Fragment Hopping-Based Design of Novel Biphenyl-DAPY Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Significantly Improved Anti-Resistance Efficacy

  • J Med Chem. 2023 Apr 13;66(7):4755-4767. doi: 10.1021/acs.jmedchem.2c01900.
Ya-Li Sang  1  2  3 ,  Christophe Pannecouque  4 ,  Erik De Clercq  4 ,  Shuai Wang  1  2 ,  Fen-Er Chen  1  2  3
Affiliations
  • 1. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
  • 2. Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
  • 3. School of Science, Harbin Institute of Technology (Shenzhen), Shenzhen 518055, China.
  • 4. Rega Institute for Medical Research, KU Leuven, Herestraat 49, Leuven B-3000, Belgium.
PMID: 36996328 DOI: 10.1021/acs.jmedchem.2c01900
Abstract

To enhance the anti-resistance efficacy of our previously reported non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) 4, a series of novel biphenyl-DAPY derivatives were developed using the fragment-hopping strategy. Most of the compounds 8a-v exhibited remarkably improved anti-HIV-1 potency. The most active compound 8r proved to be exceptionally potent against the wild-type HIV-1 (EC50 = 2.3 nM) and five mutant strains, such as K103N (EC50 = 8 nM) and E138K (EC50 = 6 nM), significantly better than 4. The new DAPY analogue was 8-fold less cytotoxic and had a 17-fold higher selectivity index (CC50 = 40.77 μM, SI > 17391) than etravirine and rilpivirine. Also, it displayed favorable pharmacokinetic properties with an oral bioavailability of 31.19% and weak sensitivity toward both CYP and hERG. No apparent acute toxicity (2 g/kg) and tissue damage occurred. These findings will further expand the possibility of successfully identifying biphenyl-DAPY analogues as highly potent, safe, and orally active NNRTIs for HIV treatment.

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