RSS-Feed abonnieren
DOI: 10.1055/a-2577-0837
Design, Synthesis, and In Silico Studies of 1,2,3-Triazole-Linked Coumarin–Chalcone Hybrids as Potential Antifungal Agents
We appreciate the funding provided by the Institute of Eminence (IOE), University of Delhi, which has contributed to further research and development.
We dedicate this article to the fond memory of our beloved late Professor Ashok K. Prasad.
Abstract
Fungal infections are a growing global health concern due to their rising incidence and increasing resistance to existing drugs. With the aim of developing new antifungal candidates, this study introduces a series of novel coumarin–chalcone hybrids linked through a 1,2,3-triazole moiety. The hybrids were synthesized using Cu(I)-catalyzed azide–alkyne cycloaddition, with optimized conditions giving yields of 75–85%. In silico absorption, distribution, metabolism, and excretion (ADME) analysis predicted favorable pharmacokinetic properties, suggesting that the products have potential as drug-like candidates. Molecular-docking studies revealed strong binding interactions with sterol 14α-demethylase, a crucial enzyme in fungal ergosterol biosynthesis, indicating that the products have potential as antifungal agents. All the synthesized compounds showed a relatively more-negative binding energy than the standard fungicide hexaconazole, indicating their affinity for the active pocket. These triazole-linked coumarin–chalcone hybrids show promise as antifungal candidates due to their effective synthesis, favorable ADME properties, and strong binding interactions with sterol 14α-demethylase. They are, therefore, viable leads for further biological evaluation and potential therapeutic applications.
#
Fungal infections have escalated into a critical global health concern, marked by a rising incidence and the alarming development of resistance to existing antifungal drugs. Invasive fungal infections, in particular, pose a severe threat, contributing to high mortality rates and affecting over a billion individuals worldwide, with approximately 1.7 million deaths annually. Recognizing this, the World Health Organization has classified fungal infections as a significant public health threat.[1] [2] [3] [4]
The escalating prevalence of these infections is further compounded by the emergence of multidrug-resistant fungal strains, rendering many current antifungal therapies ineffective or excessively toxic. Consequently, there is an urgent need for more-effective treatment options. Researchers are actively exploring novel antifungal agents that offer enhanced therapeutic efficacy and reduced toxicity to combat drug resistance and high mortality rates.[5]
Among the most widely utilized antifungal treatments, azole derivatives have demonstrated remarkable efficacy by targeting ergosterol, a crucial component of the fungal cell membrane. These compounds inhibit the lanosterol 14α-demethylase enzyme, thereby disrupting ergosterol synthesis and compromising the integrity of the fungal cell membrane.[3] [6]
Because of their pivotal role in antifungal therapy, substantial research efforts have been dedicated to developing new potent molecules based on the azole scaffold to improve efficacy and overcome emerging drug resistance.[7] [8] These antifungal agents are categorized into imidazoles, containing two nitrogen atoms (e.g., ketoconazole, miconazole, clotrimazole), and triazoles, containing three nitrogen atoms (e.g., itraconazole, fluconazole). While imidazoles, with the exception of ketoconazole, are primarily used for superficial fungal infections, triazoles are effective against both superficial and systemic mycoses and offer a safety advantage due to their higher selectivity toward fungal cytochrome P-450 enzymes.[9,10] Furthermore, the triazole moiety can serve as a linker to connect two pharmacophores, yielding novel drug molecules.[11–14]
Molecular hybridization is an emerging methodology in medicinal chemistry that facilitates the design and synthesis of molecular hybrids with superior pharmacological properties by combining two or more pharmacophores for improved efficacy.[15] [16] The hybridization of 1,2,3-triazole with other antimicrobial pharmacophores represents a judicious strategic approach to the development of new and effective antifungal candidates to combat drug-sensitive and drug-resistant infections.[17] Over the past years, various conjugates incorporating this biologically valuable core have been reported, highlighting their significant fungicidal potential and potent effects on diverse disease-causing targets (Figure [1]).[18] [19] [20] [21]
In this pursuit, we focused on integrating the 1,2,3-triazole linker with coumarin and chalcone pharmacophores. Coumarins are recognized for their diverse biological activities and broad pharmacological properties, with over 1300 compounds documented.[22] [23] Recent research has demonstrated that combining coumarins with nitrogen-containing heterocyclic structures, such as azetidine, thiazolidine, thiazole, or oxadiazole, enhances their antimicrobial potency and expands their activity against a wider range of pathogens.[24,25] Given their promising biological profile, coumarin-based hybrids hold significant potential for developing novel antifungal therapeutics.[26]
Chalcones and their heterocyclic analogues exhibit antibacterial, antifungal, antiinflammatory, and anticancer properties.[27] [28] Their potent antifungal activity is attributed to their ability to disrupt fungal cell membranes and inhibit ergosterol biosynthesis.[3,29,30] The structural versatility of chalcones permits modifications that enhance efficacy against resistant fungal strains.[29–31]
Building upon the antimicrobial and antifungal activities of coumarin, triazole, and chalcone moieties, we report the synthesis, characterization, and a distribution, metabolism, and excretion (ADME) evaluation, as well as molecular-docking studies of coumarin–chalcone hybrids linked through a 1,2,3-triazole moiety (Figure [2]).
