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Indolcarboxamide, a promising pre-clinical candidate for the treatment of multi drug resistant tuberculosis

Manjunatha, Ujjini Havaldar and Rao, Srinivasa P.S. and Lakshminarayana, Suresh Bangalore and Kondreddi, Ravinder Reddy and Herve, Maxime Marcel and Bifani, Juan Pablo and Luis, Camacho and Jiricek, Jan and Sarath, Kalapala and Tan, Bee Huat and Nanjundappa, Mahesh Bangalore and Seow Hwee, Ng and Sindhu, Ravindran and Seah, Peck Gee and Thayalan, Pamela and Lee, Boon Heng and Barnes, Whitney and Anne, Goh and Arnab, Chatterjee and Kevin, Pethe and Kuhen, Kelli and Walker, John and Babu, Sreehari and Gu, Feng and Lijun, Zhang and Blasco, Francesca and Beer, David John and Weaver, Margaret and Veronique, Dartois and Glynne, Richard and Thomas, Dick and Smith, Paul William and Diagana, Thierry Tidiane and Vivian, Lim NITD and Ida, Ma (2013) Indolcarboxamide, a promising pre-clinical candidate for the treatment of multi drug resistant tuberculosis. Science Translational Medicine.

Abstract

To combat the drug resistance in tuberculosis, new chemotherapeutics active against multi-drug resistant Mycobacterium tuberculosis are urgently needed. We have identified and characterized the indolcarboxamides as a new class of anti-tubercular bactericidal agents. Genetics and lipid profiling studies identified the molecular target of indolcarboxamides as mmpL3, a transporter of TMM, a promiscuous target essential for mycobacterial cell wall biosynthesis. Two lead candidates NITD-304 and NITD-349 showed a significantly potent anti-TB activity against both drug sensitive and multi-drug resistant clinical Mtb isolates. Both compounds displayed favorable pharmacokinetic properties after oral administration in pre-clinical species. NITD-304 and NITD-349 showed no apparent inhibition of major CYP enzymes and are highly efficacious in both acute and chronic TB mouse efficacy models. Furthermore, we have assessed in vitro and in vivo safety profile of both candidates including two weeks exploratory rat toxicology studies. NITD-304 and NITD-349 show the adequate therapeutic index to justify further development for inclusion in the combination therapies for drug sensitive as well as drug resistant TB.

Item Type: Article
Additional Information: J. Med Chem manuscript Kondreddi et al describing all the NCE used in this manuscript has already been OAK approved.
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10825

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