Coumarin‐Augmented Thiazole Hybrids as Dual Anticancer and Antibacterial Agents

TL;DR

This paper introduces a new type of compound that can fight both cancer and bacteria, showing strong activity against drug-resistant bacteria and cancer cells.

Contribution

The study introduces thiazol-hydrazono-coumarin hybrids as dual-action agents targeting topoisomerases in both bacteria and cancer cells.

Findings

Compound 13 showed potent antibacterial activity with MICs as low as 0.12 μg/mL against resistant Staphylococcus aureus.

Compound 13 exhibited strong selectivity for HeLa cancer cells over normal WI-38 fibroblasts.

Molecular simulations revealed a novel hydrogen bond between compound 13 and serine-129 in S. aureus DNA gyrase.

Abstract

Coumarins are a privileged scaffold in medicinal chemistry, renowned for diverse therapeutic activities including antiviral, anticancer, and neuroprotective effects. Building on our previous work with 3‐substituted coumarins as inhibitors of tumor‐associated carbonic anhydrases, we report a novel series of thiazol‐hydrazono‐coumarins targeting the ATP‐binding domain of topoisomerase enzymes. Seventeen compounds were synthesized and evaluated for selective cytotoxicity against HeLa cells versus WI‐38 fibroblasts and for antimicrobial activity against four ESKAPE pathogens,
Escherichia coli
, and
Salmonella typhimurium
. Several derivatives showed potent antibacterial activity, with MICs as low as 0.12 μg/mL against resistant
Staphylococcus aureus
strains and inhibition zones up to 33 mm against Gram‐negative bacteria. Compound 13 exhibited strong selectivity, with an IC50 of 26.8 μg/mL in HeLa cells and 220.7 μg/mL in WI‐38 cells. The five most active compounds were studied via molecular docking and MM/GBSA to elucidate their binding to bacterial DNA gyrase, topoisomerase IV, and human topoisomerase IIα. A molecular dynamics simulation of the
S. aureus
DNA gyrase B‐compound 13 complex revealed a novel hydrogen bond between the coumarin ring and serine‐129. These findings highlight thiazol‐hydrazono‐coumarins as promising antibacterial leads with ancillary anticancer activity, supporting their potential in treating infections in immunocompromised cancer patients.

Compound 13, a coumarin‐thiazole hybrid, is shown engaging the ATP‐binding site of
S. aureus
GyrB through a novel hydrogen bond with residue SER129. The molecule exhibits dual antibacterial and anticancer activity, supporting its potential as a dual‐target topoisomerase inhibitor.

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