We envisioned that the targeted 4-{4-[(4-cinnamoylphenoxy)methyl]-1H-1,2,3-triazol-1-yl}-2H-chromen-2-ones might be synthesized by Cu(I)-catalyzed click reactions between 4-azido-2H-chromen-2-ones and various substituted propargylated chalcones (Scheme [1]). Substituted 4-azido2H-chromen-2-ones could be readily obtained from the corresponding 4-hydroxycoumarins in two steps, whereas propargylated chalcones could be synthesized from 4-hydroxyacetophenone in two steps with high yields.
The synthesis of triazole-linked coumarin–chalcone hybrid molecules involved four steps. In the first step, 4-hydroxyacetophenone (2) was allowed to react with propargyl bromide (3) in the presence of K2CO3 in N,N-dimethylformamide (DMF) at room temperature for 12 hours to afford 1-[4-(prop-2-yn-1-yloxy)phenyl]ethan-1-one (4) (Scheme [2]).[32] In the second step, propargylated chalcone derivatives 6a–o were synthesized by following a reported procedure involving a base-catalyzed aldol condensation reaction of 1-[4-(prop-2-yn-1-yloxy)phenyl]ethan-1-one (4) with a series of substituted aromatic aldehydes 5a–o (Scheme [2]).[32] All the products were obtained in good to excellent yield.
Substituted 4-hydroxycoumarins 7a–c were obtained by following a reported procedure[33] involving a Friedel–Crafts acetylation of substituted phenols with diethyl carbonate. In the next step, 4-azidocoumarins 9a–c were accessed by a sequential two-step one-pot reaction between 4-hydroxycoumarins 7a–c and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, followed by reaction with NaN3 in the presence of 18-crown-6 (Scheme [3]).[34]
a Reaction conditions: 6a (1.0 equiv), 9a (1.1 equiv), catalyst, solvent (3 mL).
b Isolated yield.
c NR = no reaction.
To begin our study, a click reaction[35] [36] was carried out between the propargylated chalcone 6a and the azidocoumarin 9a. The reaction was performed in the presence of sodium ascorbate (NaAsc) and CuSO4·5H2O in t-BuOH at ambient temperature,[37] and afforded the desired product 10a in 45% yield (Table [1], entry 1). Subsequently, the click reaction of the propargylated chalcone 6a and azidocoumarin 9a was explored using various catalysts in the same solvent at ambient temperature to optimize both the yield and efficiency of the reaction (entries 2–4). CuI emerged as the most effective catalyst, giving a 65% yield of 10a (entry 4). In an attempt to improve the efficiency of the reaction, various solvents were screened, [THF, MeCN, DMF, DMSO, 1,4-dioxane, EtOH, MeOH, 2-methyltetrahydrofuran (2-MeTHF) and PEG 400] (entries 5–13). The highest yield (73%) of the 10a was obtained with PEG-400, whereas the other solvents gave a lower or no yield of 10a.
