2. Academic Validation
  3. Design of the naphthyl-diarylpyrimidines as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) via structure-based extension into the entrance channel

Design of the naphthyl-diarylpyrimidines as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) via structure-based extension into the entrance channel

  • Eur J Med Chem. 2021 Dec 15:226:113868. doi: 10.1016/j.ejmech.2021.113868.
Xin Jin 1,  Hu-Ri Piao 1,  Christophe Pannecouque 2,  Erik De Clercq 2,  Chunlin Zhuang 3,  Fen-Er Chen 4
Affiliations

Affiliations

  • 1 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanbian University, 977 Gongyuan Road, Yanji, Jilin Province, 133002, 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, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China. Electronic address: zclnathan@163.com.
  • 4 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanbian University, 977 Gongyuan Road, Yanji, Jilin Province, 133002, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China; Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium. Electronic address: rfchen@fudan.edu.cn.
PMID: 34583311 DOI: 10.1016/j.ejmech.2021.113868
Abstract

A series of novel naphthyl-diarylpyrimidine (DAPY) derivatives were designed and synthesized to explore the entrance channel of the non-nucleoside Reverse Transcriptase inhibitors binding pocket (NNIBP) by incorporating different flexible side chains at the C-6 position. The biological evaluation results showed that all analogues possessed promising HIV-1 inhibitory activity at the nanomolar concentration range. Three compounds (7, 9 and 39) displayed excellent potency against WT HIV-1 strain with EC50 values ranging from 5 to 10 nM and high selectivity indexes (SI = 3504, 30488 and 22846, respectively), which were higher than for nevirapine and comparable to the values for etravirine. The RT inhibition activity, preliminary structure-activity relationship and molecular docking study showed that the side chain at the C-6 position of the DAPYs occupied the entrance channel and significantly influenced anti-HIV activity and selectivity. Additionally, the physicochemical properties were investigated to evaluate the drug-like features, which indicated that introducing various substituents on the pyrimidine ring can improve solubility.

Keywords

Entrance channel; HIV-1; NNRTIs; Naphthyl-diarylpyrimidines; SARs.

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