Pyrimidine thioethers: A novel class of antidepressant agents, endowed with anxiolytic, performance enhancing and nootropic activity

Fioravanti, Rossella; Proia, Eleonora; Tyurenkov, I. N.; Куркин, Д. В.; Бакулин, Д. А.; Kovalev, N.S.; Sheikin, D. S.; Kirillov, I. A.; Nawrozkij, M. B.; Вернигора, А. А.; Brunilina, L. L.; Fiorentino, Francesco; Mladenović, Milan; Rotili, Dante; Ragno, Rino

doi:10.1016/j.ejmech.2022.114902

Cited by 2 publications

(1 citation statement)

References 31 publications

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“…To individuate the docking program able to reproduce the experimental binding poses, Plants and Smina docking software with their respective scoring functions were engaged as previously reported. , Although the docking assessment protocol used was previously shown to be effective, this time, no program/scoring function pair was able to reproduce the experimental ligand binding conformation with an acceptable root mean square deviation (RMSD) (Supporting Information Table S2–S1). At deeper analysis, the complexed experimental conformation of NL1, NL2, and NL3 overlapped by a structure-based alignment of the complexes revealed the lack of a common binding mode among the three NL derivatives.…”

Section: Resultsmentioning

confidence: 99%

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

Golovina,

Proia,

Fiorentino

et al. 2024

ACS Infect. Dis.

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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 IC50 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.

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