New Pyridinone Derivatives as Potent HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1<i>H</i>)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (<b>10</b>) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC₅₀. Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (<b>22</b>) or 3-isopropyl group (<b>23</b>) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains