2. Academic Validation
  3. Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus

Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus

  • J Med Chem. 2016 Apr 28;59(8):3689-704. doi: 10.1021/acs.jmedchem.5b01827.
Na Liu 1,  Lei Wei 1,  Li Huang 2,  Fei Yu 3 4,  Weifan Zheng 5,  Bingjie Qin 1,  Dong-Qin Zhu 1,  Susan L Morris-Natschke 6,  Shibo Jiang 3 4,  Chin-Ho Chen 2,  Kuo-Hsiung Lee 6 7,  Lan Xie 1 6
Affiliations

Affiliations

  • 1 Beijing Institute of Pharmacology & Toxicology , 27 Tai-Ping Road, Beijing 100850, China.
  • 2 Surgical Oncology Research Facility, Duke University Medical Center , Box 2926, Durham, North Carolina 27710, United States.
  • 3 Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University , Shanghai 200032, China.
  • 4 Lindsley F. Kimball Research Institute, New York Blood Center , New York, New York 10065, United States.
  • 5 Department of Pharmaceutical Sciences & BRITE Institute, North Carolina Central University , Durham, North Carolina 27707, United States.
  • 6 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599-7568, United States.
  • 7 Chinese Medicine Research and Development Center, China Medical University and Hospital , Taichung, Taiwan.
PMID: 27070547 DOI: 10.1021/acs.jmedchem.5b01827
Abstract

Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside Reverse Transcriptase Inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant.

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