2. Academic Validation
  3. Disubstituted pyrimidine-5-carboxamide derivatives as novel HIV-1 NNRTIs: Crystallographic overlay-based molecular design, synthesis, and biological evaluation

Disubstituted pyrimidine-5-carboxamide derivatives as novel HIV-1 NNRTIs: Crystallographic overlay-based molecular design, synthesis, and biological evaluation

  • Eur J Med Chem. 2022 Nov 22;246:114957. doi: 10.1016/j.ejmech.2022.114957.
Da Feng 1,  Hao Lin 1,  Liyang Jiang 1,  Jiaojiao Dai 1,  Xiaoying Zhang 1,  Zhongxia Zhou 2,  Yanying Sun 1,  Zhao Wang 1,  Erik De Clercq 3,  Christophe Pannecouque 3,  Dongwei Kang 4,  Peng Zhan 5,  Xinyong Liu 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 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; Department of Cancer Center, Shandong University, Jinan, 250117, PR China.
  • 3 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
  • 4 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 36446205 DOI: 10.1016/j.ejmech.2022.114957
Abstract

Herein, via crystallographic overlay-based molecular hybridization strategy, a series of disubstituted pyrimidine-5-carboxamide derivatives were designed by introducing an amide moiety to the central core of the lead etravirine. All the newly synthesized compounds were evaluated for their anti-HIV-1 potencies in MT-4 cells using the MTT method. Most of the synthesized compounds displayed promising Antiviral activities against the wild-type (IIIB) and a panel of HIV-1 NNRTIs-resistant strains. Especially, 21c exhibited the most potent activity (EC50 = 0.009-0.065 μM) against HIV-1 IIIB, L100I, K103N, Y181C, Y188L, and RES056, being comparable to those of etravirine. The inhibitory activity to Reverse Transcriptase (RT) was evaluated by ELISA method, and the target of the compounds was proved to be RT. Moreover, the molecular docking was investigated to clarify the binding mode of 21c with RT. Overall, the results demonstrated that 21c could serve as a lead for further modification to develop novel HIV-1 NNRTIs.

Keywords

Crystallographic overlay-based molecular hybridization; DAPY; HIV-1; NNRTIs; Pyrimidine-5-carboxamide.

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