Development of novel HEPT analogs featuring significantly improved anti-resistance potency against HIV-1 through chemical space exploration of the tolerant region I

Ruo-Lan Zhou; Christophe Pannecouque; Erik De Clercq; Shuai Wang; Fen-Er Chen

doi:10.1016/j.bioorg.2023.106783

Development of novel HEPT analogs featuring significantly improved anti-resistance potency against HIV-1 through chemical space exploration of the tolerant region I

Bioorg Chem. 2023 Nov:140:106783. doi: 10.1016/j.bioorg.2023.106783. Epub 2023 Aug 12.

Authors

Ruo-Lan Zhou¹, Christophe Pannecouque², Erik De Clercq², Shuai Wang³, Fen-Er Chen⁴

Affiliations

¹ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of C∼hemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, 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 C∼hemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China. Electronic address: shuaiwang@fudan.edu.cn.
⁴ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of C∼hemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China. Electronic address: rfchen@fudan.edu.cn.

PMID: 37595396
DOI: 10.1016/j.bioorg.2023.106783

Abstract

Our recent great interest in developing 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogs for HIV therapy identified a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) 3 (EC₅₀ = 0.01681 μM), but its therapeutic efficacy was limited by its poor anti-resistance potency. This prompted us to search for potential HEPT analogs with broad-spectrum activities, leading to the generation of a series of novel HEPT analogs through exploring the chemical space of the solvent - protein interface. Encouraging improvements in anti-resistance efficacy were observed in some of these analogs, with the most promising compound 7 g being 3 to 26 - fold more potent than 3 against five mutant strains (E138K, Y181C, L100I, K103N, and Y188L). This analog surpassed the activity and selectivity of compound 3 by approximately 2-fold (EC₅₀ = 0.007468 μM, SI = 4260). Furthermore, it was found to demonstrate feeble inhibition of CYP and hERG in vitro, and no in vivo acute toxicity. This study will further enrich the structure-activity relationships (SARs) of the HEPT scaffold, providing new guidance for the development of NNRTIs.

Keywords: AIDS; Anti-resistance; HEPT; HIV; NNRTI.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

HIV-1*
Reverse Transcriptase Inhibitors / pharmacology
Solvents
Space Flight*
Structure-Activity Relationship

Substances

Reverse Transcriptase Inhibitors
Solvents