Increasing the temperature to 50 or 60 °C improved the yield to 79 and 85%, respectively (Table [1], entries 14 and 15). However, a further increase in the temperature to 70 or 80 °C resulted in a decline in the product yield, indicating that excessively high temperatures have a detrimental effect on the reaction outcome (entries 16 and 17). Increasing the CuI concentration from 10 mol % to 20 mol % did not lead to any improvement in the yield of the desired product (entry 18), whereas a decrease in the CuI concentration to 5 mol %, resulted in an inferior yield of 51% (entry 19). Among the explored set of conditions, 10 mol % of CuI in PEG-400 as solvent at 60 °C was found to be the most favorable for synthesizing the triazole-linked coumarin-chalcone hybrid 10a (entry 15).
With the optimized reaction conditions, the click reactions of various propargylated chalcones 6a–o and azidocoumarins 9a–c were explored in PEG-400 at 60 °C. All the substrates reacted well and gave the desired triazole-linked coumarin–chalcone hybrid molecules 10a–r in good yields of 75–85% (Scheme [4]).
The structures of all the synthesized compounds were unambiguously established through spectral analyses (IR, 1H NMR, 13C NMR, 1H–1H COSY NMR, 1H–13C HETCOR NMR, DEPT-135, and HRMS). The structures of known compounds were further confirmed by comparing their physical and spectral properties with those reported in the literature.[32] [33] [34]
Next, the physicochemical properties of the synthesized analogues 10a–r were analyzed using the SwissADME online tool,[38] applying Lipinski’s Rule of Five[39] and Veber’s rule[40] to assess their drug-likeness. As shown in Table [2], all compounds except one met Veber’s criteria and only a few deviated from Lipinski’s guidelines. These computational findings indicate that the coumarin–chalcone linked-1,2,3-triazole hybrids possess favorable absorption and permeability characteristics, suggesting good potential for oral bioavailability.
a Molecular weight of the synthesized compound in g/mol.
b Number of rotatable bonds.
c Number of hydrogen-bond acceptors
d Number of hydrogen-bond donors.
e Topological polar surface area.
f Logarithm of the partition coefficient between water and n-octanol.
Molecular docking is a powerful computational technique that is widely used in drug discovery to predict the binding interactions between ligands and target proteins, assisting in the rational design of novel therapeutics. In this study, AutoDock Tools [41] was employed to analyze the binding affinity and interaction profiles of the synthesized 1,2,3-triazole-linked coumarin–chalcone hybrid derivatives with sterol 14α-demethylase (CYP51) (PDB ID: 3GW9), a key enzyme involved in ergosterol biosynthesis that is essential for maintaining the integrity of the fungal cell membrane.[3] Inhibition of this enzyme disrupts ergosterol production, leading to fungal cell death, making it a strategic target for antifungal drug development.[3]
The docking results demonstrated that all the synthesized compounds exhibited stronger binding affinities than the reference antifungal drug hexaconazole (–7.5 kcal/mol), with compounds 10k and 10n showing the most-negative binding energies of –10.6 and –10.8 kcal/mol, respectively (Table [3], entries 11 and 14). These results indicate a high binding strength and potential enhanced antifungal efficacy.
The binding interactions of compounds 10k and 10n were further analyzed to understand their molecular interactions with the active site residues of CYP51 (Figure [3] and Supporting Information, Figure S40).
The results suggested that the synthesized coumarin-chalcone linked-1,2,3-triazole hybrids 10a–r might exhibit stronger target engagement and, potentially, superior antifungal activity compared with hexaconazole.
These findings highlight the potential of 1,2,3-triazole-linked coumarin–chalcone hybrids as next-generation antifungal agents, exhibiting stronger and more specific binding interactions with CYP51 compared with conventional azole antifungals. Further biological validation through in vitro and in vivo studies will be necessary to confirm the therapeutic potential of the products and to establish them as promising candidates for antifungal drug development.
In conclusion, a novel series of coumarin-chalcone hybrids linked by a 1,2,3-triazole moiety were successfully designed and synthesized by a Cu(I)-catalyzed azide–alkyne cycloaddition, commonly known as click chemistry.[42] The optimized reaction conditions, employing PEG-400 as a solvent and CuI (10 mol%) as a catalyst at 60 °C, provided an efficient and high-yielding synthetic route, achieving yields ranging from 75 to 85%. The structural integrity of the synthesized compounds was rigorously confirmed through FT-IR, NMR, and HRMS analyses.
