TY - JOUR
T1 - Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity
AU - Franz, Nicholas D.
AU - Belardinelli, Juan Manuel
AU - Kaminski, Michael A.
AU - Dunn, Louis C.
AU - Calado Nogueira de Moura, Vinicius
AU - Blaha, Michael A.
AU - Truong, Dan D.
AU - Li, Wei
AU - Jackson, Mary
AU - North, E. Jeffrey
N1 - Funding Information:
This project was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases research grant AI116525 and the Jack and Lois Wareham Research Award. The cytotoxicity determination was supported by National Institutes of Health and the National Institute of Allergy and Infectious Diseases, Contract No. HHSN272201100009I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors would also like to thank the Department of Chemistry at Creighton University for the use of their NMR and Dr. William Jacobs (Albert Einstein College of Medicine, NY, USA) for the provision of M. tuberculosis H37Rv mc26206.
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bmc.2017.05.015
DO - 10.1016/j.bmc.2017.05.015
M3 - Article
C2 - 28545813
AN - SCOPUS:85019958724
VL - 25
SP - 3746
EP - 3755
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 14
ER -