Synthesis, characterization and SAR studies of bis(imino)pyridines as antioxidants, acetylcholinesterase inhibitors and antimicrobial agents.

Autor: Milošević MD; SI Institute of Chemistry, Technology and Metallurgy, National Institute, Department of Ecology and Techoeconomic, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia., Marinković AD; Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, 11000 Belgrade, Serbia., Petrović P; Innovation Centre of Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, 11000 Belgrade, Serbia., Klaus A; Department for Industrial Microbiology, Institute for Food Technology and Biochemistry, University of Belgrade-Faculty of Agriculture, Nemanjina 6, 11080 Belgrade, Serbia., Nikolić MG; Faculty of Sciences and Mathematics, Department of Chemistry, University of Niš, Višegradska 33, 18000 Niš, Serbia., Prlainović NŽ; Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, 11000 Belgrade, Serbia., Cvijetić IN; Innovation Center of the Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia. Electronic address: ilija@chem.bg.ac.rs.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 Sep; Vol. 102, pp. 104073. Date of Electronic Publication: 2020 Jul 06.
DOI: 10.1016/j.bioorg.2020.104073
Abstrakt: In this study we synthesized a series of sixteen bis(imino)pyridines (BIPs) starting from 2,6-diaminopyridine and various aromatic aldehydes, and evaluated their antioxidant, antibacterial, antifungal and acetylcholinesterase (AChE) inhibitory activity. The chemical structures were elucidated by FTIR, elemental analysis, ESR and HRMS. 1 H and 13 C NMR spectra couldn't be acquired due to the formation of stable, carbon-centered radical cations in a solution, as confirmed by ESR spectroscopy and DFT calculations. The in vitro antioxidant potency was evaluated using four assays: free radical scavenging activity (DPPH and ABTS), reducing power and total antioxidant capacity assay. BIPs demonstrated excellent antioxidant properties, and two derivatives proved to be more potent than reference antioxidants (ascorbic acid and Trolox) in all assays. DFT calculations on ωB97XD/6-311++g(d,p) level of theory provided valuable insights into the radical scavenging mechanism of BIPs. For hydroxyl-substituted BIPs, hydrogen atom transfer (HAT) is a predominant mechanism, while the single electron transfer coupled with proton transfer (SET-PT) governs the antioxidant activity of other derivatives. Intramolecular hydrogen bonding (IHB) plays an important role in the mechanism of antioxidant activity as revealed by noncovalent interaction analysis and rotational barrier calculations. The spin density of radical cations is localized on carbon atoms of a pyridine ring, which corroborates with g-factors and multiplicity obtained from ESR analysis. The most potent BIP exhibited moderate inhibitory activity toward AChE (IC 50  = 20 ± 4 μM), while molecular docking suggested binding at the peripheral anionic site of AChE with the MMFF94 binding enthalpy of -43.4 kcal/mol. Moderate in vitro antimicrobial activity of BIPs have been determined against several pathogenic bacterial strains: Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus and clinical isolate of methicillin resistant S. aureus (MRSA). The antifungal activity of BIPs toward Candida albicans was also confirmed. The similarity ensemble approach combined with molecular docking suggested leucyl aminopeptidase as the probable antimicrobial target for the three most potent BIP derivatives.
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.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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