The emergence of drug-resistant viruses continues to be an obstacle to effectively controlling the HIV/AIDS pandemic. The development of novel drugs with high potency and the ability to fully eradicate HIV-1 infections is therefore of critical importance. Novel pyrazole derivatives were synthesized from 3-benzoylbenzofurans and characterized by mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. The 3-benzoyl benzofurans were determined to be highly cytotoxic in TZM-bl cells, while their pyrazole derivatives were mild to non-cytotoxic. Evaluation of anti-HIV activities in pseudoviruses revealed two 3-benzoyl benzofurans (3g and 4b) and pyrazoles (5f and 5h) as the most potent inhibitors. The IC50 values of 4b and 5f were 0.49 ± 0.11 µM and 0.39 ± 0.13 µM in Q23 and 0.12 ± 0.05 µM and 1.00 ± 0.15 µM in the CAP210 pseudovirus, respectively. Further evaluations for mechanism of action involved the time of addition assay and direct enzyme inhibition, which showed that 3g and 4b were non-nucleotide reverse transcriptase inhibitors while 5f and 5h inhibited HIV entry. Additionally, 3g, 4b, and 5h were found to be mild inhibitors of HIV-1 protease, while 5f was the most active protease inhibitor. The IC50 value of 5f was 31.59 ± 3.83 µM, and it displayed interactions with the active site of HIV-1 PR, suggesting competitive inhibition using molecular docking. The promising anti-HIV activities of 5f in pseudoviruses and HIV-PR motivate its further development for antiretroviral drugs.
This article is Open Access
Please