Novel Benzoxazin-3-one Derivatives: Design, Synthesis, Molecular Modeling, Anti-HIV-1 and Integrase Inhibitory Assay

Introduction: Integrase is a validated drug target for anti-HIV-1 therapy. The second generation integrase inhibitors display π-stacking interaction ability with 3’-end nucleotide as a streamlined metal chelating pharmacophore. Methods: In this study, we introduced benzoxazin-3-one scaffold for integrase inhibitory potential as bioisostere replacement strategy of 2-benzoxazolinone. Results: Molecular modeling studies revealed that amide functionality alongside oxadiazole heteroatoms and sulfur in the second position of oxadiazole ring could mimic the metal chelating pharmacophore. The halobenzyl ring occupies hydrophobic site created by the cytidylate nucleotide (DC-16). Conclusion: The most potent and selective compound displayed 110 μM IC50 with a selectivity index of more than 2.