In silico ADME analysis revealed favorable pharmacokinetic profiles for the synthesized hybrids. Notably, the majority of the compounds adhered to Lipinski’s and Veber’s rules, indicating good drug-likeness and potential oral bioavailability. Furthermore, molecular-docking studies corroborated the antifungal potential of these hybrids, demonstrating strong binding interactions with sterol 14α-demethylase (CYP51), a crucial enzyme in fungal ergosterol biosynthesis. Significantly, the binding energies of the synthesized compounds were more negative than that of the standard fungicide hexaconazole, highlighting their potent affinity toward the active site of the enzyme.
Overall, this study demonstrated the promise of these triazole-linked coumarin–chalcone hybrids as potential antifungal candidates. Their efficient synthesis, characterized molecular interactions, and favorable ADME properties position them as viable leads for further biological evaluation and potential therapeutic applications.
#
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We appreciate the assistance provided by USIC and the Department of Chemistry, University of Delhi, for recording NMR, HRMS and IR data. K.K. and S.K. thank CSIR for Awards of Senior Research Fellowships.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2577-0837.
- Supporting Information
-
References and Notes
- 1 Kainz K, Bauer MA, Madeo F, Carmona-Gutierrez D. Microb. Cell 2020; 7: 143
- 2 Bongomin F, Gago S, Oladele RO, Denning DW. J. Fungi 2017; 3: 57
- 3 Kathiravan MK, Salake AB, Chothe AS, Dudhe PB, Watode RP, Mukta MS, Gadhwe S. Bioorg. Med. Chem. 2012; 20: 5678
- 4 Calderone R, Sun N, Gay-Andrieu F, Groutas W, Weerawarna P, Prasad S, Alex D, Li D. Future Microbiol. 2014; 9: 791
- 5 Bitla S, Gayatri AA, Puchakayala MR, Bhukya VK, Vannada J, Dhanavath R, Kuthati B, Kothula D, Sagurthi SR, Atcha KR. Bioorg. Med. Chem. Lett. 2021; 41: 128004
- 6a Van Daele R, Spriet I, Wauters J, Maertens J, Mercier T, Van Hecke S, Brüggemann R. Med. Mycol. J. 2019; 57: S328
- 6b Nguyen M.-VH, Davis MR, Wittenberg R, Mchardy I, Baddley JW, Young BY, Odermatt A, Thompson GR. III. Clin. Infect. Dis. 2020; 70: 2593
- 7 Stewart AG, Paterson DL. Expert Opin. Pharmacother. 2021; 22: 1857
- 8 Shafiei M, Peyton L, Hashemzadeh M, Foroumadi A. Bioorg. Chem. 2020; 104: 104240
- 9 Sheehan DJ, Hitchcock CA, Sibley CM. Clin. Microbiol. Rev. 1999; 12: 40
- 10 Martins Teixeira M, Teixeira Carvalho D, Sousa E, Pinto E. Pharmaceuticals 2022; 15: 1427
- 11 Agalave SG, Maujan SR, Pore VR. Chem. Asian J. 2011; 6: 2696
- 12 Guo H.-Y, Chen Z.-A, Shen Q.-K, Quan Z.-S. J. Enzyme Inhib. Med. Chem. 2021; 36: 1115
- 13 Zhou C.-H, Wang Y. Curr. Med. Chem. 2012; 19: 239
- 14 Khan J, Rani A, Aslam M, Maharia RS, Pandey G, Nand B. Tetrahedron 2024; 162: 134122
- 15 Bérubé G. Expert Opin. Drug Discovery 2016; 10: 281
- 16 Ramprasad J, Sthalam VK, Thampunuri RL. M, Bhukya S, Ummanni R, Balasubramanian S, Pabbaraja S. Bioorg. Med. Chem. Lett. 2019; 29: 126671
