Novel tight binding PETT, HEPT and DABO-based non-nucleoside inhibitors of HIV-1 reverse transcriptase

Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are a key component of effective combination antiretroviral therapies for HIV/AIDS. NNRTIs despite their chemical diversity, bind to a common allosteric site of HIV-1 RT, the primary target for anti-AIDS chemotherapy, and noncompetitively inhibit DNA polymerization. NNRTIs currently in clinical use have a low genetic barrier to resistance and therefore, the need for novel NNRTIs active against drug-resistant mutants selected by current therapies is of paramount importance. We describe the chemistry and biological evaluation of highly potent novel phenethylthiazolylthiourea (PETT), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the hydrophobic binding pocket of HIV-1 RT. These NNRTIs were rationally designed by molecular modeling and docking studies using a novel composite binding pocket that predicted how drug-resistant mutations would change the RT binding pocket shape, volume, and chemical make-up and how these changes could affect NNRTI binding. Several ligand derivatization sites were identified for docked NNRTIs that fit the composite binding pocket. The best fit was determined by calculating an inhibition constant (Ludi K-i) of the docked compound for the composite binding pocket. Compounds with a Ludi K-i of < 1 mu M were identified as the most promising tight binding NNRTIs. These NNRTIs displayed high selective indices with robust anti-HIV-1 activity against the wild-type and drug-resistant isolates carrying multiple RT gene mutations. The high rate of treatment failure due to the emergence of drug resistance mutations makes the discovery of broad-spectrum PETT, HEPT and DABO-based NNRTIs useful as a component of effective combination regimens.