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. 2013 Dec 15;23(24):6593-7.
doi: 10.1016/j.bmcl.2013.10.059. Epub 2013 Nov 1.

Novel Piperidinylamino-Diarylpyrimidine Derivatives With Dual Structural Conformations as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

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Novel Piperidinylamino-Diarylpyrimidine Derivatives With Dual Structural Conformations as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Xuwang Chen et al. Bioorg Med Chem Lett. .

Abstract

A series of novel piperidinylamino-diarylpyrimidine (pDAPY) derivatives with dual structural conformations was designed through a molecular hybridization strategy and expected to bind into the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-1 RT in a flexible manner. A cell-based antiviral screening assay showed that some compounds were active against both wild-type and drug-resistant mutant virus strains (K103N+Y181C RT) of HIV-1 (compound 10b3 with EC50 = 0.047 and 4.6 μM, selectivity index = 2145 and 22, respectively). Molecular simulation studies indicated that compound 10b3 could maintain the key hydrophobic interaction and hydrogen bonds with the NNIBP of two RT/ligand complexes. In particular, it could simultaneously occupy the protein/solvent interface and the entrance channel. Exploring these hybrid molecules with dual binding conformations might provide optional chemical scaffolds as novel HIV-1 reverse transcriptase inhibitors (HIV-1 NNRTIs).

Keywords: DAPY; Dual conformations; HIV-1 NNRTIs; Molecular hybridization; Piperidin-4-yl-aminopyrimidines.

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