Synthesis and biological activity of imidazole phenazine derivatives as potential inhibitors for NS2B-NS3 dengue protease.

A series of new imidazole-phenazine derivatives were synthesized via a two-step process. The condensation of 2,3-diaminophenazine and benzaldehyde derivatives proceeds with intermediate formation of an aniline Schiff base, which undergoes subsequent cyclodehydrogenation . The structures of the synthesized compounds were characterized by 1D and 2D NMR, FTIR and HRMS. A total of thirteen imidazole phenazine derivatives were synthesized and validated for their inhibitory activity as anti-dengue agents by an in vitro DENV2 NS2B-NS3 protease assay using a fluorogenic Boc-Gly-Arg-Arg-AMC substrate. Two para-substituted imidazole phenazines, and , were found to be promising lead molecules for novel NS2B-NS3 protease inhibitors with IC of 54.8 μM and 71.9 μM, respectively, compared to quercetin as a control (IC 104.8 μM). The study was performed using AutoDock Vina to identify the binding energy and conformation of and with the active site of the DENV2 NS2B-NS3 protease Wichapong model. The results indicate better binding properties of and with calculated binding energies of -8.5 and -8.4 kcal mol, respectively, compared to the binding energy of quercetin of -7.2 kcal mol, which corroborates well with the experimental observations.