- 17 Haroun M, Tratrat C, Kochkar H, Nair AB. Curr. Top. Med. Chem. 2021; 21: 462
- 18 Yadav M, Lal K, Kumar A, Kumar A, Kumar D. J. Mol. Struct. 2022; 1261: 132867
- 19 Dongamanti A, Bommidi VL, Arram G, Sidda R. Heterocycl. Commun. 2014; 20: 293
- 20 Akolkar SV, Nagargoje AA, Shaikh MH, Warshagha MZ. A, Sangshetti JN, Damale MG, Shingate BB. Arch. Pharm. (Weinheim, Ger.) 2020; 353: e2000164
- 21 Yan W, Wang X, Li K, Li TX, Wang J.-J, Yao K.-C, Cao L.-L, Zhao S.-S, Ye Y.-H. Pestic. Biochem. Physiol. 2019; 156: 160
- 22 Stefanachi A, Leonetti F, Pisani L, Catto M, Carotti A. Molecules 2018; 23: 250
- 23 Arya CG, Chandrakanth M, Fabitha K, Thomas NM, Pramod RN, Gondru R, Banothu J. Results Chem. 2022; 4: 100631
- 24 Ronad PM, Noolvi MN, Sapkal S, Dharbhamulla S, Maddi VS. Eur. J. Med. Chem. 2010; 45: 85
- 25 Raghu M, Nagaraj A, Reddy CS. J. Heterocycl. Chem. 2009; 46: 261
- 26 Shaikh MH, Subhedar DD, Khan FA. K, Sangshetti JN, Shingate BB. Chin. Chem. Lett. 2016; 27: 295
- 27 Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z. Chem. Rev. 2017; 117: 7762
- 28 Dhaliwal JS, Moshawih S, Goh KW, Loy MJ, Hossain MS, Hermansyah A, Kotra V, Kifli N, Goh HP, Dhaliwal SK. S, Yassin H, Ming LC. Molecules 2022; 27: 7062
- 29 Mahapatra DK, Bharti SK, Asati V. Eur. J. Med. Chem. 2015; 101: 496
- 30 Gupta D, Jain DK. J. Adv. Pharm. Technol. Res. 2015; 6: 141
- 31 Shakil NA, Singh MK, Kumar J, Sathiyendiran M, Kumar G, Singh MK, Pandey RP, Pandey A, Parmar VS. J. Environ. Sci. Health, Part B 2010; 45: 524
- 32a Banu HN, Kalluraya B, Manju N, Ramu R, Patil SM, Rai KM. L, Kumar N. ChemistrySelect 2023; 8: e202203578
- 32b Manna T, Pal K, Jana K, Misra AK. Bioorg. Med. Chem. Lett. 2019; 29: 126615
- 32c Bonvicini F, Gentilomi GA, Bressan F, Gobbi S, Rampa A, Bisi A, Belluti F. Molecules 2019; 24: 372
- 32d Yu B, Qi P.-P, Shi X.-J, Huang R, Guo H, Zheng Y.-C, Yu D.-Q, Liu H.-M. Eur. J. Med. Chem. 2016; 117: 241
- 32e Kumar B, Kumar M, Dwivedi AR, Kumar V. ChemMedChem 2018; 13: 705
- 33 Maikhuri VK, Bohra K, Srivastava S, Kavita K, Prasad AK. Synth. Commun. 2019; 49: 3140
- 34a Singla H, Maikhuri VK, Kavita K, Prasad AK. ChemistrySelect 2023; 8: e202203412
- 34b Khandaker TA, Hess JD, Aguilera R, Andrei G, Snoeck R, Schols D, Pradhan P, Lakshman MK. Eur. J. Org. Chem. 2019; 5610
- 35a Tiwari VK, Mishra BB, Mishra KB, Mishra N, Singh AS, Chen X. Chem. Rev. 2016; 116: 3086
- 35b Agrahari AK, Bose P, Jaiswal MK, Rajkhowa S, Singh AS, Hotha S, Mishra N, Tiwari VK. Chem. Rev. 2021; 121: 7638
- 35c Tiwari VK, JaiswalM K, Rajkhowa S, Singh SK. Click Chemistry . Springer Nature Singapore; Singapore: 2024
- 36a Meldal M, Diness F. Trends Chem. 2020; 2: 569
- 36b Yuan Y, Liang G. Org. Biomol. Chem. 2014; 12: 865
- 37 Arora A, Kumar S, Kumar S, Dua A, Singh BK. Org. Biomol. Chem. 2024; 22: 4922
- 38 SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 42717.
