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

Autor: Rashamuse TJ; Advanced Materials Division, Mintek, 200 Malibongwe Drive, Randburg 2125, South Africa; Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS 2050, South Africa., Harrison AT; Advanced Materials Division, Mintek, 200 Malibongwe Drive, Randburg 2125, South Africa., Mosebi S; Advanced Materials Division, Mintek, 200 Malibongwe Drive, Randburg 2125, South Africa., van Vuuren S; Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa., Coyanis EM; Advanced Materials Division, Mintek, 200 Malibongwe Drive, Randburg 2125, South Africa. Electronic address: MabelC@mintek.co.za., Bode ML; Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS 2050, South Africa. Electronic address: Moira.Bode@wits.ac.za.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Jan 01; Vol. 28 (1), pp. 115210. Date of Electronic Publication: 2019 Nov 09.
DOI: 10.1016/j.bmc.2019.115210
Abstrakt: 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 IC 50 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.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: