatives 7a-f and 8a-f were reported by Y. Shi and C. H. Zhou ( Figure 3) (Table 1) [27]. Particularly, bis-triazole 8a and its hydrochloride 8e gave the most potent antimicrobial efficacy (MIC = 1-4 µg/mL) against four Gram-positive bacteria (S. aureus ATCC 25923, (MRSA), B. subtilis ATCC 6633, and M. luteus ATCC 4698), four Gram-negative bacteria (E. coli ATCC 25922, P. vulgaris ATCC 6896, S. typhi ATCC 9484 and S. dysenteriae ATCC 49550); as well as three fungi (C. albicans ATCC 76615, S. cerevisiae ATCC 9763, and A. fumigatus ATCC 96918). Other mono-triazole compounds 7a-c, bis-triazole 8a-c, hydrochloride mono-triazole 7e-f, and hydrochloride bis-triazole 7e-f showed comparable or superior anti-MRSA activity than the clinical antibacterial drugs enoxacin (MIC = 1-4 µg/mL) and chloromycin (MIC = 4-16 µg/mL). Compounds 7a, 8a, and 8e exhibited comparable antifungal potency against C. albicans and S. cerevisiae (MIC = 2-4 µg/mL) than the positive control fluconazole (MIC = 1-2 µg/mL) and showed strongest inhibition toward A. fumigatus (MIC = 2-48 µg/mL), whereas fluconazole gave MIC = 128 µg/mL. In conclusion, the alkyl linker has provided better activity compared to the phenyl linker in both monomers as well as dimear triazolo-coumarins. In general, coumarin-bis-triazoles 7 exhibit stronger antimicrobial efficiency compared to their corresponding mono-triazole derivatives 8. The authors pointed out that water-soluble hydrochloride salts have shown stronger antibacterial and antifungal efficacy in comparison with their corresponding poor water-soluble triazole precursors. They postulated that the conversion of triazoles into their hydrochlorides could modulate the lipid/water partition coefficient, affect their diffusion in bacterial cells, as well as interact with bacterial cells and tissues. Thus, water-soluble salts might improve the pharmacological properties of these new triazole analogs. They assume that further studies will help to understand the mechanism of actions of these derivatives.
The microwave-aided synthesis of dimers of ten distinct coumarin-1,2,3-triazoles containing an alkyl spacer (35a-j) was reported by Ashok et al. in 2018 [45] (Figure 6). The synthesized compounds were screened for their antimicrobial activity against two Grampositive strains, B. subtilis (ATCC 6633) and S. aureus (ATCC 6538), two Gram-negative strains, E. coli (ATCC 11229) and P. vulgaris (ATCC 29213), and two fungal strains, A. niger (ATCC 9029) and C. albicans (ATCC 10231). The compound 35j showed MIC values of 3.125-6.25 µg/mL and 12.5 µg/mL, four bacterial and two fungal strains, respectively. The compound 35j was discovered to be more effective than the other investigated compounds against the tested bacterial and fungal strains. Except for compound 35j, compounds 35e and 35i demonstrated modest activity against bacterial strains with MIC values of 6.25-12.5 µg/mL. Compounds 35d, 35e, and 35i displayed better antifungal activity with MIC values of 12.5-25 µg/mL. Coumarin-triazoles with alkyl linker (n = 6 and 8) have produced comparable antibacterial (35e and 35i) as well as antifungal activity, indicating that the long linker could have played a role in getting the desired activity. López-Rojas et al. [46] reported a series of coumarin-1,2,3-triazole derivatives with diverse alkyl, phenyl, and heterocycles at C-4 of the triazole nucleus via copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction (36a-m and 37a-m) ( Figure 6) ( Table 4). The antibacterial activity of each molecule was evaluated against Gram-positive bacteria, B. subtilis, S. aureus, and