TY  - JOUR
AU  - Milošević, Milena D.
AU  - Marinković, Aleksandar
AU  - Petrović, Predrag
AU  - Klaus, Anita
AU  - Nikolić, Milica G.
AU  - Prlainović, Nevena Ž.
AU  - Cvijetić, Ilija
PY  - 2020
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/4254
AB  - 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 13C 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 (IC50 = 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.
PB  - Elsevier
T2  - Bioorganic Chemistry
T1  - Synthesis, characterization and SAR studies of bis(imino)pyridines as antioxidants, acetylcholinesterase inhibitors and antimicrobial agents
VL  - 102
DO  - 10.1016/j.bioorg.2020.104073
ER  - 

@article{
author = "Milošević, Milena D. and Marinković, Aleksandar and Petrović, Predrag and Klaus, Anita and Nikolić, Milica G. and Prlainović, Nevena Ž. and Cvijetić, Ilija",
year = "2020",
abstract = "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 13C 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 (IC50 = 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.",
publisher = "Elsevier",
journal = "Bioorganic Chemistry",
title = "Synthesis, characterization and SAR studies of bis(imino)pyridines as antioxidants, acetylcholinesterase inhibitors and antimicrobial agents",
volume = "102",
doi = "10.1016/j.bioorg.2020.104073"
}

Milošević, M. D., Marinković, A., Petrović, P., Klaus, A., Nikolić, M. G., Prlainović, N. Ž.,& Cvijetić, I.. (2020). Synthesis, characterization and SAR studies of bis(imino)pyridines as antioxidants, acetylcholinesterase inhibitors and antimicrobial agents. in Bioorganic Chemistry
Elsevier., 102.
https://doi.org/10.1016/j.bioorg.2020.104073

Milošević MD, Marinković A, Petrović P, Klaus A, Nikolić MG, Prlainović NŽ, Cvijetić I. Synthesis, characterization and SAR studies of bis(imino)pyridines as antioxidants, acetylcholinesterase inhibitors and antimicrobial agents. in Bioorganic Chemistry. 2020;102.
doi:10.1016/j.bioorg.2020.104073 .

Milošević, Milena D., Marinković, Aleksandar, Petrović, Predrag, Klaus, Anita, Nikolić, Milica G., Prlainović, Nevena Ž., Cvijetić, Ilija, "Synthesis, characterization and SAR studies of bis(imino)pyridines as antioxidants, acetylcholinesterase inhibitors and antimicrobial agents" in Bioorganic Chemistry, 102 (2020),
https://doi.org/10.1016/j.bioorg.2020.104073 . .