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

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.