OBJECTIVES: To investigate the antileprosy potential of a set of original compounds with antimycobacterial activity. METHODS: We developed a facile synthesis of 2-chloro-3-cyano-5-nitropyridine and synthesized a series of 3-cyano-2-dialkyldithiocarbamoyl-5-nitropyridine derivatives. In vivo therapeutic efficacy against Mycobacterium leprae was assessed in the infected mouse footpad model. RESULTS: The compounds were active in vitro against Mycobacterium smegmatis, Mycobacterium aurum, Mycobacterium vaccae and Mycobacterium fortuitum, with MICs generally in the range of 0.4-6.25 mg/L. Reduction of the bacterial load in vivo in the mouse footpad and toxic side effects were dependent on the individual structure of the compounds and on the doses applied. Compounds 2a, 3a and 3b reduced the number of M. leprae by two orders of magnitude, comparable to the effect of dapsone. Co-administration of compounds 2a and 3a with dapsone synergistically enhanced the activity. In addition, these compounds were well tolerated over the treatment period of 7.5 months. CONCLUSIONS: Individual synthetic dithiocarbamate derivatives have promising antileprosy activity.
OBJECTIVES: To investigate the antileprosy potential of a set of original compounds with antimycobacterial activity. METHODS: We developed a facile synthesis of 2-chloro-3-cyano-5-nitropyridine and synthesized a series of 3-cyano-2-dialkyldithiocarbamoyl-5-nitropyridine derivatives. In vivo therapeutic efficacy against Mycobacterium leprae was assessed in the infected mouse footpad model. RESULTS: The compounds were active in vitro against Mycobacterium smegmatis, Mycobacterium aurum, Mycobacterium vaccae and Mycobacterium fortuitum, with MICs generally in the range of 0.4-6.25 mg/L. Reduction of the bacterial load in vivo in the mouse footpad and toxic side effects were dependent on the individual structure of the compounds and on the doses applied. Compounds 2a, 3a and 3b reduced the number of M. leprae by two orders of magnitude, comparable to the effect of dapsone. Co-administration of compounds 2a and 3a with dapsone synergistically enhanced the activity. In addition, these compounds were well tolerated over the treatment period of 7.5 months. CONCLUSIONS: Individual synthetic dithiocarbamate derivatives have promising antileprosy activity.
Authors: Thomas R Lane; Fabio Urbina; Laura Rank; Jacob Gerlach; Olga Riabova; Alexander Lepioshkin; Elena Kazakova; Anthony Vocat; Valery Tkachenko; Stewart Cole; Vadim Makarov; Sean Ekins Journal: Mol Pharm Date: 2021-12-29 Impact factor: 5.364
Authors: Vadim Makarov; Giulia Manina; Katarina Mikusova; Ute Möllmann; Olga Ryabova; Brigitte Saint-Joanis; Neeraj Dhar; Maria Rosalia Pasca; Silvia Buroni; Anna Paola Lucarelli; Anna Milano; Edda De Rossi; Martina Belanova; Adela Bobovska; Petronela Dianiskova; Jana Kordulakova; Claudia Sala; Elizabeth Fullam; Patricia Schneider; John D McKinney; Priscille Brodin; Thierry Christophe; Simon Waddell; Philip Butcher; Jakob Albrethsen; Ida Rosenkrands; Roland Brosch; Vrinda Nandi; Sowmya Bharath; Sheshagiri Gaonkar; Radha K Shandil; Venkataraman Balasubramanian; Tanjore Balganesh; Sandeep Tyagi; Jacques Grosset; Giovanna Riccardi; Stewart T Cole Journal: Science Date: 2009-03-19 Impact factor: 47.728
Authors: Vadim Makarov; Benoit Lechartier; Ming Zhang; João Neres; Astrid M van der Sar; Susanne A Raadsen; Ruben C Hartkoorn; Olga B Ryabova; Anthony Vocat; Laurent A Decosterd; Nicolas Widmer; Thierry Buclin; Wilbert Bitter; Koen Andries; Florence Pojer; Paul J Dyson; Stewart T Cole Journal: EMBO Mol Med Date: 2014-02-05 Impact factor: 12.137
Authors: Galina R Demina; Vadim A Makarov; Vadim D Nikitushkin; Olga B Ryabova; Galina N Vostroknutova; Elena G Salina; Margarita O Shleeva; Anna V Goncharenko; Arseny S Kaprelyants Journal: PLoS One Date: 2009-12-16 Impact factor: 3.240