Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1 NNRTIs: Design, synthesis and biological evaluation

• Published in: Chinese chemical letters 2021-12, Vol.32 (12), p.4053-4057
• Main Authors: Feng, Da, Wei, Fenju, Sun, Yanying, Sharma, Prem Prakash, Zhang, Tao, Lin, Hao, Rathi, Brijesh, De Clercq, Erik, Pannecouque, Christophe, Kang, Dongwei, Zhan, Peng, Liu, Xinyong
• Format: Article
• Language: English
• Subjects: Boronic acid; DAPY; HIV-1; Molecular dynamics simulation; NNIBP; NNRTIs
• ISSN: 1001-8417; 1878-5964
• DOI: 10.1016/j.cclet.2021.02.033

To address the drug resistance, a series of novel boronic acid-containing diarylpyrimidine (DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies, and compound 10j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 IIIB, L100I and K103N strains. [Display omitted] Drug resistance remains to be a serious problem with type I human immunodeficiency virus (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs). A series of novel boronic acid-containing diarylpyrimidine (DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies, taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells. Compound 10j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 IIIB [wild-type (WT) strain], L100I and K103N strains, with 50% effective concentration (EC50) values of 7.19–9.85 nmol/L. Moreover, 10j inhibited the double-mutant strain RES056 with an EC50 value of 77.9 nmol/L, which was 3.3-more potent than that of EFV (EC50 = 260 nmol/L) and comparable to that of ETR (EC50 = 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase (RT) with 50% inhibition concentration (IC50) value of 0.1837 μmol/L. Furthermore, molecular dynamics simulation indicated that 10j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10j could serve as a lead molecule for further modification to address virus-drug resistance.