E. faecalis, Gram-negative bacteria, E. coli, P. vulgaris, K. pneumonia, P. aeruginosa, and the fungus C. albicans for antifungal activity. Compounds 36a, 36b, 36f, 37h, and 37k exhibited potential activity against E. faecalis at MICs ranging from 2.5 to 50.0 µg/mL. The most effective compound was found to be 36b, with the 2-OMe-Ph group linked to the triazole nucleus and an OCH 2 linker. In contrast, the comparable isoster 37b (-NHCH 2 -) was found to be 64-fold less active than 36b. Subsequently, compounds 36c (3-OMe-Ph) and 36d (4-OMe-Ph) had 8-and 16-fold less antibacterial activity than 36b, respectively. The location of the OMe group on the phenyl ring also plays a significant influence on the activity. In order to be a successful antimicrobial drug Candidate, it should display the least toxicity toward normal cells. The authors evaluated the active compounds 36a, 36b, 36f, 37h, and 37k for toxicity (hemolytic activity) against human erythrocytes, and all tested compounds demonstrated low toxicity toward human erythrocytes.  In 2018, Savanur et al. [47] established new series of coumarin, quinolinone, and benzyl-linked 1,2,3-triazole derivatives (38a-b, 39a-k, 40a-g, 41a-f) via click chemistry, as portrayed in Figure 6, and subjected the molecules to antimicrobial studies. Synthesized coumarin-triazole compounds were screened for antibacterial studies against Grampositive bacteria, E. coli (NCIM 5346), P. aeruginosa (NCIM 5514), and B. bronchiseptica (NCIM 5346), and Gram-negative bacteria, S. aureus (NCIM 5345), B. subtilis (NCIM 2920), and (NCIM 5346) ( Table 4). With a MIC of 1.0 µg/mL, compound 39j with chloro and methoxy substitution on coumarin was extremely effective against S. aureus and P. aeruginosa. Additionally, compound 39j exhibited excellent activity with MICs of 8.0 µg/mL, 16 µg/mL, and 16 µg/mL against B. subtilis, B. cereus, and B. bronchiseptica, respectively. Apart from compound 39j, compounds 40g (chloro substitution at C-6 on coumarin and 1-azacoumarin) and 41f (chloro-substituted triazoles with benzyl group) demonstrated excellent activity against S. aureus with MICs of 1.0 µg/mL, which is comparable to the standard dose of ciprofloxacin (1.0 µg/mL). Further, the molecules tested for their antifungal assay against eight Candida fungal strain species (yeast specimens), included C. albicans, C. tropicalis, C. utilis, C. krusei, and Aspergillus species (filamentous fungi), such as A. fumigatus, A. niger, R. oryzae, and R. bataticola. Of all the compounds tested, 39i and 39j (with chloro and methoxy substitution) were highly active with MIC 1.0 µg/mL against Candida species. Compound 39e was excellent with MICs of 1.0 µg/mL and MIC of 2.0 µg/mL against C. krusei and C. albicans, respectively. Furthermore, 40f, a quinolinone analog with methyl substitution, was found to be a highly-active compound against C. albicans, C. utilis, and C. krusei with MICs 1.0 µg/mL, 2.0 µg/mL, and 4.0 µg/mL, respectively. Additionally, the same compound (40f) was also found to be very active against A. niger with MIC of 1.0 µg/mL. The in silico analysis showed that the active compounds (39f and 39h) bind to the active sites of the two antifungal target proteins (1FI4 and 3LD6). Interestingly, compound 39h showed the highest binding affinity (−11.0 kcal/mol) toward 1FI4, whereas 39f displayed favorable interaction (−12.5 kcal/mol) toward 3LD6. The authors believe that these compounds represent a new platform for antimicrobial activity and could be further optimized therapeutically. In 2018, Savanur et al. [47] established new series of coumarin, quinolinone, and