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3,5-Dinitrobenzoate and 3,5-Dinitrobenzamide Derivatives: Mechanistic, Antifungal, and in Silico Studies

Abstract:

Fungal infections, including those caused by Candida spp., are recognized in immunocompromised individuals for their high rates of morbidity and mortality. Microorganism resistance to conventional drugs compromises treatment effectiveness and yet also reveals the need to develop new drugs. In many compounds, nitro groups contribute to antimicrobial activity; thus, the inhibitory activity of a collection of twenty esters and amides (derived from 3,5-dinitrobenzoic acid) against Candida spp. was elucidated using microdilution methods to determine the Minimum Inhibitory Concentration (MIC) and Minimum Fungicide Concentration (MFC), as well as probable mechanisms of action. The structures of the synthesized compounds were characterized by FTIR spectroscopy, 1H-NMR, 13C NMR, and HRMS. Of the tested derivatives, ten presented fungicidal activity against at least one of the tested strains. Ethyl 3,5-dinitrobenzoate (2) exhibited the most potent antifungal activity against Candida albicans (MIC = 125 μg/mL; 0.52 mM), Candida krusei (MIC = 100 μg/mL; 4.16 mM), and Candida tropicalis (MIC = 500 μg/ml; 2.08 mM). The structure of the second most potent derivative (propyl 3,5-dinitrobenzoate (3) reveals that esters with short alkyl side chains exhibit better biological activity profiles. Compounds 2 and 3 presented a mechanism of action involving the fungal cell membrane. Though compound 2 modeling against C. albicans revealed a multitarget antifungal mechanism of action, involving various cellular processes, interference in the synthesis of ergosterol was observed. Our results demonstrate that certain ester derivatives containing aromatic ring nitro groups may be useful in the search for new antifungal drugs.