DOI: 10.5176/2345-783X_PHARMA16.25

Authors: Zahra Hajimahdi and Afshin Zarghi


HIV-1 represents the etiological agent of the acquired immune deficiency syndrome (AIDS).
Though the current combination of anti-HIV drugs which termed the Highly Active Anti-Retroviral Therapy (HAART) has improved quality of life for infected patients, the emergence of drug-resistant HIV mutant strains, drug toxicity and cost are major problems during HIV treatment. However, resistance to marketed anti-HIV drugs is increasing at an alarming rate. Therefore, there is an urgent need to discover more effective therapeutic targets and new lead molecules. HIV-1 integrase as one of the key enzymes for HIV-1 replication represents a crucial target for antiretroviral drugs, because it has no counterpart in mammalian cells. In this research, aimed at the discovery of new compounds as anti-HIV-1 agents, the HIV-1 integrase inhibitors were selected as a lead to design new analogues.
The quinolone derivatives are taken great interest in due to their extremely versatile nature, easily synthesized at low cost on a large scale and well-known biochemical properties. Therefore, we selected 4-quinolone-3-carboxylic acid as a template to design new anti-HIV compounds. A new series of quinolone-3-carboxylic acids featuring different hydrophobic groups at C-6 position were synthesized. Novel compounds were prepared starting from the 4-aminoacetophenone in 4 steps based on Gould-Jacobs reaction. The structure of the synthesized compounds was confirmed by IR, LC-MS (ESI) and 1H-NMR. Then obtained compounds were evaluated for their activity against single cycle replicable HIV NL4-3 as inhibition rate of p24 expression in Hela cells cultures. A docking study was performed to explain the probable mechanism of action of synthesized compounds.

Results and discussion
The inhibitory effect of synthesized compounds against HIV was studied by single cycle replication assay as previously developed in our laboratory. The results showed that all synthesized compounds possessed anti-HIV activity with p24 inhibition rates of 40-80{6e6090cdd558c53a8bc18225ef4499fead9160abd3419ad4f137e902b483c465} at 100 M concentration. A docking study using the crystallographic data available for PFV integrase including its complexes with Mg2+‏ and Raltegravir (FDA-approved HIV integrase inhibitor), revealed that the active compounds could occupy same space near Raltegravir and interact with the Mg2‏+ ions in the active site. Thus, the anti-HIV activity of the synthesized compounds might involve a metal chelating mechanism.

Keywords: Anti-HIV, Docking studies, Quinolone


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