benzyl-linked 1,2,3-triazole derivatives (38a-b, 39a-k, 40a-g, 41a-f) via click chemistry, as portrayed in Figure 6, and subjected the molecules to antimicrobial studies. Synthesized coumarin-triazole compounds were screened for antibacterial studies against Gram-positive bacteria, E. coli (NCIM 5346), P. aeruginosa (NCIM 5514), and B. bronchiseptica (NCIM   Kolichala et al. [48] reported the regioselective synthesis and antibacterial activity of 6-[(l-ethyl-lH-l,2,3-triazol-4-yl)methoxy]-4-methyl-2H-chromen-2-ones (42a-l), as depicted in Figure 6 ( Table 4). The disclosed compounds were examined using the paper disc technique against the bacterial strains E. coli (Gram-negative) and S. aureus (Gram-positive). According to the authors, each analog exhibited good to moderate activity. The compounds  42b, 42e, 42f, 42g, 42i, 42h, and 42l among the studied compounds showed relatively moderate to exceptional activity (MIC range 8-32 µg/mL), but they did not compare standard drugs in this study. Chityala et al. [49] reported the synthesis and antibacterial activity of coumarin-1,2,3-triazoles (43a-c) ( Figure 6) ( Table 4). The compounds were evaluated for antibacterial assay against bacterial strains E. coli, K. pneumonia, P. aeruginosa, S. aureus, and S. pyogenes. Compounds 43a-c portrayed excellent results, as confirmed by their MIC values ranging from 5.5-17.5µg/mL. PEG-400 was used as an environmentally acceptable catalyst by Shaikh et al. [50] to explain the synthesis and antibacterial activity of a series of substituted coumarin-1,2,4-triazolidine-3-thiones 44a-i ( Figure 6). Grampositive (S. aureus, B. subtilis), Gram-negative (E. coli, P. aeruginosa), and four fungus strains (C. albicans, A. niger, A. flavus, and A. fumigatus) were used to assess the antibacterial activity of all the adducts. Excellent antibacterial activity was revealed by compounds 44a, 44b, 44c,  44h, 44i, 44a, and 44b against S. aureus, B. subtilis, and E. coli strains with MICs ranging from 0.8 to 1.6 µg/mL. All the tested substances had a mediocre effect on the P. aeruginosa bacterial strain. To elucidate the interaction mechanism of these compounds with target proteins, authors performed molecular docking studies and identified the target protein of E. coli FabH (Fatty acid biosynthesis, enzyme H). The compound 44d docked well, and three important hydrogen bonding interactions were shown (PDB ID 1HNJ) in this study.
Bhagat et al. [51] synthesized a library of indolinedione-coumarin hybrids 45a-g, 46a-g, and 47a-g ( Figure 6) ( Table 4). All the synthesized hybrid molecules were screened for antibacterial assay against two Gram-positive bacteria (S. aureus, M. smegmatis) and two Gram-negative bacteria (E. coli, S. enteric). Among these tested microorganisms, S. aureus was the most sensitive, and E. coli was the most resistant one. Among all the compounds (45a-g) tested, 45b arose as the most potent one with ZoI of 2.5 and 1.3 cm for bacterial strains, S. aureus and S. enteric, respectively. Additionally, compounds 45a-g were tested for antifungal studies against four fungal strains (C. albicans, A. mali, Penicillium sp., and F. oxysporum). Of all the molecules, 45a (ZoI 2.5 cm) and 45b (ZoI 1.3 cm) exhibited excellent antifungal activity for the fungal strain Penicillium sp. The molecular docking studies revealed the probable mechanism of action of these analogs. The docking studies displayed binding interactions of 45b within the catalytic active site of S. aureus DHFR. This potent indolinedione-coumarin hybrid 45b could be further developed as an antimicrobial agent.