- 39 Lipinski CA. Drug Discov. Today Technol. 2004; 1: 337
- 40 Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. J. Med. Chem. 2002; 45: 2615
- 41 Sanner MF. J. Mol. Graph Model 1999; 17: 57
- 42 1,2,3-Triazole-Linked Coumarin–Chalcone Hybrids 10a–r; General Procedure In a 50 mL round-bottomed flask, the appropriate propargylated chalcone 6 (1.96 mmol) and 4-azidocoumarin 9 (2.28 mmol) were dissolved in PEG-400. CuI (10 mol %, 0.19 mmol) was added, and the resulting mixture was stirred at 60 °C for 4–6 h until the reaction was complete (TLC). The product was then extracted with EtOAc, and the solution was concentrated under reduced pressure in a rotary evaporator. The resulting crude product was purified by column chromatography [silica gel, EtOAc–PE (gradient)]. 4-[4-({4-[(2E)-3-Phenylprop-2-enoyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]-2H-chromen-2-one (10a) Purified by column chromatography (silica gel, 40% EtOAc–PE) as a white solid; yield: 85%; mp 201–203 °C. IR (KBr): 3140, 1710, 1656, 1587, 1438, 1170, 1017, 1240, 1050, 997 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.10 (s, 1 H), 8.08 (d, J = 8.9 Hz, 2 H), 7.86 (dd, J = 8.2, 1.6 Hz, 1 H), 7.82 (d, J = 15.8 Hz, 1 H), 7.71–7.64 (m, 3 H), 7.55 (d, J = 15.6 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.42 (dd, J = 5.0, 1.9 Hz, 3 H), 7.36–7.40 (m, 1 H), 7.10 (d, J = 8.9 Hz, 2 H), 6.59 (s, 1 H), 5.44 (s, 2 H). 13C NMR (100.6 MHz, CDCl3): δ = 188.8, 161.7, 159.7, 154.5, 146.8, 144.8, 144.5, 135.1, 133.9, 132.1, 131.1, 130.6, 129.1, 128.6, 125.6, 125.3, 124.0, 121.8, 117.8, 114.7, 114.4, 110.3, 61.9. HRMS (ESI): m/z [M + H]+ calcd for C27H20N3O4: 450.1448; found: 450.1455.
Corresponding Author
Publikationsverlauf
Eingereicht: 28. Februar 2025
Angenommen nach Revision: 07. April 2025
Accepted Manuscript online:
07. April 2025
Artikel online veröffentlicht:
30. Juni 2025
© 2025. Thieme. All rights reserved
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
-
References and Notes
- 1 Kainz K, Bauer MA, Madeo F, Carmona-Gutierrez D. Microb. Cell 2020; 7: 143
- 2 Bongomin F, Gago S, Oladele RO, Denning DW. J. Fungi 2017; 3: 57
- 3 Kathiravan MK, Salake AB, Chothe AS, Dudhe PB, Watode RP, Mukta MS, Gadhwe S. Bioorg. Med. Chem. 2012; 20: 5678
- 4 Calderone R, Sun N, Gay-Andrieu F, Groutas W, Weerawarna P, Prasad S, Alex D, Li D. Future Microbiol. 2014; 9: 791
- 5 Bitla S, Gayatri AA, Puchakayala MR, Bhukya VK, Vannada J, Dhanavath R, Kuthati B, Kothula D, Sagurthi SR, Atcha KR. Bioorg. Med. Chem. Lett. 2021; 41: 128004
- 6a Van Daele R, Spriet I, Wauters J, Maertens J, Mercier T, Van Hecke S, Brüggemann R. Med. Mycol. J. 2019; 57: S328
