2. Academic Validation
  3. Structural optimization of pyridine-type DAPY derivatives to exploit the tolerant regions of the NNRTI binding pocket

Structural optimization of pyridine-type DAPY derivatives to exploit the tolerant regions of the NNRTI binding pocket

  • Eur J Med Chem. 2016 Oct 4:121:352-363. doi: 10.1016/j.ejmech.2016.05.054.
Wenmin Chen 1,  Peng Zhan 1,  Dirk Daelemans 2,  Jiapei Yang 1,  Boshi Huang 1,  Erik De Clercq 2,  Christophe Pannecouque 3,  Xinyong Liu 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China.
  • 2 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium.
  • 3 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium. Electronic address: Christophe.Pannecouque@rega.kuleuven.be.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 27267005 DOI: 10.1016/j.ejmech.2016.05.054
Abstract

Based on the crystallographic studies of diarylpyrimidines (DAPYs), we embarked on incorporating the hydrophilic piperidyl or morpholinyl group into the known DAPY derivatives bearing the pyridine moiety as a core structure, with the double aim to exploit additional interactions with the HIV-1 NNRTI binding pocket (NNIBP), as well as to improve the compound solubility. The Antiviral evaluation result show that the most potent compounds I-8b2, I-8b3, I-8b4 and I-8c3 exhibited anti-HIV-1 (IIIB) strain activity ranging from 7.4 nM to 9.4 nM (SI = 168-1283), superior to FDA-approved drugs of nevirapine (NVP), lamivudine (3TC) and delavirdine (DLV), and comparable to etravirine (ETV), zidovudine (AZT) and efavirenz (EFV). Additionally, compounds I-8c2 and I-8c3 showed moderate activity against NNRTI resistant strains baring mutations K103N and Y181C with EC50 values of 6.2 μM and 6.8 μM, respectively. Preliminary structure-activity relationships (SARs), Reverse Transcriptase inhibition efficacy and molecular modeling of selected compounds are also presented. These outcomes support our design hypothesis and demonstrate that the piperidyl group modified pyridine-typed DAPY derivatives are highly potent NNRTIs with improved water solubility.

Keywords

Diarylpyrimidines; HIV; Morpholinyl; NNRTI; Piperidyl; Pyridine.

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