Design, Synthesis, and In Silico Studies of 1,2,3-Triazole-Linked Coumarin–Chalcone Hybrids as Potential Antifungal Agents

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.

Key words

coumarins - chalcones - click reaction - antifungal drugs - medicinal chemistry

Publication History

Received: 28 February 2025

Accepted after revision: 07 April 2025

Accepted Manuscript online:
07 April 2025

Article published online:
30 June 2025

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• 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.