- 6b Nguyen M.-VH, Davis MR, Wittenberg R, Mchardy I, Baddley JW, Young BY, Odermatt A, Thompson GR. III. Clin. Infect. Dis. 2020; 70: 2593
- 7 Stewart AG, Paterson DL. Expert Opin. Pharmacother. 2021; 22: 1857
- 8 Shafiei M, Peyton L, Hashemzadeh M, Foroumadi A. Bioorg. Chem. 2020; 104: 104240
- 9 Sheehan DJ, Hitchcock CA, Sibley CM. Clin. Microbiol. Rev. 1999; 12: 40
- 10 Martins Teixeira M, Teixeira Carvalho D, Sousa E, Pinto E. Pharmaceuticals 2022; 15: 1427
- 11 Agalave SG, Maujan SR, Pore VR. Chem. Asian J. 2011; 6: 2696
- 12 Guo H.-Y, Chen Z.-A, Shen Q.-K, Quan Z.-S. J. Enzyme Inhib. Med. Chem. 2021; 36: 1115
- 13 Zhou C.-H, Wang Y. Curr. Med. Chem. 2012; 19: 239
- 14 Khan J, Rani A, Aslam M, Maharia RS, Pandey G, Nand B. Tetrahedron 2024; 162: 134122
- 15 Bérubé G. Expert Opin. Drug Discovery 2016; 10: 281
- 16 Ramprasad J, Sthalam VK, Thampunuri RL. M, Bhukya S, Ummanni R, Balasubramanian S, Pabbaraja S. Bioorg. Med. Chem. Lett. 2019; 29: 126671
- 17 Haroun M, Tratrat C, Kochkar H, Nair AB. Curr. Top. Med. Chem. 2021; 21: 462
- 18 Yadav M, Lal K, Kumar A, Kumar A, Kumar D. J. Mol. Struct. 2022; 1261: 132867
- 19 Dongamanti A, Bommidi VL, Arram G, Sidda R. Heterocycl. Commun. 2014; 20: 293
- 20 Akolkar SV, Nagargoje AA, Shaikh MH, Warshagha MZ. A, Sangshetti JN, Damale MG, Shingate BB. Arch. Pharm. (Weinheim, Ger.) 2020; 353: e2000164
- 21 Yan W, Wang X, Li K, Li TX, Wang J.-J, Yao K.-C, Cao L.-L, Zhao S.-S, Ye Y.-H. Pestic. Biochem. Physiol. 2019; 156: 160
- 22 Stefanachi A, Leonetti F, Pisani L, Catto M, Carotti A. Molecules 2018; 23: 250
- 23 Arya CG, Chandrakanth M, Fabitha K, Thomas NM, Pramod RN, Gondru R, Banothu J. Results Chem. 2022; 4: 100631
- 24 Ronad PM, Noolvi MN, Sapkal S, Dharbhamulla S, Maddi VS. Eur. J. Med. Chem. 2010; 45: 85
- 25 Raghu M, Nagaraj A, Reddy CS. J. Heterocycl. Chem. 2009; 46: 261
- 26 Shaikh MH, Subhedar DD, Khan FA. K, Sangshetti JN, Shingate BB. Chin. Chem. Lett. 2016; 27: 295
- 27 Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z. Chem. Rev. 2017; 117: 7762
- 28 Dhaliwal JS, Moshawih S, Goh KW, Loy MJ, Hossain MS, Hermansyah A, Kotra V, Kifli N, Goh HP, Dhaliwal SK. S, Yassin H, Ming LC. Molecules 2022; 27: 7062
- 29 Mahapatra DK, Bharti SK, Asati V. Eur. J. Med. Chem. 2015; 101: 496
- 30 Gupta D, Jain DK. J. Adv. Pharm. Technol. Res. 2015; 6: 141
- 31 Shakil NA, Singh MK, Kumar J, Sathiyendiran M, Kumar G, Singh MK, Pandey RP, Pandey A, Parmar VS. J. Environ. Sci. Health, Part B 2010; 45: 524
- 32a Banu HN, Kalluraya B, Manju N, Ramu R, Patil SM, Rai KM. L, Kumar N. ChemistrySelect 2023; 8: e202203578
- 32b Manna T, Pal K, Jana K, Misra AK. Bioorg. Med. Chem. Lett. 2019; 29: 126615
- 32c Bonvicini F, Gentilomi GA, Bressan F, Gobbi S, Rampa A, Bisi A, Belluti F. Molecules 2019; 24: 372
