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

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 M^pro (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.