From copper(I)-catalyzed click reaction between various substituted terminal alkynes and arylazides, coumarin-based 1,4-disubstituted 1,2,3-triazoles [65a-l] (Figure 8) were synthesized through microwave irradiation [54]. All the prepared compounds were screened for their antibacterial potential against S. aureus, E. coli, B. subtilis, and K. pneumonia at concentrations of 10 µg mL −1 and 20 µg mL −1 , respectively. Amongst all the newly prepared coumarin triazoles, 65a (32 mm), 65d (32 mm), 65g (34 mm), and 65j (34 mm) were highly active toward E. coli because of the presence of the methoxy group in the triazole ring. Furthermore, compounds 65k (26 mm) and 65l (27 mm) have demonstrated nearly similar activity to that of the standard drug gatifloxacin (30 mm). Synthesized compounds [65a-l] were also screened for their in vitro antifungal potential through three fungal organisms such as A. flavus, F. sporum, and A. niger, at a concentration of 50 µg mL −1 , and the results with ZoI range from 10.3mm to 18.8mm and have been mostly comparable to the standard drug Clotrimazole (Table 5). It was noticed that among all the prepared compounds, 65a, 65b, 65c, 65j, 65k, and 65l exhibited good activity through three pathogenic fungi due to the presence of fluorine and methoxy groups on coumarin and triazole rings. The remaining compounds displayed comparable activity to Clotrimazole as a standard drug. In this series of compounds, the chloro and bromo halogens, along with the methoxy substitutions on both phenyl rings, seem to be important for obtaining comparable antimicrobial activity. Singh et al. reported the synthesis and antimicrobial evaluation of a series of new coumarin-tagged β-lactam triazole hybrids [66a-o] [55] (Figure 8). Antimicrobial activity studies concluded that compounds containing chloro and methyl groups (66c and 66i) exhibited moderate antimicrobial activity toward P. aeruginosa (18.97% inhibition at 32 µg/mL) and C. albicans (21.65% inhibition at 32 µg/mL) strains, respectively. Conversely, all the screened compounds were found to be less active than the standard drugs, such as Colistin and Vancomycin for bacterial and Fluconazole for fungal strains (Table 5). From copper(I)-catalyzed click reaction between various substituted terminal alkynes and arylazides, coumarin-based 1,4-disubstituted 1,2,3-triazoles [65a-l] (Figure 8) were synthesized through microwave irradiation [54]. All the prepared compounds were screened for their antibacterial potential against S. aureus, E. coli, B. subtilis, and K. pneumonia at concentrations of 10 μg mL −1 and 20 μg mL −1 , respectively. Amongst all the newly prepared coumarin triazoles, 65a (32 mm), 65d (32 mm), 65g (34 mm), and 65j (34 mm) were highly active toward E. coli because of the presence of the methoxy group in the triazole ring. Furthermore, compounds 65k (26 mm) and 65l (27 mm) have demonstrated    (Figure 8) under microwave irradiation and evaluated their antimicrobial activity (Table 5) [56]. The coumarins linked with 1,2,3-triazoles (67k) (5 µg/mL MIC) and (67g) (10 µg/mL MIC) revealed good antibacterial activity compared with the standard drug Ciprofloxacin (0.2 µg/mL MIC) against all the tested bacteria. Additionally, 67n (150 µg/mL MIC) displayed better antifungal activity compared to other prepared coumarins linked with 1,2,3-triazoles but was not promising when compared with the standard drug fluconazole (20 µg/mL MIC). A series of new 1,2,3-triazole-tethered coumarin conjugates [68a-g and 69a-g] (Figure 8) (Table 5) were prepared via the click chemistry approach in excellent yields and screened for their antifungal activity toward five fungal strains such as C. albicans, F. oxysporum, A. flavus, A. niger and C. neoformans [57]. Furthermore, 1,2,3-triazole-tethered coumarin conjugates 68b, 68d, 68e, 69b, and 69e demonstrated excellent antifungal activity with MIC values ranging from 12.5 to 25 µg/mL compared with the standard drug miconazole with lower MIC values. The molecular docking studies of novel triazole-coumarin conjugates disclosed that they have a high affinity toward the active site of enzyme P450 cytochrome lanosterol 14α-demethylase. This docking study offers a new platform for the structurebased drug design development for antimicrobial agents. Kalkhambkar et al. reported the antimicrobial activity of coumarin-and 1-azacoumarin-linked triazoles against four bacterial and six fungal microorganisms [58]. Among them, chloro-substituted coumarin (70c) (4 µg/mL MIC) and azacoumarin (70b) (16 µg/mL MIC) compounds exhibited the highest antibacterial activity toward S. aureus. On the other hand, methyl (71b) (4 µg/mL MIC) and bromo-substituted coumarin (70g) (6 µg/mL MIC) demonstrated better antifungal activity against C. utills and C. krusei, whereas dimethyl-substituted azacoumarins (70f and 71g) (1.0 µg/mL MIC) exhibited comparable antifungal activity toward C. albicans compared to standard drugs Itraconazole and Miconazole. The design and synthesis of three new 3-arylcoumarin derivatives (72a-b and 73) (Figure 8) were reported by Pavic et al. [59]. In addition, antibacterial activity studies were done against Gram-positive bacteria, three S. aureus strains, including methicillin-resistant S. aureus (MRSA), E. faecium, and L. monocytogenes, Gram-negative bacterial strain P. aeruginosa, and four Candida species including C. albicans, C. glabrata, C. krusei and C. parapsilosis. Unfortunately, all three new 3-arylcoumarin derivatives (72a,b, and 73) are virtually inactive against the pathogens.
