Conformational restriction design of thiophene-biphenyl-DAPY HIV-1 non-nucleoside reverse transcriptase inhibitors

Yali Sang; Sheng Han; Christophe Pannecouque; Erik De Clercq; Chunlin Zhuang; Fener Chen

doi:10.1016/j.ejmech.2019.111603

Conformational restriction design of thiophene-biphenyl-DAPY HIV-1 non-nucleoside reverse transcriptase inhibitors

Eur J Med Chem. 2019 Nov 15:182:111603. doi: 10.1016/j.ejmech.2019.111603. Epub 2019 Aug 8.

Authors

Yali Sang¹, Sheng Han¹, Christophe Pannecouque², Erik De Clercq², Chunlin Zhuang³, Fener Chen⁴

Affiliations

¹ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, People's Republic of China.
² Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
³ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, People's Republic of China. Electronic address: zclnathan@163.com.
⁴ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, People's Republic of China. Electronic address: rfchen@fudan.edu.cn.

PMID: 31421633
DOI: 10.1016/j.ejmech.2019.111603

Abstract

Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2'-fluoro and 3'-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2'-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC₅₀ = 14 and 17 nM, respectively) and RT enzyme (EC₅₀ = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC₅₀ = 264.19 μM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs.

Keywords: Biphenyl-DAPY; Conformational restriction; HIV-1; Molecular modeling; NNRTIs.

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Biphenyl Compounds / chemistry
Biphenyl Compounds / pharmacology*
Cell Line
Dose-Response Relationship, Drug
Drug Design*
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects
HIV-1 / enzymology*
Humans
Microbial Sensitivity Tests
Molecular Conformation
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*
Structure-Activity Relationship
Thiophenes / chemistry
Thiophenes / pharmacology*

Substances

Anti-HIV Agents
Biphenyl Compounds
Pyrimidines
Reverse Transcriptase Inhibitors
Thiophenes
diphenyl
HIV Reverse Transcriptase