A coumarin-based analogue of thiacetazone as dual covalent inhibitor and potential fluorescent label of HadA in mycobacterium tuberculosis

ACS Infectious Diseases Journal

A novel coumarin-based molecule, designed as a fluorescent surrogate of a thiacetazone-derived antitubercular agent, was quickly and easily synthesized from readily available starting materials. This small molecule, coined Coum-TAC, exhibited a combination of appropriate physicochemical and biological properties, including resistance toward hydrolysis and excellent antitubercular efficiency similar to that of well-known thiacetazone derivatives, as well as efficient covalent labeling of HadA, a relevant therapeutic target to combat Mycobacterium tuberculosis. More remarkably, Coum-TAC was successfully implemented as an imaging probe that is capable of labeling Mycobacterium tuberculosis in a selective manner, with an enrichment at the level of the poles, thus giving for the first time relevant insights about the polar localization of HadA in the mycobacteria.

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A coumarin-based analogue of thiacetazone as dual covalent inhibitor and potential fluorescent label of HadA in mycobacterium tuberculosis

Asma Farjallah a,i, Laurent R. Chiarelli c, Martin Forbak d, Giulia Degiacomi c, Mathieu Danel a, Fernanda Goncalves a,f, Chantal Carayon f, Cendrine Seguin g, Marco Fumagalli c, Monika Záhorszká d, Elodie Vega e, Souhir Abid h,i, Anna Grzegorzewicz j, Mary Jackson j, Antonio Peixoto e, Jana Korduláková d, Maria Rosalia Pasca c, Christian Lherbet a,b and Stefan Chassaing a,b

a. ITAV, Université de Toulouse, CNRS USR3505, UPS, 1 place Pierre Potier, 31106 Toulouse Cedex 1, France

b. Laboratoire de Synthèse, Réactivité Organiques & Catalyse (LASYROC), Institut de Chimie, CNRS-UMR7177, Université de Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France

c. Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Pavia, Italy

d. Department of Biochemistry, Comenius University in Bratislava, Faculty of Natural Sciences, Mlynská Dolina, Ilkovičova 6, 84215 Bratislava, Slovakia

e. Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 205 route de Narbonne, 31400 Toulouse, France

f. Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique (SPCMIB), Université Paul Sabatier-Toulouse III/ CNRS (UMR5068), 118 route de Narbonne, F-31062 Toulouse

g. Laboratoire de Conception et Application de Molécules Bioactives (LCAMB), CNRS-UMR7199, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France

h. Chemistry Department, College of Science and Arts, Jouf University, Al Qurayyat, KSA

i. Laboratoire de Chimie Appliquée: Hétérocycles, Corps Gras et Polymères, Faculté des sciences de Sfax, Université de Sfax, Tunisie

j. Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682, United States

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ACS Infect. Dis. 2021, 7, 3, 552–565
https://doi.org/10.1021/acsinfecdis.0c00325
Copyright © 2021 American Chemical Society

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June 10, 2021