Back to Search
Start Over
(Heteroarylmethyl)benzoic Acids as a New Class of Bacterial Cystathionine γ-Lyase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling.
- Source :
-
ACS infectious diseases [ACS Infect Dis] 2024 Jun 14; Vol. 10 (6), pp. 2127-2150. Date of Electronic Publication: 2024 May 21. - Publication Year :
- 2024
-
Abstract
- Antibiotic resistance is one of the most serious global health threats. Therefore, there is a need to develop antimicrobial agents with new mechanisms of action. Targeting of bacterial cystathionine γ-lyase (bCSE), an enzyme essential for bacterial survival, is a promising approach to overcome antibiotic resistance. Here, we described a series of (heteroarylmethyl)benzoic acid derivatives and evaluated their ability to inhibit bCSE or its human ortholog hCSE using known bCSE inhibitor NL2 as a lead compound. Derivatives bearing the 6-bromoindole group proved to be the most active, with IC <subscript>50</subscript> values in the midmicromolar range, and highly selective for bCSE over hCSE. Furthermore, none of these compounds showed significant toxicity to HEK293T cells. The obtained data were rationalized by ligand-based and structure-based molecular modeling analyses. The most active compounds were also found to be an effective adjunct to several widely used antibacterial agents against clinically relevant antibiotic-resistant strains of such bacteria as Staphylococcus aureus , Klebsiella pneumoniae , and Pseudomonas aeruginosa . The most potent compounds, 3h and 3i, also showed a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. Finally, compound 3i manifested potentiating activity in pneumonia, sepsis, and infected-wound in vivo models.
- Subjects :
- Animals
Humans
Mice
HEK293 Cells
Klebsiella pneumoniae drug effects
Microbial Sensitivity Tests
Pseudomonas aeruginosa drug effects
Pseudomonas aeruginosa enzymology
Staphylococcus aureus drug effects
Structure-Activity Relationship
Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents pharmacology
Benzoates chemical synthesis
Benzoates pharmacology
Cystathionine gamma-Lyase antagonists & inhibitors
Cystathionine gamma-Lyase metabolism
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors pharmacology
Models, Molecular
Subjects
Details
- Language :
- English
- ISSN :
- 2373-8227
- Volume :
- 10
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- ACS infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 38771206
- Full Text :
- https://doi.org/10.1021/acsinfecdis.4c00136