SYNTHESIS, MOLECULAR MODELING STUDY, AND BIOLOGICAL EVALUATION OF N-ACYL-ANTHRANOYLANTHRANILIC ACID DERIVATIVES AND THEIR CYCLIZED BENZOXAZINONES AS NOVEL HIV-1 NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Document Type : Original Article

Authors

1 Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt./ Present Affiliation, Department of Medicinal Chemistry, Faculty of Pharmacy, South Valley University, Qena, 83511, Egypt.

2 Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.

Abstract

N-Acylanthranoylanthranilic acids (5a–n)and their cyclized 4H-benzo [d][1,3] oxazin-4-one derivatives (6a–n) were prepared via a three-step process.The synthesized compoundswere then screened to determine their human immunodeficiency virus (HIV-1) nonnucleoside reverse transcriptase (NNRT) inhibition activity. The half-maximal inhibitory concentrations of the compounds, (IC50), were found to be in the range of 30 nM–123 µM, using nevirapine as a reference HIV drug. The reverse transcriptase inhibition activity of the compounds was shown to be distinctly affected by the cyclized motif and the nature of the appended N-acyl moiety. Selected active compounds, 5a, 6d, 6h, and 6k (IC50 50 / IC50 . Most of the designed compounds fulfill Lipinski's requirements of druggability. Molecular docking studies reveal H–π, H–O (N), π–π, and halogen bonding between the docked compounds and the residues within the allosteric binding pocket close to the RT active site. The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO)- derived energy descriptors are shown to be useful predictive tools for reverse transcriptase inhibition (RTI) activity and in silico binding to mutant nucleophilic side chain residues in the nonnucleoside inhibitor binding pocket motif.

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