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

Paulo F. M. Oliveira (1, 2, 3) , Brigitte Guidetti (2, 3) , Alain Chamayou (1) , Christiane André-Barrès (2, 3) , Jan Madacki (4) , Jana Kordulakova (4) , Giorgia Mori (5) , Beatrice Silvia Orena (5) , Laurent Roberto Chiarelli (5) , Maria Rosalia Pasca (5) , Christian Lherbet (2, 3) , Chantal Carayon (2, 3) , Stephane Massou (3) , Michel Baron (1) , Michel Baltas (3, 2)

1 RAPSODEE - Centre de recherche d'Albi en génie des procédés des solides divisés, de l'énergie et de l'environnement
2 SPCMIB - Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique
3 UT3 - Université Toulouse III - Paul Sabatier
4 Comenius University in Bratislava
5 UNIPV - Università degli Studi di Pavia = University of Pavia

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.

Mots clés: Mycobacterium tuberculosis; mechanochemistry; hydrazone

Domaines: Sciences de l'ingénieur [physics]

Paulo F. M. Oliveira, Brigitte Guidetti, Alain Chamayou, Christiane André-Barrès, Jan Madacki, et al.. Mechanochemical Synthesis and Biological Evaluation of Novel Isoniazid Derivatives with Potent Antitubercular Activity. Molecules, 2017, 22 (9), art.1457 - 27p. ⟨10.3390/molecules22091457⟩. ⟨hal-01631582⟩