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Molecules 2017, 22(9), 1457; doi:10.3390/molecules22091457

Mechanochemical Synthesis and Biological Evaluation of Novel Isoniazid Derivatives with Potent Antitubercular Activity

1
Department of Process Engineering, Université de Toulouse, Mines-Albi, CNRS UMR 5302, Centre RAPSODEE, Campus Jarlard, 81013 Albi, France
2
Department of Chemistry, Université de Toulouse, UPS, CNRS UMR 5068, LSPCMIB, 118 Route de Narbonne, 31062 Toulouse, France
3
CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, LSPCMIB, UMR-5068, 118 Route de Narbonne, 31062 Toulouse, France
4
Department of Biochemistry, Comenius University in Bratislava, Faculty of Natural Sciences, Mlynská Dolina, Ilkovičova 6, 84215 Bratislava, Slovakia
5
Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia; via Ferrata 1, 27100 Pavia, Italy
Current address: Université de Lille, UMET, Unité Matériaux et Transformations, CNRS UMR 8207, F-59000 Lille, France.
*
Authors to whom correspondence should be addressed.
Received: 2 July 2017 / Revised: 19 July 2017 / Accepted: 24 July 2017 / Published: 1 September 2017
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [9621 KB, uploaded 4 September 2017]   |  

Abstract

A series of isoniazid derivatives bearing a phenolic or heteroaromatic coupled frame were obtained by mechanochemical means. Their pH stability and their structural (conformer/isomer) analysis were checked. The activity of prepared derivatives against Mycobacterium tuberculosis cell growth was evaluated. Some compounds such as phenolic hydrazine 1a and almost all heteroaromatic ones, especially 2, 5 and 7, are more active than isoniazid, and their activity against some M. tuberculosis MDR clinical isolates was determined. Compounds 1a and 7 present a selectivity index >1400 evaluated on MRC5 human fibroblast cells. The mechanism of action of selected hydrazones was demonstrated to block mycolic acid synthesis due to InhA inhibition inside the mycobacterial cell. View Full-Text
Keywords: Mycobacterium tuberculosis; mechanochemistry; hydrazone Mycobacterium tuberculosis; mechanochemistry; hydrazone
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Oliveira, P.F.M.; Guidetti, B.; Chamayou, A.; André-Barrès, C.; Madacki, J.; Korduláková, J.; Mori, G.; Orena, B.S.; Chiarelli, L.R.; Pasca, M.R.; Lherbet, C.; Carayon, C.; Massou, S.; Baron, M.; Baltas, M. Mechanochemical Synthesis and Biological Evaluation of Novel Isoniazid Derivatives with Potent Antitubercular Activity. Molecules 2017, 22, 1457.

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