Reviews
Chunlin Zhuang, Christophe Pannecouque, Erik De Clercq, Fener Chen. Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years[J]. Acta Pharmaceutica Sinica B, 2020, 10(6): 961-978

Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years
Chunlin Zhuanga,b, Christophe Pannecouqued, Erik De Clercqd, Fener Chena,b,c
a Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China;
b Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China;
c Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China;
d Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium
Abstract:
Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio) thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (S-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure-activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed.
Key words:    HIV-1    NNRTIs    HENTs    S-DABOs    DATAs    DAPYs    Structure-based optimization    Fragment-based drug design    Molecular hybridization    Bioisosterism   
Received: 2019-08-31     Revised: 2019-10-08
DOI: 10.1016/j.apsb.2019.11.010
Funds: This work was funded by grants from the National Natural Science Foundation of China (81872791 and 21372050); the Young Elite Scientists Sponsorship Program by the China Association for Science and Technology (2017QNRC061); National Key R&D Program of China (2017YFA0506000) and the Key Research and Development Program of Ningxia (2019BFG02017 and 2018BFH02001, China). We thank Ningxia Medical University for providing the sources of molecular modeling.
Corresponding author: Fener Chen     Email:rfchen@fudan.edu.cn
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Chunlin Zhuang
Christophe Pannecouque
Erik De Clercq
Fener Chen

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