Identification of Boronate-Containing Diarylpyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-11, Vol.27 (21), p.7538
• Main Authors: Feng, Da, Lin, Hao, Jiang, Liyang, Wang, Zhao, Sun, Yanying, Zhou, Zhongxia, Clercq, Erik De, Pannecouque, Christophe, Kang, Dongwei, Zhan, Peng, Liu, Xinyong
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Amino acids; Anti-HIV agents; Antiviral agents; Boron; boronate; Cytotoxicity; DAPY; DNA polymerases; drug design; FDA approval; HIV; HIV (Viruses); HIV-1; Human immunodeficiency virus; NMR; NNIBP; NNRTIs; Nuclear magnetic resonance; Nucleosides; Reverse transcriptase inhibitors
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27217538

In this study, privileged boronic acid ester was introduced into the right wing of etravirine (ETR) to obtain a series of novel boronate-containing derivatives. These newly synthesized derivatives were evaluated for their anti-HIV potency in MT-4 cells using the MTT method, and their inhibitory activity to HIV-1 reverse transcriptase (RT) was assayed by the ELISA method. Most of the synthesized compounds displayed promising antiviral activity against the wild-type and a wide range of HIV-1 mutant strains. In particular, 4a exhibited the most potent activity against the wild-type and a panel of single mutations (L100I, K103N, Y181C, and E138K) with EC50 values ranging from 0.005 to 0.648 μM, which were much superior to those of nevirapine (EC50 = 0.151 μM). Moreover, 4b turned out to be an effective inhibitor against the double-mutant strains F227L + V106A and RES056 with EC50 values of 3.21 and 2.30 μM, respectively. RT inhibition activity and molecular docking were also investigated.