rilpivirine and pyrimidine

A series of novel heteroaromatic-difluoro-biphenyl-diarylpyrimidines were designed as non-nucleoside anti-HIV inhibitors targeting reverse transcriptase by a fragment-based replacement strategy with the purpose of improving the druggability. Hopping five- or six-membered heterocycle groups on the biphenyl moiety as bioisosterism for intrinsically cyanophenyl gave 23 derivatives. All of these compounds possessed excellent HIV-1 inhibitory activity in the nanomolar range. Among them,

Topics: Animals; Anti-HIV Agents; Dose-Response Relationship, Drug; Female; HIV Reverse Transcriptase; HIV-1; Humans; Male; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Models, Molecular; Molecular Structure; Pyrimidines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Inhibitors; Structure-Activity Relationship

This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.

Topics: Anti-HIV Agents; Benzophenones; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Design; HIV Reverse Transcriptase; HIV-1; HIV-2; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pyrimidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship