Synthesis and biological evaluation of cyclohexanpyridin-2(1H)-one analogues as novel HIV-1 NNRTIs

Gibrán Rodríguez-Vega 1, 2, #, Julio Cesar Abarca-Magaña 3, #, Nancy Vanessa Castro-Perea 1, Mirna Berenice Ruiz-Rivera 3, José Luis Medina-Franco 4, Leonor Huerta-Hernández 3 and Daniel Chávez 1,*

1 National Technological of Mexico /Tijuana Technological Institute, Center for Graduate and Research in Chemistry, Postal Box 1166, Tijuana, Baja California 22000, Mexico.
2 Academic Unit of Chemical Biological and Pharmaceutical Sciences, Autonomous University of Nayarit, Tepic, Nayarit 63000, Mexico.
3 Biomedical Research Institute, Department of Immunology,National Autonomous University of Mexico, Mexico City 04510, Mexico.
4 DIFACQUIM Research group, Department of Pharmacy, School of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico.
# Authors contributed equally to this work.
Research Article
World Journal of Advanced Research and Reviews, 2024, 22(03), 369–385
Article DOI: 10.30574/wjarr.2024.22.3.1684
Publication history: 
Received on 24 April 2024 revised on 01 June 2024; accepted on 03 June 2024
In the search and development of new non-nucleoside reverse transcriptase inhibitor (NNRTI) compounds that are more effective against HIV-1, eight C-4 alkylated cyclohexanpyridinone derivatives of the alkyloxy and alkylamino type were synthesized. Compounds were characterized by spectroscopic and spectrometric techniques. In addition, their inhibitory effect against reverse transcriptase (RT), inhibition of HIV in vitro and cytotoxicity in JLTRG cells was evaluated. Compound 8e showed reasonable cellular antiviral activity (EC50 = 28.78 μM), moderate inhibition against RT (IC50 = 69.8 μM), and was not cytotoxic at the concentrations evaluated. Docking and molecular dynamics studies corroborate favorable binding to the HIV IT allosteric site with 8e, providing a basis for the design of more potent analogues.
HIV-1; NNRTI; Reverse transcriptase; Pyridinones; Docking; Cytotoxicity; HIV infectivity; Molecular dynamics
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