Structure-activity relationships of bensulfuron methyl and its derivatives as novel agents against drug-resistant Candida auris

Abstract

With the emergence of the human pathogen Candida auris as a threat to human health, there is a strong demand to identify effective medicines to prevent the harm caused by such drug-tolerant human fungi. Herein, a series of 33 new derivatives of bensulfuron methyl (BSM) were synthesized and characterized by ¹ H NMR, ¹³ C NMR, and HRMS. Among the target compounds, 8a possessed the best K_i value of 1.015 μM against C. auris acetohydroxyacid synthase (CauAHAS) and an MIC value of 6.25 μM against CBS10913, a clinically isolated strain of C. auris. Taken together the structures of BSM and the synthesized compounds, it was found that methoxy groups at both meta-position of pyrimidine ring are likely to provide desirable antifungal activities. Quantum calculations and molecular dockings were performed to understand the structure-activity relationships. The present study has hence provided some interesting clues for the discovery of novel antibiotics with this distinct mode of action.

Keywords: Candida auris; acetohydroxyacidsynthase; antifungal agent; bensulfuron methyl derivative; drug resistance.