Issue 23, 2025

Synthesis and anti-SARS-CoV-2 potential of novel coumarin hybrids: a combined wet/dry lab approach targeting MPro, Nsp15 and spike protein

Abstract

This study focuses on the synthesis of novel hybrids with a coumarin scaffold as potential SARS-CoV-2 inhibitors. All the novel coumarin-1,2,4-triazole hybrids 14(a–h) and phenylacetamide linked coumarin derivatives 17(a–h) were synthesized by following a standard procedure in good to excellent yields i.e., 51–75% for 14(a–h) and 62–82% for 17(a–h). The synthesized derivatives were subjected to in silico modelling to evaluate their anti-SARS-CoV-2 potential, targeting Mpro (main protease), Nsp15 (nonstructural protein) and spike protein. Among all, compounds 14b and 14c expressed excellent potency against their respective targets with corresponding binding affinities of −9.5 kcal mol−1 (6VWW), −9.2 kcal mol−1 (6Y84), and −8.6 (6WPT) kcal mol−1, even better than all standards i.e., chloroquine, lopinavir, remdesivir, favipiravir, and nirmatrelvir. The stability of the potent compounds (14b and 14c) was further supported by a 100 ns MD simulation, emphasizing their potent and stable interactions with the main protease, endoribonuclease, and spike protein. The current study highlights the coumarin-based conjugates 14(a–h) and 17(a–h) as attractive and promising candidates for future pharmacological interventions against SARS-CoV-2.

Graphical abstract: Synthesis and anti-SARS-CoV-2 potential of novel coumarin hybrids: a combined wet/dry lab approach targeting MPro, Nsp15 and spike protein

Supplementary files

Article information

Article type
Paper
Submitted
14 Apr 2025
Accepted
23 May 2025
First published
03 Jun 2025
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2025,15, 18577-18592

Synthesis and anti-SARS-CoV-2 potential of novel coumarin hybrids: a combined wet/dry lab approach targeting MPro, Nsp15 and spike protein

R. Kausar, A. Mansha, A. F. Zahoor and M. Haroon, RSC Adv., 2025, 15, 18577 DOI: 10.1039/D5RA02615F

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