Preliminary structure - Activity relationships and biological evaluation of novel antitubercular indolecarboxamide derivatives against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains
Journal of Medicinal Chemistry
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States; Department of Medicine, Center for Tuberculosis Research, Johns Hopkins School of Medicine, Baltimore, MD 21231-1044, United States; KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, 719 Umbilo Road, Durban 4001, KwaZulu-Natal, South Africa; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789, United States; Dipartimento Farmaceutico, University of Parma, Via G. P. Usberti 27/a, Parma 43121, Italy; Merrimack Pharmaceuticals, 1 Kendall Square, Cambridge, MA 02139-1670, United States; College of Pharmacy, Chicago State University, 9501 South King Drive, Chicago, IL 60628-1598, United States
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. © 2013 American Chemical Society.
6,7 dihydro 2 nitro 6 (4 trifluoromethoxybenzyloxy) 5h imidazo[2,1 b][1,3]oxazine; bedaquiline; indole 2 carboxamide; tuberculostatic agent; unclassified drug; animal cell; antibacterial activity; article; bacterial strain; chemical modification; controlled study; drug sensitivity; minimum inhibitory concentration; multidrug resistance; Mycobacterium tuberculosis; nonhuman; structure activity relation; Vero cell; Animals; Antitubercular Agents; Cell Survival; Cercopithecus aethiops; Colony Count, Microbial; Drug Design; Drug Resistance, Bacterial; Female; High-Throughput Screening Assays; Indoles; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Serum Bactericidal Test; Solubility; Structure-Activity Relationship; Vero Cells