Natural Coumarin-Hybridized Thiazolylbenzonitriles as New Structural Scaffolds to Exert Potentially Multitargeting Supramolecular Antibacterial Behavior

Abstract

A unique type of natural coumarin skeleton-based thiazolylbenzonitriles as novel structural scaffolds to exert potential multitargeting supramolecular antibacterial behavior was developed for the first time from resorcinol through multi-step reactions. All the new compounds were characterized by NMR and HRMS spectra. Structure-activity relationships revealed that the ethoxycarbonyl group was the optimal substituent to exert the effective supramolecular antibacterial action of benzopyronyl thiazolylbenzonitriles (BTBs), and BTB 13a gave an extremely low MIC value of 0.002 mM against Staphylococcus aureus 29213, being 3-fold more active than norfloxacin. Compound 13a exerting the most effective supramolecular antibacterial behaviour possessed favourable druggability with no obvious haemolysis, acceptable cytotoxicity and low propensity to induce bacterial resistance. A series of medicinal chemobiological evaluations disclosed that BTB 13a could not only intercalate into DNA to produce stable biosupramolecular complexes to block DNA replication, and form biosupermolecules with DNA gyrase, but also disturb cell membrane to tempt leakage of intracellular contents, fluctuate the metabolism and induce oxidative stress, finally resulting in bacterial cell death. Moreover, the promising BTB 13a exhibited good in vivo antibacterial efficacy against Staphylococcus aureus 29213. These results implied that benzopyronyl thiazolylbenzonitriles possessed large promise as novel structural antibacterial members to combat Staphylococcus aureus 29213.

Keywords

Benzoprone / Thiazole / Benzonitrile / Antibacterial / Membrane rupture

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2025 SIOC, CAS, Shanghai, & WILEY-VCH GmbH.