Structure-based discovery of novel piperidine-biphenyl-DAPY derivatives as non-nucleoside reverse transcriptase inhibitors featuring improved potency, safety, and selectivity: From piperazine-biphenyl-DAPYs to piperidine-biphenyl-DAPYs

  • Eur J Med Chem. 2024 Jul 10:276:116668. doi: 10.1016/j.ejmech.2024.116668.
Wen-Juan Huang  1 ,  Christophe Pannecouque  2 ,  Erik De Clercq  2 ,  Shuai Wang  3 ,  Fen-Er Chen  4
Affiliations
  • 1. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China.
  • 2. Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
  • 3. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China. Electronic address: [email protected].
  • 4. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 38996652 DOI: 10.1016/j.ejmech.2024.116668
Abstract

Starting from our previously reported nonnucleoside Reverse Transcriptase Inhibitor (NNRTI, 3), continuous efforts were made to enhance its potency and safety through a structure-based drug design strategy. This led to the discovery of a series of novel piperidine-biphenyl-diarylpyrimidines (DAPYs). Compound 10p, the most active compound in this series, exhibited an EC50 value of 6 nM against wide-type HIV-1 strain, which was approximately 560-fold more potent than the initial compound 3 (EC50 = 3.36 μM). Furthermore, significant improvements were observed in cytotoxicity and selectivity (CC50 > 202.17 μM, SI > 33144) compared to compound 3 (CC50 = 14.84 μM, SI = 4). Additionally, compound 10p demonstrated increased inhibitory activity against clinically mutant virus strains (EC50 = 7-63 nM). Further toxicity evaluation revealed that compound 10p exhibited minimal CYP enzyme and hERG inhibition. Importantly, single-dose acute toxicity testing did not result in any fatalities or noticeable pathological damage in mice. Therefore, compound 10p can be regarded as a lead candidate for guiding further development of biphenyl-diarylpyrimidine NNRTIs with favorable druggability for HIV therapy.

Keywords
AIDS; DAPYs; HIV-1; NNRTIs; Safety.
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