Design, synthesis and biological evaluation of imidazole and oxazole fragments as HIV-1 integrase-LEDGF/p75 disruptors and inhibitors of microbial pathogens.

We describe here the synthesis of libraries of novel 1-subtituted-5-aryl-1H-imidazole, 5-aryl-4-tosyl-4,5-dihydro-1,3-oxazole and 5-aryl-1,3-oxazole fragments via microwave (MW)-assisted cycloaddition of para-toluenesulfonylmethyl isocyanide (TosMIC) to imines and aldehydes. The compounds obtained were biologically evaluated in an AlphaScreen HIV-1 IN-LEDGF/p75 inhibition assay with six imidazole-based compounds (16c, 16f, 17c, 17f, 20a and 20d) displaying more than 50% inhibition at 10 µM, with IC50 values ranging from 7.0 to 30.4 µM. Additionally the hypothesis model developed predicts all active scaffolds except 20d to occupy similar areas as the N-heterocyclic (A) moiety and two aromatic rings (B and C) of previously identified inhibitor 5. These results indicate that the identified compounds represent a viable starting point for their use as templates in the design of next generation inhibitors targeting the HIV-1 IN and LEDGF/p75 protein-protein interaction. In addition, the in vitro antimicrobial properties of these fragments were tested by minimum inhibitory concentration (MIC) assays showing that compound 16f exhibited a MIC value of 15.6 µg/ml against S. aureus, while 17f displayed a similar MIC value against B. cereus, suggesting that these compounds could be further developed to specifically target those microbial pathogens.

The evaluation of statins as potential inhibitors of the LEDGF/p75-HIV-1 integrase interaction.

Lovastatin was identified through virtual screening as a potential inhibitor of the LEDGF/p75-HIV-1 integrase interaction. In an AlphaScreen assay, lovastatin inhibited the purified recombinant protein-protein interaction (IC50 = 1.97 ± 0.45 µm) more effectively than seven other tested statins. None of the eight statins, however, yielded antiviral activity in vitro, while only pravastatin lactone yielded detectable inhibition of HIV-1 integrase strand transfer activity (31.65% at 100 µm). A correlation between lipophilicity and increased cellular toxicity of the statins was observed.