Synthesis, biological evaluation and mechanistic studies of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as a new structural class of antimicrobials

In spite of several attempts to develop newer pharmacophores as potential antimicrobial agents, the benz-imidazole scaffold is still considered as one of the most sought after structural component towards the design of compounds that act against a wide spectrum of microbes. Herein, we report the design and synthesis of a new structural class of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as antimicrobial agents. The most potent analog, 6g shows IC50 of 1.3 mu M, 2.7 mu M, 10.8 mu M, 5.4 mu M and 10.8 mu M against Cryptococcus neoformans, Candida albicans, Candida parapsilosis, Escherichia coli and Staphylococcus aureus, respectively. Interestingly 6g exhibits selectivity towards the cryptococcal cells with fungicidal behavior. Propidium iodide uptake study shows permeabilization of pathogenic cells in the presence of 6g. Flow cytometric analysis confirms that cell death is predominantly due to apoptosis. Moreover, electron microscopic analysis specifies that it shrinks, dis-rupts and initiate pore(s) formation in the cell membrane leading to cell lysis.

Automated summary

Despite attempts to develop newer pharmacophores, the benz-imidazole scaffold remains highly sought after for designing antimicrobial compounds. This study reports the synthesis of a new class of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as potent antimicrobial agents, with analog 6g showing significant activity against various microorganisms. It exhibits selectivity towards cryptococcal cells and induces cell death through apoptosis, with cell membrane disruption and pore formation observed.