Design, synthesis and biological evaluation of imidazole and oxazole fragments as HIV-1 integrase-LEDGF/p75 disruptors and inhibitors of microbial pathogens. Issue 1 (1st January 2020) - Rashamuse, Thompho J.
Graphical abstract: Abstract: We describe here the synthesis of libraries of novel 1-subtituted-5-aryl-1 H -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.