2. Academic Validation
  3. Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus

Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus

  • Eur J Med Chem. 2018 May 10:151:339-350. doi: 10.1016/j.ejmech.2018.03.059.
Ye Tian 1,  Zhaoqiang Liu 1,  Jinghan Liu 2,  Boshi Huang 1,  Dongwei Kang 1,  Heng Zhang 1,  Erik De Clercq 3,  Dirk Daelemans 3,  Christophe Pannecouque 3,  Kuo-Hsiung Lee 4,  Chin-Ho Chen 5,  Peng Zhan 6,  Xinyong Liu 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
  • 2 School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, 210009, Nanjing, PR China.
  • 3 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium.
  • 4 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
  • 5 Surgical Science, Department of Surgery, Duke University Medical Center, Durham, NC, 27710, United States.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 29635166 DOI: 10.1016/j.ejmech.2018.03.059
Abstract

Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a "triazole tail" occupying the entrance channel in the NNRTI binding pocket of the Reverse Transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC50 of 0.02-1.77 μM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.015 μM, CC50 = 40.15 μM), pyrrolidin-1-ylmethanone (3b8, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.014 μM, CC50 = 58.09 μM) and morpholinomethanone (3b9, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.027 μM, CC50 = 180.90 μM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed.

Keywords

Diarylnicotinamide; Drug design; Entrance channel; HIV-1; NNRTIs; Triazole.

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