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Design and synthesis of N-(3-sulfamoylphenyl)amides as Trypanosoma brucei leucyl-tRNA synthetase inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 May 05; Vol. 217, pp. 113319. Date of Electronic Publication: 2021 Mar 08. - Publication Year :
- 2021
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Abstract
- The protozoan parasite Trypanosoma brucei (T. brucei) causes human African trypanosomiasis (HAT), which is a fatal and neglected disease in the tropic areas, and new treatments are urgently needed. Leucyl-tRNA synthetase (LeuRS) is an attractive target for the development of antimicrobial agents. In this work, starting from the hit compound thiourea ZCL539, we designed and synthesized a series of amides as effective T. brucei LeuRS (TbLeuRS) synthetic site inhibitors. The most potent compounds 74 and 91 showed IC <subscript>50</subscript> of 0.24 and 0.25 μM, which were about 700-fold more potent than the starting hit compound. The structure-activity relationship was also discussed. These compounds provided a new scaffold and lead compounds for further development of antitrypanosomal agents.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Amides chemical synthesis
Amides chemistry
Antiprotozoal Agents chemical synthesis
Antiprotozoal Agents chemistry
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Leucine-tRNA Ligase metabolism
Molecular Structure
Parasitic Sensitivity Tests
Structure-Activity Relationship
Trypanosoma brucei brucei enzymology
Amides pharmacology
Antiprotozoal Agents pharmacology
Drug Design
Enzyme Inhibitors pharmacology
Leucine-tRNA Ligase antagonists & inhibitors
Trypanosoma brucei brucei drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 217
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33725631
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113319