Design Synthesis and Evaluation of Novel HIV 1 Integrase Inhibitors

Abstract

Acquired immune deficiency syndrome (AIDS) is caused by infection with human immunodeficiency virus (HIV). HIV IN has been shown to be a potential target for the management of AIDS, with the entry of raltegravir, elvitegravir and dolutegravir in the clinic. Moreover, due to absence of HIV-1 IN homologue in human cells, it is an attractive target for development of new anti HIV therapy. The search for small molecule HIV-1 IN inhibitors has proven to be challenging due to toxicity and bioavailability issues. The aim was therefore; to design, synthesize and evaluate small molecular HIV-1 IN inhibitors of various structural scaffolds. To start with, the compounds reported to inhibit strand transfer step of HIV-1 IN were studied to find a suitable prototype. Then various structural modifications of prototype compounds were done to derive series of analogues. After synthesis, HIV IN inhibition was studied at 10and#956;M in enzyme inhibition assay and most active compounds were screened further for IC50 determination. To verify hypotheses, docking analysis with Schrodinger suite was performed for which pdb ID 1QS4 was chosen and docking protocol was validated. Further, cell based anti-HIV activity was done to evaluate the effect on HIV infection and cell viability. In first series, N-(4-fluorophenyl)-6-methyl-2-oxo-4-substituted phenyl-1,2,3,4-tetrahydro pyrimidine-5-carboxamide derivatives were synthesized. Docking and in vitro studies revealed that these compounds showed interactions with catalytical site of HIV-1 IN and four compounds PK-A5, PK-A6, PK-A16 and PK-A18 exhibited significant percentage inhibition of HIV-1 IN with IC50 values less than 4.91 and#956;M. There was reasonably good correlation between docking simulation and isolated enzyme assay results. However, none of the derivative was active against HIV-1 and HIV-2 below their cytotoxic concentration. This indicates that these types of compounds can be excluded from further exploration for anti-HIV activity. Next, 4-oxo-6-substituted phenyl-2-thioxo-1,2,3,4-tetrahydro