883016-34-0Relevant articles and documents
Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity
Franz, Nicholas D.,Belardinelli, Juan Manuel,Kaminski, Michael A.,Dunn, Louis C.,Calado Nogueira de Moura, Vinicius,Blaha, Michael A.,Truong, Dan D.,Li, Wei,Jackson, Mary,North, E. Jeffrey
, p. 3746 - 3755 (2017)
Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole-2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole-based compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics.
INHIBITORS OF DRUG-RESISTANT MYCOBACTERIUM TUBERCULOSIS
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, (2015/11/16)
The present invention provides novel indoleamide compounds for treating tuberculosis, including drug-resistant M-tuberculosis, compositions comprising the indoleamides and methods of using the indoleamides in conjunction with other biologically active agents for the treatment of tuberculosis in a subject in need thereof.
Design, synthesis, and biological evaluation of indole-2-carboxamides: A promising class of antituberculosis agents
Kondreddi, Ravinder Reddy,Jiricek, Jan,Rao, Srinivasa P. S.,Lakshminarayana, Suresh B.,Camacho, Luis R.,Rao, Ranga,Herve, Maxime,Bifani, Pablo,Ma, Ngai Ling,Kuhen, Kelli,Goh, Anne,Chatterjee, Arnab K.,Dick, Thomas,Diagana, Thierry T.,Manjunatha, Ujjini H.,Smith, Paul W.
, p. 8849 - 8859 (2013/12/04)
Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One of the hits, indole-2-carboxamide analog (1), had low micromolar potency against Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and low aqueous solubility. Structure-activity relationship studies revealed that attaching alkyl groups to the cyclohexyl ring significantly improved Mtb activity but reduced solubility. Furthermore, chloro, fluoro, or cyano substitutions on the 4- and 6-positions of the indole ring as well as methyl substitution on the cyclohexyl ring significantly improved metabolic stability. 39 and 41, the lead candidates, displayed improved in vitro activity compared to most of the current standard TB drugs. The low aqueous solubility could not be mitigated because of the positive correlation of lipophilicity with Mtb potency. However, both compounds displayed favorable oral pharmacokinetic properties in rodents and demonstrated in vivo efficacy. Thus, indole-2-carboxamides represent a promising new class of antituberculosis agents.
