Jump to main content
Jump to site search


Discovery of Novel Diarylpyrimidines as Potent HIV-1 NNRTIs by Investigating the Chemical Space of Less Explored “Hydrophobic Channel”

Abstract

New series of diarylpyrimidines (DAPYs) were designed, synthesized and evaluated as novel HIV-1 NNRTIs to further explore the chemical space surrounding the “hydrophobic channel” of NNRTIs binding pocket (NNIBP), guided by the comprehensive analysis of X-ray structural biology data of HIV-1 RT/NNRTIs complexes and molecular modeling. Encouragingly, most of the synthesized DAPYs were found to be active against HIV-1wild-type (WT) strain with EC50 values ranging from 3 nM to 63 nM, and displayed significantly reduced cytotoxicity compared with etravirine (ETV) and rilpivirine (RPV). Among them, two most promising compounds Z10 (EC50 = 3 nM) and Z13 (EC50 = 3 nM) showed equivalent potency against HIV-1 WT to the reference drugs efavirenz (EFV, EC50 = 3 nM) and ETV (EC50 = 3 nM). Notably, Z13 also showed the most potent activity against HIV-1 mutant strains including K103N (EC50 = 10 nM), E138K (EC50 = 22 nM) and RES056 (EC50= 0.935 μM). Against mutant strains Y181C, Y188L and F227L+V106A, Z17 showed double-digit nanomolar inhibitory activity with EC50 values 27 nM, 98 nM and 30 nM, respectively. The structure-activity relationships (SARs) and molecular docking studies provided important clues for further molecular elaboration. Collectively, this study provides useful information to guide lead optimization and drug discovery via exploration of this seldom investigated region.

Back to tab navigation

Publication details

The article was received on 17 Nov 2017, accepted on 19 Dec 2017 and first published on 19 Dec 2017


Article type: Paper
DOI: 10.1039/C7OB02828H
Citation: Org. Biomol. Chem., 2017, Accepted Manuscript
  •   Request permissions

    Discovery of Novel Diarylpyrimidines as Potent HIV-1 NNRTIs by Investigating the Chemical Space of Less Explored “Hydrophobic Channel”

    X. Z. Zhou, T. Liu, D. Kang, Z. Huo, G. Wu, D. Daelemans, E. De Clercq, C. Pannecouque, P. Zhan and X. Liu, Org. Biomol. Chem., 2017, Accepted Manuscript , DOI: 10.1039/C7OB02828H

Search articles by author

Spotlight

Advertisements