Abstract
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•Novel series of linezolid-based oxazolidinones were designed and synthesized by selected modifications.•Potent anticandidiasis activity exhibited by oxazolidinone (2, 3a) against 14 strains of C.albicans.•Demonstration of mechanism of action by the inhibition of ergosterol biosynthesis.•Excellent antitubercular activity displayed by oxazolidinone (2, 3a), comparable to linezolid.•Computational studies revealed the superior or comparable binding affinity of the oxazolidinone towards the biological receptors than controls.
The quest for new antifungal and antitubercular drugs is a need of the hour because of morbid co-pathogenesis and an increase in immunocompromised patients. One of the ways forward is to explore and repurpose the established pharmacophores for the desired application. Oxazolidinones are well-known antibacterial agents, with few investigations reported to exploit their antifungal properties. Herein, we report the design and synthesis of a series of linezolid-based oxazolidinones as potent anticandidiasis and antitubercular agents. Studies revealed that two of the novel oxazolidinones 2 and 3a exhibited excellent anticandidiasis activity against different Candida fungus strains, superior to standard drugs. Mechanistic and docking studies revealed that oxazolidinones were better inhibitors of the ergosterol biosynthesis pathway than the controls used. In addition, the oxazolidinones 2 and 3a also exhibited prominent inhibitory activity against M. tuberculosis H37Rv with MIC values of 1 and 2 μg/ml, respectively. Computational studies demonstrated the binding of the compounds to the transcriptional regulatory repressor protein, which was reinforced by the molecular dynamics simulations. The pharmacophore modeling experiments validated the molecular docking results in both the target proteins.