Uracil-coumarin hybrids (74a-g) ( Figure 9) were screened for their antibacterial activities against a panel of drug-susceptible and drug-resistant Gram-negative and Grampositive pathogens (Table 6). Antibacterial activities resulted in two lead molecules, 74b, the fluoro substitution on a pyrimidine-dione ring (MIC = 11.7 µg/mL) and 74c, the chloro substitution on a pyrimidine-dione ring (MIC = 7.23 µg/mL), which were found comparable to that of standard drug Levofloxacin's MIC value of 3.12 µg/mL [60]. A series of new benzoxazole-coumarin-linked 1,2,3-triazoles (75a-p) (Figure 9) ( Table 6) were prepared from conventional as well as microwave irradiation methods in good purity and yields and were studied for their antibacterial activity toward panel of Gram-positive and Gram-negative bacteria [61]. The benzoxazole-coumarin-linked 1,2,3-triazoles 75m and 75o displayed excellent antimicrobial results for all tested microorganisms at MICs ranging from 3.12 to 6.25 µg/mL in comparison with the marketed drugs. The antimicrobial activity results demonstrated that the compounds 75m and 75o highlighted the importance of the presence as well as the position of the methyl group. The antimicrobial activity of coumarin-tethered 1,2,3-triazoles (76a-i) was evaluated toward a panel of pathogenic microorganisms, including the bacterial pathogens E. coli, B. subtilis, S. aureus, and fungal stains A. niger, A. flavus and C. albicans by Kariyappa et al. Antimicrobial results indicate that the prepared coumarin-tethered 1,2,3-triazoles (76a-i) (Figure 9) showed medium to good antimicrobial activities with MIC values of 6.5-75.0 µg/mL toward bacteria and 12.5-100.0 µg/mL against fungal species. The results, which were comparable with the standard drugs, employed ciprofloxacin (12.5-25.0 µg/mL) against bacteria and nystatin (25.0-50.0 µg/mL) toward fungi [62]. Narkhede et al. reported the preparation and antimicrobial activity of coumarin triazole derivatives (77a-e) (Figure 9) ( Table 6). All coumarin triazole derivatives (77a-e) displayed around 44-51% inhibition against E. coli and S. aureus, whereas they did not show any activity toward S. typhi. It should be noted that antifungal data revealed that compounds 77c and 77d established the broadest spectrum of inhibitory activity (74.07% and 66.66%) toward A. flavus. The remaining coumarin triazole derivatives 77c, 77d, and 77e are inactive against C. albicans; 77a and 77b were inactive against A. flavus [63].   Undesirably, all 3-(1,2,3)-trazolyl-coumarin derivatives [78a-w] had MICs higher than 128 µg/mL against all tested bacterial species (Table 6). In 2022, Kamble et al. reported the synthesis of a series of new triazolothiadiazine-coumarin hybrid derivatives (79a-n) ( Figure 9) through a green and versatile synthetic route using agro waste extract WELPSA catalyzed cyclocondensation [65]. All the synthesized compounds were screened in vitro for their antifungal activity against three pathogenic fungi strains viz., A. niger, C. albicans, and P. citranum. New triazolothiadiazine-coumarin hybrid derivatives 79a (14 mm), 79d (12 mm), 79f (16 mm), 79j (15 mm), and 79m (11 mm) are good inhibitors for A. niger, whereas 79a (16 mm), 79g (14 mm), and 79m (14 mm) are respective inhibitors for C. albicans, and compounds 79b (10 mm), 79d (12m m), and 79e (11 mm) are decent inhibitors for P. citranum ( Table 6). The remaining compounds have displayed hopeful results suggesting that triazolothiadiazine-coumarin hybrid analogs could be further developed as promising drug Candidates.  