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Tytuł:
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Disubstituted pyrimidine-5-carboxamide derivatives as novel HIV-1 NNRTIs: Crystallographic overlay-based molecular design, synthesis, and biological evaluation.
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Autorzy:
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Feng D; 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.
Lin H; 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.
Jiang L; 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.
Dai J; 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.
Zhang X; 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.
Zhou Z; 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.
Sun Y; 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.
Wang Z; 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.
Clercq E; Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
Pannecouque C; Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
Kang D; 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: .
Zhan P; 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: .
Liu X; 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: .
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Źródło:
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European journal of medicinal chemistry [Eur J Med Chem] 2023 Jan 15; Vol. 246, pp. 114957. Date of Electronic Publication: 2022 Nov 22.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
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MeSH Terms:
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Anti-HIV Agents*/chemistry
HIV-1*/metabolism
Structure-Activity Relationship ; Molecular Docking Simulation ; Drug Design ; HIV Reverse Transcriptase ; Reverse Transcriptase Inhibitors/chemistry ; Pyrimidines/chemistry
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Contributed Indexing:
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Keywords: Crystallographic overlay-based molecular hybridization; DAPY; HIV-1; NNRTIs; Pyrimidine-5-carboxamide
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Substance Nomenclature:
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0C50HW4FO1 (etravirine)
0 (Anti-HIV Agents)
EC 2.7.7.49 (HIV Reverse Transcriptase)
0 (Reverse Transcriptase Inhibitors)
0 (Pyrimidines)
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Entry Date(s):
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Date Created: 20221129 Date Completed: 20230103 Latest Revision: 20230103
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Update Code:
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20240105
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DOI:
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10.1016/j.ejmech.2022.114957
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PMID:
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36446205
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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 (EC 50 = 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier Masson SAS. All rights reserved.)