Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection.
Our team had previously identified certain indolecarboxamides that represented a new chemical scaffold that showed promising anti-TB activity at both an in vitro and in vivo level. Based on mutational analysis using bacteria found resistant to one of these indolecarboxamides, we identified the trehalose monomycolate transporter MmpL3 as the likely target of these compounds. In the present work, we now further elaborate on the SAR of these compounds, which has led in turn to the identification of a new analog, 4,6-difluoro-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-indole-2-carboxamide (26), that shows excellent activity against drug-sensitive (MIC = 0.012 μM; SI ≥ 16000), multidrug-resistant (MDR), and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains, has superior ADMET properties, and shows excellent activity in the TB aerosol lung infection model. Compound 26 is also shown to work in synergy with rifampin. Because of these properties, we believe that indolecarboxamide 26 is a possible candidate for advancement to human clinical trials.
Department of Pharmaceutical Sciences, College of Pharmacy, Chicago State University , 9501 South King Drive, Chicago, Illinois 60628, United States.|Department of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University , 2575 Yorba Linda Boulevard, Fullerton, California 92831, United States.
Jozef
J
Stec
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.|Department of Biological, Chemical, and Physical Sciences, Roosevelt University , 425 S. Wabash Avenue, Chicago, Illinois 60605, United States.
Oluseye K
OK
Onajole
Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine , 1550 Orleans Street, Baltimore, Maryland 21231-1044, United States.
Shichun
S
Lun
Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine , 1550 Orleans Street, Baltimore, Maryland 21231-1044, United States.
Haidan
H
Guo
Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine , 1550 Orleans Street, Baltimore, Maryland 21231-1044, United States.
Benjamin
B
Merenbloom
Department of Pharmaceutical Sciences, Università degli Studi di Milano , via Mangiagalli 25, I-20133 Milan, Italy.
Giulio
G
Vistoli
Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine , 1550 Orleans Street, Baltimore, Maryland 21231-1044, United States.|Howard Hughes Medical Institute , 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, United States.
William R
WR
Bishai
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
Alan P
AP
Kozikowski
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D026901:Membrane Transport Proteins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000378:metabolism
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D007211:Indoles; D026901:Membrane Transport Proteins; C000599913:MmpL3 protein, Mycobacterium tuberculosis