701202-07-5Relevant academic research and scientific papers
INHIBITORS OF DRUG-RESISTANT MYCOBACTERIUM TUBERCULOSIS
-
Page/Page column 21; 23; 24, (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.
Preliminary structure - Activity relationships and biological evaluation of novel antitubercular indolecarboxamide derivatives against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains
Onajole, Oluseye K.,Pieroni, Marco,Tipparaju, Suresh K.,Lun, Shichun,Stec, Jozef,Chen, Gang,Gunosewoyo, Hendra,Guo, Haidan,Ammerman, Nicole C.,Bishai, William R.,Kozikowski, Alan P.
, p. 4093 - 4103 (2013/06/27)
Tuberculosis (TB) remains one of the leading causes of mortality and morbidity worldwide, with approximately one-third of the world's population infected with latent TB. This is further aggravated by HIV coinfection and the emergence of multidrug- and extensively drug-resistant (MDR and XDR, respectively) TB; hence the quest for highly effective antitubercular drugs with novel modes of action is imperative. We report herein the discovery of an indole-2-carboxamide analogue, 3, as a highly potent antitubercular agent, and the subsequent chemical modifications aimed at establishing a preliminary body of structure-activity relationships (SARs). These efforts led to the identification of three molecules (12-14) possessing an exceptional activity in the low nanomolar range against actively replicating Mycobacterium tuberculosis, with minimum inhibitory concentration (MIC) values lower than those of the most prominent antitubercular agents currently in use. These compounds were also devoid of apparent toxicity to Vero cells. Importantly, compound 12 was found to be active against the tested XDR-TB strains and orally active in the serum inhibition titration assay.
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.
