Facile Syntheses and Molecular-Docking of Novel Substituted 3,4-Dimethyl-1H-pyrrole-2-carboxamide/carbohydrazide Analogues with Antimicrobial and Antifungal Properties

Abstract

The article describes the use of facile one-pot, high-yielding reactions to synthesize substituted 3,4-dimethyl-1<i>H</i>-pyrrole-2-carboxamides <b>3a</b>-<b>m</b> and carbohydrazide analogues <b>5a</b>-<b>l</b> as potential antifungal and antimicrobial agents. The structural identity and purity of the synthesized compounds were assigned based on appropriate spectroscopic techniques. Synthesized compounds were assessed in vitro for antifungal and antibacterial activity. The compounds <b>5h</b>, <b>5i</b> and <b>5j</b> were found to be the most potent against <i>Aspergillus</i><i>fumigatus</i>, with MIC values of 0.039 mg/mL. The compound <b>5f</b> bearing a 2, 6-dichloro group on the phenyl ring was found to be the most active broad spectrum antibacterial agent with a MIC value of 0.039 mg/mL. The mode of action of the most promising antifungal compounds (one representative from each series; <b>3j</b> and <b>5h</b>) was established by their molecular docking with the active site of sterol 14α-demethylase. Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds in the access channel away from catalytic heme iron of the enzyme, which suggested that the tested compounds inhibit this enzyme and would avoid heme iron-related deleterious side effects observed with many existing antifungal compounds.