2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies

Dongwei Kang; Francesc X Ruiz; Yanying Sun; Da Feng; Lanlan Jing; Zhao Wang; Tao Zhang; Shenghua Gao; Lin Sun; Erik De Clercq; Christophe Pannecouque; Eddy Arnold; Peng Zhan; Xinyong Liu

doi:10.1021/acs.jmedchem.1c00268

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2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies

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2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies

Dongwei Kang, Francesc X Ruiz, Yanying Sun, Da Feng, Lanlan Jing, Zhao Wang, Tao Zhang, Shenghua Gao, Lin Sun, Erik De Clercq, …

Journal of medicinal chemistry, Vol.64(7), pp.4239-4256

04/08/2021

DOI: https://doi.org/10.1021/acs.jmedchem.1c00268

PMID: 33734714

Abstract

There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead led to the identification of a potent inhibitor . yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of toward the NNRTI-adjacent site as a lead development strategy. Furthermore, demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of as a promising anti-HIV-1 drug candidate.

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Title: 2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies
Creators: Dongwei Kang - China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, Jinan 250012, Shandong, PR China
Francesc X Ruiz - Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, United States
Yanying Sun - 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, Jinan 250012, Shandong, PR China
Da Feng - 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, Jinan 250012, Shandong, PR China
Lanlan Jing - 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, Jinan 250012, Shandong, PR China
Zhao Wang - 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, Jinan 250012, Shandong, PR China
Tao Zhang - 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, Jinan 250012, Shandong, PR China
Shenghua Gao - 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, Jinan 250012, Shandong, PR China
Lin Sun - 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, Jinan 250012, Shandong, PR China
Erik De Clercq - Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Katholieke Universiteit Leuven, Herestraat 49 Postbus 1043 (09.A097), Leuven B-3000, Belgium
Christophe Pannecouque - Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Katholieke Universiteit Leuven, Herestraat 49 Postbus 1043 (09.A097), Leuven B-3000, Belgium
Eddy Arnold - Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, United States
Peng Zhan - China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, Jinan 250012, Shandong, PR China
Xinyong Liu - China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, Jinan 250012, Shandong, PR China
Publication Details: Journal of medicinal chemistry, Vol.64(7), pp.4239-4256
Date published: 04/08/2021
Academic Unit: Center for Advanced Biotechnology and Medicine
Language: English
Resource Type: Journal article
Identifiers: 991031654469004646