Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 2: Discovery of novel [1,2,4]Triazolo[1,5-a]pyrimidines using a structure-guided core-refining approach.

Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives were rationally designed via structure-based core refining approach, synthesized through the readily accessible synthetic methods and evaluated for their anti-HIV activities in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against the wild-type HIV-1 III B . Particularly, compound 7n was the most potent inhibitor against wild-type and K103N/Y181C double resistant mutant strain of HIV-1, possessing EC 50 values of 0.02 μM and 7.6 μM, respectively, which were much better than or similar to nevirapine (NVP, EC 50 = 0.15 μM, 2.9 μM) and delavirdine (DLV, EC 50 = 0.07 μM, >36 μM). Besides, some other compounds, 5b , 7c , 7e , 7f , and 7m , were also endowed with favorable anti-HIV-1 potency (EC 50 = 0.07, 0.05, 0.05, 0.07, and 0.05 μM, respectively), which were better than or similar to those of NVP and DLV, suggesting a high potential to further develop this type of bridgehead nitrogen heterocycle as a novel class of NNRTIs with improved antiviral efficacy and resistance profile. The selected compound, 7i , was found moderately inhibitory towards RT (IC 50 = 0.39 μM), which was higher than for ETV (IC 50 = 0.56 μM). Preliminary structure–activity relationships (SARs) and molecular modeling of these new analogues were detailed in this manuscript. [ABSTRACT FROM AUTHOR]