2. Academic Validation
  3. Discovery of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles as potent HIV-1 NNRTIs with improved anti-resistance and drug-like profiles

Discovery of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles as potent HIV-1 NNRTIs with improved anti-resistance and drug-like profiles

  • Eur J Med Chem. 2023 Oct 5;258:115605. doi: 10.1016/j.ejmech.2023.115605.
Xiangyi Jiang 1,  Boshi Huang 1,  Waleed A Zalloum 2,  Chin-Ho Chen 3,  Xiangkai Ji 1,  Zhen Gao 1,  Jiaojiao Dai 1,  Minghui Xie 1,  Dongwei Kang 1,  Erik De Clercq 4,  Christophe Pannecouque 4,  Xinyong Liu 5,  Peng Zhan 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
  • 2 Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821, Jordan.
  • 3 Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC, 27710, USA.
  • 4 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U.Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
PMID: 37393790 DOI: 10.1016/j.ejmech.2023.115605
Abstract

Taking our previously reported HIV-1 NNRTIs BH-11c and XJ-10c as lead compounds, series of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles were designed to improve anti-resistance and drug-like profiles. According to the three rounds of in vitro Antiviral activity screening, compound 12g was the most active inhibitor against wild-type and five prevalent NNRTI-resistant HIV-1 strains with EC50 values ranging from 0.024 to 0.0010 μM. This is obviously better than the lead compound BH-11c and the approved drug ETR. Detailed structure-activity relationship was investigated to provide valuable guidance for further optimization. The MD simulation study indicated that 12g could form additional interactions with residues around the binding site in HIV-1 RT, which provided reasonable explanations for its improved anti-resistance profile compared to ETR. Furthermore, 12g showed significant improvement in water solubility and other drug-like properties compared to ETR. The CYP enzymatic inhibitory assay indicated that 12g was unlikely to induce CYP-mediated drug-drug interactions. 12g pharmacokinetics parameters were investigated and it displayed a long half-life of 6.59 h in vivo. The properties of compound 12g make it a promising lead compound for the development of new generation of antiretroviral drugs.

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