4-Phenylcoumarin derivatives as new HIV-1 NNRTIs: Design, synthesis, biological activities, and computational studies

Rasha Z Batran; Ahmed Sabt; Mohammed A Khedr; Abdou K Allayeh; Christophe Pannecouque; Asmaa F Kassem

doi:10.1016/j.bioorg.2023.106918

4-Phenylcoumarin derivatives as new HIV-1 NNRTIs: Design, synthesis, biological activities, and computational studies

Bioorg Chem. 2023 Dec:141:106918. doi: 10.1016/j.bioorg.2023.106918. Epub 2023 Oct 14.

Authors

Rasha Z Batran¹, Ahmed Sabt², Mohammed A Khedr³, Abdou K Allayeh⁴, Christophe Pannecouque⁵, Asmaa F Kassem⁶

Affiliations

¹ Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo 12622, Egypt. Electronic address: rasha_batran@yahoo.com.
² Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo 12622, Egypt.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Kuwait.
⁴ Water Pollution Research Department, Environment and Climate Change Institute, National Research Centre, Dokki, Cairo 12622, Egypt.
⁵ Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
⁶ Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo 12622, Egypt.

PMID: 37866206
DOI: 10.1016/j.bioorg.2023.106918

Abstract

A series of 4-phenylcoumarin derivatives was synthesized and evaluated for their cellular anti-HIV-1 and HIV-2 activities as well as their inhibitory effects against HIV-1 reverse transcriptase (RT). The hydrazone compound 8b and the ethylthiosemicarbazide derivative 4c showed the best inhibition activity against wild-type (WT) HIV-1. The promising compounds were further evaluated against HIV-1 RT and exhibited significant inhibitory activity with compound 8b showing comparable effect to the reference NNRTI Efavirenz (IC₅₀ = 9.01 nM). Structure activity relationship study revealed the importance of 6-chloro and 4-phenyl substituents for optimum activity, as well as the 5-atoms linker (=N-NH-CO-CH₂-O-) at position 7 of coumarin scaffold that can support the rotation and flexibility of compound 8b to fit well in the binding pocket. The molecular docking of compound 8b demonstrated a typical seahorse binding mode with better binding interactions that covered more residues when compared to Efavirenz.

Keywords: 4-Phenylcoumarins; Computational studies; HIV; Hydrazones; NNRTIs.

MeSH terms

Anti-HIV Agents* / chemistry
Coumarins / pharmacology
Drug Design
HIV Reverse Transcriptase
HIV-1*
Molecular Docking Simulation
Reverse Transcriptase Inhibitors / chemistry
Structure-Activity Relationship

Substances

efavirenz
4-phenylcoumarin
Reverse Transcriptase Inhibitors
Coumarins
HIV Reverse Transcriptase
Anti-HIV Agents