Synthesis and biological evaluation of DAPY–DPEs hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Abstract

A series of new DAPY–DPEs hybrids, combined the important pharmacophores of DAPYs and DPEs, has been synthesized and biologically evaluated for their anti-HIV activities against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Many promising candidates with potent inhibitory activity (wild-type) within the EC50 range from 0.16 to 0.013μM were obtained. In particular, 3c, 3p, 3r and 3s displayed low nM level EC50 values (35, 13, 50 and 17nM, respectively) and high selectivity (9342, 25131, 2890 and 11338, respectively), which were much more potent than NVP (EC50=0.31μM, SI=48), 3TC (EC50=2.24μM, SI>39), DDI (EC50=23.20μM, SI>9) and DLV (EC50=0.65μM, SI>67), and comparable to AZT (EC50=0.0071μM, SI>13144) and EFV (EC50=0.0062μM, SI>1014). The HIV-1 reverse transcriptase inhibitory assay confirmed that these DAPY–DPEs hybrids targeted HIV-1 RT. Molecular simulation was performed to investigate the potential binding mode of the newly synthesized compounds. And reasonable explanation for the activity results was discussed with docking method.