Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3746-3755 |
| Number of pages | 10 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 25 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 15 2017 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry
Cite this
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.
In: Bioorganic and Medicinal Chemistry, Vol. 25, No. 14, 15.07.2017, p. 3746-3755.Research output: Contribution to journal › Article
}
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
PY - 2017/7/15
Y1 - 2017/7/15
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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UR - http://www.scopus.com/inward/citedby.url?scp=85019958724&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2017.05.015
DO - 10.1016/j.bmc.2017.05.015
M3 - Article
VL - 25
SP - 3746
EP - 3755
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 14
ER -