Novel 2-alkylthio-1-benzylimidazole-5-carboxylic Acid Derivatives Targeting Gp41: Design, Synthesis, and In Vitro Anti-HIV Activity Evaluation

Background: Although current available medications have increased the quality of life in HIV-infected patients, there are still some shortcomings in HIV treatment arising from viral resistance, drug side effects, and the high cost of medication. Therefore, there is an urgent need for some suitable HIV inhibitors with different mechanisms of action. Gp41, located on the HIV cell surface, plays an important role in the fusion of viral and host cell membranes. With the same structure in different HIV strains, gp41 seems to be a promising target for developing novel HIV fusion inhibitors. Objective: Based on the essential structural elements of gp41 inhibitors, two series of compounds were prepared, and their inhibitory effect on HIV cell growth was investigated. Compared to the known small-molecule gp41 inhibitors, 2-Alkylthio-1-benzylimidazole-5-carboxylic acid (series I) and (E)-4-{[5-(((1-benzyl-1H-1,2,3-triazol-4-yl)methoxyimino)methyl)-2-(alkylthio)-1H-imidazol- 1-yl]methyl}benzoic acid derivatives (series II) were found to have a more flexible skeleton with extra moieties interacting with the gp41 key residues. Methods: In silico drug design approaches, including molecular docking and molecular dynamics simulations, were employed to design these novel compounds prior to preparation. The designed compounds exhibited proper chemical interactions and stable complexes with gp41. Then, the selected candidates were efficiently synthesized, and their anti-HIV-1 and anti-HIV-2 activities, as well as their cellular cytotoxicity in MT-4 cells were determined. Results: None of the compounds belonging to the series I were active against HIV-1 and HIV-2 replication in cell cultures, and most of the compounds in series II exhibited significant cytotoxicity against MT-4 cells in low micromolar concentrations. Conclusion: The smaller molecular structures of the compounds in series I might be responsible for their poor anti-HIV effects. The high toxicity of the series II compounds on the host cell makes it impossible to assess their anti-HIV activities.