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Design, synthesis, and biological testing of biphenylmethyloxazole inhibitors targeting HIV-1 reverse transcriptase.

Carter ZJ, Hollander K, Spasov KA, Anderson KS, Jorgensen WL
Bioorg Med Chem Lett 129216 (2023)
Cited: 2 times
EuropePMC logo PMID: 36871704

Abstract

We report non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) using a biphenylmethyloxazole pharmacophore. A crystal structure of benzyloxazole 1 was obtained and suggested the potential viability of biphenyl analogues. In particular, 6a, 6b, and 7 turned out to be potent NNRTIs with low-nanomolar activity in enzyme inhibition and infected T-cell assays, and with low cytotoxicity. Though modeling further suggested that analogues with fluorosulfate and epoxide warheads might provide covalent modification of Tyr188, synthesis and testing did not find evidence for this outcome.

Articles citing this publication (2)

  1. Exploring novel HIV-1 reverse transcriptase inhibitors with drug-resistant mutants: A double mutant surprise. Hollander K, Chan AH, Frey KM, Hunker O, Ippolito JA, Spasov KA, Yeh YJ, Jorgensen WL, Ho YC, Anderson KS. Protein Sci 32 e4814 (2023)
  2. Evolutionary Monte Carlo of QM Properties in Chemical Space: Electrolyte Design. Karandashev K, Weinreich J, Heinen S, Arismendi Arrieta DJ, von Rudorff GF, Hermansson K, von Lilienfeld OA. J Chem Theory Comput 19 8861-8870 (2023)


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