Coumarin-based C-2 cycloalkylated histidine derivatives: Design, synthesis, biological evaluation, molecular docking and MD simulation studies as potential antimicrobial agents

Despite numerous attempts to develop new pharmacophores as promising antimicrobials, the coumarin scaffold remains one of the foremost sought moiety in the design of molecules. Herein, we report the new structural class of coumarin-based C-2 cycloalkylated histidine hybrids as potential antimicrobial agents. The most promising compound 11n displayed IC₅₀ of 0.27 µg/mL, 1.1 µg/mL, 4.4 µg/mL and 4.4 µg/mL against Crptococcus neoformans, Candida albicans, Escherichia coli and Staphylococcus aureus, respectively. Interestingly, 11n displays fungicidal activity on growing cryptococcal cells with high selectivity. The presence of 11n lead to the permeabilization of fungal cells as confirmed by propidium iodide uptake study. Moreover, scanning electron microscopy revealed that it causes shrinkage and disruptions in the cell membranes, which is responsible for the cell lysis. Molecular docking analysis revealed that 11n have a distinct H-bonding with TYR409 and TRP94 which are lacking in the co-crystal ligand and are predicted that these are responsible for the potency of the compound. Moreover, the results of the MD simulation analysis showed that the protein-ligand complex exhibits substantial binding interactions with a variety of amino acids and is stable for 100 ns. Additionally, ADMET analysis depicted that these molecules have considerable ADME properties.