Nontoxic combretafuranone analogues with high in vitro antibacterial activity

0495960 - ÚMG 2019 RIV FR eng J - Journal Article
Horký, P. - Voracova, M. - Konečná, K. - Sedlák, David - Bartůněk, Petr - Vacek, J. - Kuneš, J. - Pour, M.
Nontoxic combretafuranone analogues with high in vitro antibacterial activity.
European Journal of Medicinal Chemistry. Roč. 143, January (2018), s. 843-853. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA MŠMT LO1220; GA MŠMT LM2015063
Institutional support: RVO:68378050
Keywords : Combretastatin analogue * Combretafuranone * Furanone * Synthesis * Cytotoxic * Antibacterial
OECD category: Organic chemistry
Impact factor: 4.833, year: 2018

A library of thirty two 3,4-diphenylfuranones related to both combretastatin A-4 and antifungal 5-(acyloxymethyl)-3-(halophenyl)-2,5-dihydrofuran-2-ones was prepared. Cytotoxic effects on a panel of cancer and normal cell lines and antiinfective activity were evaluated, and the data were complemented with tests for the activation of caspase 3 and 7. High cytotoxicity was observed in some of the halogenated analogues, eg. 3-(3,4-dichlorophenyl)-4-(4-methylphenyl)-2,5-dihydrofuran-2-one with IC50 0.12-0.23 mu M, but the compounds were also highly toxic against non-malignant control cells. More importantly, notable antibacterial activity indicating G(+) selectivity has been found in the 3,4-diarylfuranone class of compounds for the first time. Hydroxymethylation of furanone C5 knocked out cytotoxic effects (up to 40 mu M) while maintaining significant activity against Staphylococcus strains in some derivatives. MIC95 of the most promising compound, 3-(4-bromophenyl)-5,5-bis(hydroxymethyl)-4-(4-methylphenyl)-2,5-dihydrofuran-2-one against S. aureus strain ATCC 6538 was 0.98 mu M (0.38 mu g/mL) and 3.9 mu M (1.52 mu g/mL) after 24 and 48 h, respectively. (C) 2017 Elsevier Masson SAS. All rights reserved.
Permanent Link: http://hdl.handle.net/11104/0288804