Design,synthesis and biological evaluation of imidazole and oxazole fragments as HIV-1 integrase-LEDGF/p75 disruptors and inhibitors of microbial pathogens |
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| Institution: | 1. Advanced Materials Division, Mintek, 200 Malibongwe Drive, Randburg 2125, South Africa;2. Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS 2050, South Africa;3. Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa;1. School of Pharmacy, Lanzhou University, Lanzhou 730000, China;2. Experimental Center of Medicine, General Hospital of Lanzhou Military Command, Lanzhou 730050, China;1. Department of Physics, Faculty of Arts and Sciences, Amasya University, 05100 Amasya, Turkey;2. Department of Biology, Faculty of Arts and Sciences, Amasya University, 05100 Amasya, Turkey;3. Department of Pre-School Education, Faculty of Education, Amasya University, 05100 Amasya, Turkey;4. Department of Machinery and Metal Technologies, Merzifon Vocational School, Amasya University, 05300 Merzifon, Turkey;5. Department of Chemistry, Faculty of Arts and Sciences, Amasya University, 05100 Amasya, Turkey;1. Department of Pharmacy, University of Groningen, A. Deusinglaan 1, Groningen 9700AV, The Netherlands;2. Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece;1. School of Chemistry and Environment, South China Normal University, Guangzhou 510006, China;2. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;3. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA;4. Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;1. Departments of Discovery Chemistry and Molecular Technologies, 5 Research Parkway, Wallingford, CT 06492, USA;2. Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA;3. Biocon-Bristol-Myers Squibb Research Center, Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka 560099, India;4. Department of Discovery Chemistry Synthesis, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA;5. ViiV Healthcare, 36 East Industrial Parkway, Branford, CT 06405, USA;6. Assembly Biosciences, Inc. 331 Oyster Point Blvd, San Francisco, CA 94080, USA |
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| Abstract: | 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. |
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| Keywords: | TosMIC 5-aryl-1 3-oxazoles HIV-1 integrase LEDGF/p75 Antibacterial |
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