Unfolding the Potential of Pyrrole- and Indole-Based Allylidene Hydrazine Carboximidamides as Antimicrobial Agents

Abstract

Antimicrobial drug resistance is a significant global health challenge, causing hundreds of thousands of deaths annually and severely impacting healthcare systems worldwide. Several reported antimicrobial compounds have a guanidine motif, as the positive charge on guanidine promotes cell lysis. Therefore, pyrrole- and indole-based allylidene hydrazine carboximidamide derivatives with guanidine motifs are proposed as antimicrobial agents that mimic cationic antimicrobial peptides (CAMPs). A total of 72 derivatives having pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide and indol-3-yl-phenyl allylidene hydrazine carboximidamide scaffolds were assessed for their inhibitory potential against a panel of Gram-positive and Gram-negative bacteria. Analogs 1j, 1k, 1s, 2j, 2q, 4a, 4c, 4h, 5b, 6a, and 6d exhibited potent broad-spectrum antimicrobial activity better than the standard antibiotics. Also, these compounds showed no cytotoxicity up to 3-fold of the minimum inhibitory concentration, and structure–activity relationship was established. Further, the most active compound, 6a, showed a strong biofilm disruption, acted on the bacterial membrane, and lysed it. The further development of these compounds as novel antimicrobial agents is warranted.