(Heteroarylmethyl)benzoic Acids as a New Class of Bacterial Cystathionine γ-Lyase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling.

Autor: Golovina A; Sirius University of Science and Technology, Olympic Avenue, 1, Sirius , Krasnodar Region 354340, Russia., Proia E; Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5 , Rome 00185, Italy., Fiorentino F; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, Rome 00185, Italy., Yunin M; Sirius University of Science and Technology, Olympic Avenue, 1, Sirius , Krasnodar Region 354340, Russia., Kasatkina M; Sirius University of Science and Technology, Olympic Avenue, 1, Sirius , Krasnodar Region 354340, Russia., Zigangirova N; National Research Centre of Epidemiology and Microbiology named after N. F. Gamaleya, Russian Health Ministry, Gamaleya St.18 , 123098 Moscow, Russia., Soloveva A; National Research Centre of Epidemiology and Microbiology named after N. F. Gamaleya, Russian Health Ministry, Gamaleya St.18 , 123098 Moscow, Russia., Sysolyatina E; National Research Centre of Epidemiology and Microbiology named after N. F. Gamaleya, Russian Health Ministry, Gamaleya St.18 , 123098 Moscow, Russia., Ermolaeva S; National Research Centre of Epidemiology and Microbiology named after N. F. Gamaleya, Russian Health Ministry, Gamaleya St.18 , 123098 Moscow, Russia., Novikov R; Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, 32 Vavilov St. , Moscow 119991, Russia., Silonov S; Sirius University of Science and Technology, Olympic Avenue, 1, Sirius , Krasnodar Region 354340, Russia.; Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Avenue , St. Petersburg 194064, Russia., Pushkin S; Sirius University of Science and Technology, Olympic Avenue, 1, Sirius , Krasnodar Region 354340, Russia., Mladenović M; Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12 , Kragujevac 34000, P.O. Box 60, Serbia., Isakova J; Sirius University of Science and Technology, Olympic Avenue, 1, Sirius , Krasnodar Region 354340, Russia., Belik A; Sirius University of Science and Technology, Olympic Avenue, 1, Sirius , Krasnodar Region 354340, Russia., Nawrozkij M; Sirius University of Science and Technology, Olympic Avenue, 1, Sirius , Krasnodar Region 354340, Russia., Rotili D; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, Rome 00185, Italy., Ragno R; Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5 , Rome 00185, Italy., Ivanov R; Sirius University of Science and Technology, Olympic Avenue, 1, Sirius , Krasnodar Region 354340, Russia.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2024 Jun 14; Vol. 10 (6), pp. 2127-2150. Date of Electronic Publication: 2024 May 21.
DOI: 10.1021/acsinfecdis.4c00136
Abstrakt: 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 50 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.
Databáze: MEDLINE