In vitro and in silico investigation of 3-acylhydrazone-4-quinolone derivatives as antiviral agents against human Immunodeficiency Virus Type 1 (HIV-1)
DOI:
https://doi.org/10.1590/s2175-97902026e24801Keywords:
Quinolones, Acylhydrazone, HIV-1, Reverse transcriptase, Antivirals, Molecular dockingAbstract
Increasing numbers of HIV infections have been reported over the last years. Despite the availability of antiretroviral therapy, the emergence of drug-resistant strains and side effects of marketed drugs makes the search for new drugs needed. Herein, we investigated the antiviral potential of 3-acylhydrazone 4-quinolones (compounds 2-4) against HIV-1 replication in MT-2 cells, their mechanism of action, and pharmacokinetic and toxicological (ADMET) properties using in vitro and in silico methods. All compounds showed lower cytotoxicity (CC50 > 700 µM) than the drug zidovudine (CC50 = 128 µM). Compound 2 showed the most potent anti-HIV-1 activity (EC50 = 3.37 µM), followed by compounds 3 (EC50 = 3.79 µM) and 4 (EC50 = 4.03 µM). Mechanistic studies indicated that these compounds act at post-entry steps of virus replication, such as reverse transcription. Enzymatic assays confirmed that compounds 2 and 4 (IC50 = 29.52 µM and 22.77 µM) inhibit HIV-1 reverse transcriptase (RT). Molecular docking with HIV-1 RT showed that compounds 2 and 4, but not 3, share a similar binding mode with the non-nucleoside RT inhibitor delavirdine, explaining their different activity. Further, ADMET studies reinforced their potential as drug candidates which, in turn, support the design of new derivatives as anti-HIV-1 drug candidates.
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