Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors

• 18 new compounds were designed, synthesized as the anti-drug resistant HIV NNRTIs.
• All the new molecules were evaluated for their biological activities against HIV.
• Compound 1d displayed anti HIV-1 activities 47 fold than that of AZT.
• Compound 1d also showed activities against double mutated HIV-1 and HIV-2 strain.
• SAR study including the docking analysis was also investigated deeply.

This article reports the design, synthesis and antiviral evaluation of a new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The basic skeleton of these target 18 molecules is diarylpyrimidine featuring a substituted amino group between the pyrimidine scaffold and the aryl wing. All of the new compounds have been characterized by spectra analysis. The entire target molecules were evaluated for their in vitro anti-HIV activity with controlling group of FDA approved drugs. Most of them showed good to potent activities against wild-type (WT) HIV-1 with IC50 values in the range of 0.0175–69.21 μM. 2-(4-Cyanophenylamino)-4-(2-cyanovinylphenylhydrazonomethyl)pyrimidine (1d) displayed potent anti-HIV-1 activity against WT HIV-1 with a selectivity index (SI) of 106367 and an IC50 value of 1.75 nM, which was 47 fold lower than that of AZT. Compound 1d also showed a broad-spectrum inhibitory activity, with an IC50 value of 5.33 μM and 5.05 μM against both HIV-1 double-mutated (K103N/Y181C) strain and HIV-2 strain, respectively. The preliminary structure–activity relationship (SAR) was also investigated. The binding modes with HIV-1 RT for both the wild type and mutant type have also been discussed.

A series of new diarylpyrimidine analogues featuring a functional substituted amino group between the pyrimidine scaffold and the aryl wing have been designed and synthesized, which were also evaluated as anti-drug-resistant HIV reverse transcriptase inhibitors.Figure optionsDownload as PowerPoint slide