In the same year, synthesis and antimicrobial activity of a novel class of 4-[(40hydroxymethylphenyl)-1H-10,20,30-triazol-1-yl-methyl]-2H-chromen-2-ones (80a-j) ( Figure 9) were reported from Suresh et al. [66]. The investigation of the antimicrobial activities of the prepared coumarinyl-derivatives (80a-j) toward three Gram-positive bacterial strains, S. aureus, B. subtilis, M. luteus, and three Gram-negative bacterial strains, E. coli, K. pneumonia, P. aeruginosa, were carried out ( Table 6). Few of the coumarin derivatives exhibited medium to good activity with MIC values ranging from 9.3-37.50 µg/mL in DMSO. However, compounds 80f (9.3 mm, 9.3 mm, 18.75 mm, and 9.3), 80g (18.75 mm, 9.3 mm, 9.3 mm, and 18.75 mm), and 80h (18.75 mm, 9.3 mm, 9.3 mm, and 18.75) displayed great activity against S. aureus, B. subtilis, M. luteus, and E. coli, respectively. This could be due to the existence of the t-butyl group/aromatic rings in the compounds 80f, 80g, and 80h. The prepared compounds (80a-j) were also subjected to antifungal activity to determine their zone of inhibition. The antifungal activities have been completed with A. fumigatus, T. vivide, C. lipolytic, and A. niger. The coumarinyl derivatives 80f (18 mm, and 18 mm), 80g (20 mm, and 19 mm), and 80h (20 mm, and 18 mm) are highly active toward the fungal strains A. fumigatus and T. vivide, respectively. However, medium activity was observed toward the other strains, C. lipolytica and A. niger. The antifungal potential trends are as follows: 80g ≈ 80h > 80f > 80c > 80b > 80a ≈ 80i ≈ 80j > 80d > 80e. In summary, antifungal properties follow the same pattern as discussed for the antibacterial properties [66]. The molecular docking studies using the most potent compounds 80f, 80g, and 80h with N-terminal domain of DNA binding protein of S. aureus (4PQL), a long-chain secondary alcohol dehydrogenase protein of M. luteus (6QKN), and lipase of B. subtilis (1ISP) revealed their mechanism of action and produced improved activity. High binding affinity with target proteins confirms that these analogs are extremely active antibacterial agents.

Conclusions
The MDR strains are posing serious health threats, especially in developing countries. Therefore, there is a great need to develop novel antibiotics to overcome MDR microbial strains. The coumarin-and triazole-based compounds are potential structural motifs because of their drug-like properties and high therapeutic indexes. Both pharmacophores have been extensively utilized in the development of several clinical drugs. Medicinal chemists are now actively engaged in combining both coumarin and triazole moieties to obtain novel and highly effective single-molecule antibiotic drug Candidates. Our review abridges the known reports of various coumarin triazoles or triazole-coumarin derivatives and their antimicrobial activities. As summarized in the above sections, the presence of both coumarin and triazole functionalities in a single molecule has enhanced the efficacy of antimicrobial activities. The above information aims to aid the medical research community in developing novel, potent, and safe antimicrobial drug Candidates to combat the MDR in microbial diseases.