Journal
ACTA PHARMACEUTICA SINICA B
Volume 10, Issue 6, Pages 961-978Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2019.11.010
Keywords
HIV-1; NNRTIs; HENTs; S-DABOs; DATAs; DAPYs; Structure-based optimization; Fragment-based drug design; Molecular hybridization; Bioisosterism
Categories
Funding
- National Natural Science Foundation of China [81872791, 21372050]
- Young Elite Scientists Sponsorship Program by the China Association for Science and Technology [2017QNRC061]
- National Key R&D Program of China [2017YFA0506000]
- Key Research and Development Program of Ningxia (China) [2019BFG02017, 2018BFH02001]
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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. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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