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.

Yali Sang ¹, Sheng Han ¹, Christophe Pannecouque ², Erik De Clercq ², Chunlin Zhuang ³, Fener Chen ⁴

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.

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