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

• Published in: European journal of medicinal chemistry 2014-10, Vol.85, p.293-303
• Main Authors: Wang, Liu, Tian, Ye, Chen, Wenmin, Liu, Hong, Zhan, Peng, Li, Dongyue, Liu, Huiqing, De Clercq, Erik, Pannecouque, Christophe, Liu, Xinyong
• Format: Article
• Language: English
• Subjects: [1,2,4]Triazolo[1,5-a]pyrimidine; anti-HIV activities; Bridgehead nitrogen heterocycle; DAPY; Drug Design; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Models, Molecular; Molecular modeling; Mutation; Nitrogen - chemistry; Protein Conformation; Pyrimidines - chemistry; Pyrimidines - pharmacology; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; Structure–activity relationships
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.07.104

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 IIIB. Particularly, compound 7n was the most potent inhibitor against wild-type and K103N/Y181C double resistant mutant strain of HIV-1, possessing EC50 values of 0.02 μM and 7.6 μM, respectively, which were much better than or similar to nevirapine (NVP, EC50 = 0.15 μM, 2.9 μM) and delavirdine (DLV, EC50 = 0.07 μM, >36 μM). Besides, some other compounds, 5b, 7c, 7e, 7f, and 7m, were also endowed with favorable anti-HIV-1 potency (EC50 = 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 (IC50 = 0.39 μM), which was higher than for ETV (IC50 = 0.56 μM). Preliminary structure–activity relationships (SARs) and molecular modeling of these new analogues were detailed in this manuscript. A series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives were synthesized and evaluated as inhibitors of the HIV-1 wild-type and double mutant (K103N + Y181C) RES056 strains in this article. [Display omitted] •[1,2,4]Triazolo[1,5-a]pyrimidines were identified as effective HIV-1 inhibitors.•7n show anti-HIV-1 activity with EC50 of 0.02 μM (wt) and 7.6 μM (RES056).•Preliminary SARs and molecular modeling of these new analogues were detailed.