Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years

Chunlin Zhuang; Christophe Pannecouque; Erik De Clercq; Fener Chen

doi:10.1016/j.apsb.2019.11.010

Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years

Acta Pharm Sin B. 2020 Jun;10(6):961-978. doi: 10.1016/j.apsb.2019.11.010. Epub 2019 Nov 21.

Authors

Chunlin Zhuang^{1

2}, Christophe Pannecouque³, Erik De Clercq³, Fener Chen^{1

2

4}

Affiliations

¹ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
² Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
³ Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium.
⁴ Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China.

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.

Keywords: AIDS, acquired immunodeficiency syndrome; Bioisosterism; DAPY, diarylpyrimidine; DAPYs; DATA, diaryltriazine; DATAs; DLV, delavirdine; DOR, doravirine; ECD, electronic circular dichroism; EFV, efavirenz; ETR, etravirine; FDA, U.S. Food and Drug Administration; Fragment-based drug design; HAART, highly active antiretroviral therapy; HENT, napthyl-HEPT; HENTs; HEPT, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine; HIV, human immunodeficiency virus; HIV-1; INSTI, integrase inhibitor; Molecular hybridization; NNIBP, NNRTI binding pocket; NNRTI, non-nucleoside reverse transcriptase inhibitor; NNRTIs; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; PK, pharmacokinetic; PROTAC, proteolysis targeting chimera; RPV, rilpivirine; RT, reverse transcriptase; S-DABO, thio-dihydro-alkoxy-benzyl-oxopyrimidine; S-DABOs; SAR, structure–activity relationship; SBDD, structure-based drug design; SFC, supercritical fluid chromatography; SI, selectivity index; Structure-based optimization; UNAIDS, the Joint United Nations Programme on HIV/AIDS; ee, enantiomeric excess.

Publication types

Review