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Novel benzoxazin-3-one derivatives: Design, synthesis, molecular modeling, anti-HIV-1 and integrase inhibitory assay

Author(s):

Mahdieh Safakish, Zahra Hajimahdi, Rouhollah Vahabpour, Rezvan Zabihollahi and Afshin Zarghi*  

Abstract:


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.

Method: In this study, we introduced benzoxazin-3-one scaffold for integrase inhibitory potential as bioisoster replacement strategy of 2-benzoxazolinone.

Result: 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 occupy hydrophobic site created by the cytidylate nucleotide (DC-16).

Conclusion: The most potent and selective compound displayed 110 µM IC50 with selectivity index of more than 2.

Keywords:

AIDS, HIV-1, Integrase, Strand transfer inhibitor, Benzoxazin-3-one, Docking

Affiliation:

Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Medical Lab Technology Department, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Medical Lab Technology Department, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran



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