- 32d Yu B, Qi P.-P, Shi X.-J, Huang R, Guo H, Zheng Y.-C, Yu D.-Q, Liu H.-M. Eur. J. Med. Chem. 2016; 117: 241
- 32e Kumar B, Kumar M, Dwivedi AR, Kumar V. ChemMedChem 2018; 13: 705
- 33 Maikhuri VK, Bohra K, Srivastava S, Kavita K, Prasad AK. Synth. Commun. 2019; 49: 3140
- 34a Singla H, Maikhuri VK, Kavita K, Prasad AK. ChemistrySelect 2023; 8: e202203412
- 34b Khandaker TA, Hess JD, Aguilera R, Andrei G, Snoeck R, Schols D, Pradhan P, Lakshman MK. Eur. J. Org. Chem. 2019; 5610
- 35a Tiwari VK, Mishra BB, Mishra KB, Mishra N, Singh AS, Chen X. Chem. Rev. 2016; 116: 3086
- 35b Agrahari AK, Bose P, Jaiswal MK, Rajkhowa S, Singh AS, Hotha S, Mishra N, Tiwari VK. Chem. Rev. 2021; 121: 7638
- 35c Tiwari VK, JaiswalM K, Rajkhowa S, Singh SK. Click Chemistry . Springer Nature Singapore; Singapore: 2024
- 36a Meldal M, Diness F. Trends Chem. 2020; 2: 569
- 36b Yuan Y, Liang G. Org. Biomol. Chem. 2014; 12: 865
- 37 Arora A, Kumar S, Kumar S, Dua A, Singh BK. Org. Biomol. Chem. 2024; 22: 4922
- 38 SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 42717.
- 39 Lipinski CA. Drug Discov. Today Technol. 2004; 1: 337
- 40 Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. J. Med. Chem. 2002; 45: 2615
- 41 Sanner MF. J. Mol. Graph Model 1999; 17: 57
- 42 1,2,3-Triazole-Linked Coumarin–Chalcone Hybrids 10a–r; General Procedure In a 50 mL round-bottomed flask, the appropriate propargylated chalcone 6 (1.96 mmol) and 4-azidocoumarin 9 (2.28 mmol) were dissolved in PEG-400. CuI (10 mol %, 0.19 mmol) was added, and the resulting mixture was stirred at 60 °C for 4–6 h until the reaction was complete (TLC). The product was then extracted with EtOAc, and the solution was concentrated under reduced pressure in a rotary evaporator. The resulting crude product was purified by column chromatography [silica gel, EtOAc–PE (gradient)]. 4-[4-({4-[(2E)-3-Phenylprop-2-enoyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]-2H-chromen-2-one (10a) Purified by column chromatography (silica gel, 40% EtOAc–PE) as a white solid; yield: 85%; mp 201–203 °C. IR (KBr): 3140, 1710, 1656, 1587, 1438, 1170, 1017, 1240, 1050, 997 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.10 (s, 1 H), 8.08 (d, J = 8.9 Hz, 2 H), 7.86 (dd, J = 8.2, 1.6 Hz, 1 H), 7.82 (d, J = 15.8 Hz, 1 H), 7.71–7.64 (m, 3 H), 7.55 (d, J = 15.6 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.42 (dd, J = 5.0, 1.9 Hz, 3 H), 7.36–7.40 (m, 1 H), 7.10 (d, J = 8.9 Hz, 2 H), 6.59 (s, 1 H), 5.44 (s, 2 H). 13C NMR (100.6 MHz, CDCl3): δ = 188.8, 161.7, 159.7, 154.5, 146.8, 144.8, 144.5, 135.1, 133.9, 132.1, 131.1, 130.6, 129.1, 128.6, 125.6, 125.3, 124.0, 121.8, 117.8, 114.7, 114.4, 110.3, 61.9. HRMS (ESI): m/z [M + H]+ calcd for C27H20N3O4: 450.1448; found: 450.1455.
