Cvijetic IN

References (3)

Title : Synthesis, characterization and SAR studies of bis(imino)pyridines as antioxidants, acetylcholinesterase inhibitors and antimicrobial agents - Miloevi_2020_Bioorg.Chem_102_104073
Author(s) : Milosevic MD , Marinkovic AD , Petrovic P , Klaus A , Nikolic MG , Prlainovic N , Cvijetic IN
Ref : Bioorg Chem , 102 :104073 , 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 (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 omegaB97XD/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 muM), 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.
ESTHER : Miloevi_2020_Bioorg.Chem_102_104073
PubMedSearch : Miloevi_2020_Bioorg.Chem_102_104073
PubMedID: 32693308

Title : The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents - Vitorovic-Todorovic_2019_Chem.Biol.Interact_13ChEPon_309_108714
Author(s) : Vitorovic-Todorovic MD , Worek F , Perdih A , Bauk SD , Vujatovic TB , Cvijetic IN
Ref : Chemico-Biological Interactions , 309 :108714 , 2019
Abstract : Acetylcholinesterase (AChE) is an enzyme which terminates the cholinergic neurotransmission, by hydrolyzing acetylcholine at the nerve and nerve-muscle junctions. The reversible inhibition of AChE was suggested as the pre-treatment option of the intoxications caused by nerve agents. Based on our derived 3D-QSAR model for the reversible AChE inhibitors, we designed and synthesized three novel compounds 8-10, joining the tacrine and aroylacrylic acid phenylamide moieties, with a longer methylene chain to target two distinct, toplogically separated anionic areas on the AChE. The targeted compounds exerted low nanomolar to subnanomolar potency toward the E. eel and human AChE's as well as the human BChE and showed mixed inhibition type in kinetic studies. All compounds were able to slow down the irreversible inhibition of the human AChE by several nerve agents including tabun, soman and VX, with the estimated protective indices around 5, indicating a valuable level of protection. Putative noncovalent interactions of the selected ligand 10 with AChE active site gorge were finally explored by molecular dynamics simulation suggesting a formation of the salt bridge between the protonated linker amino group and the negatively charged Asp74 carboxylate side chain as a significant player for the successful molecular recognition in line with the design strategy. The designed compounds may represent a new class of promising leads for the development of more effective pre-treatment options.
ESTHER : Vitorovic-Todorovic_2019_Chem.Biol.Interact_13ChEPon_309_108714
PubMedSearch : Vitorovic-Todorovic_2019_Chem.Biol.Interact_13ChEPon_309_108714
PubMedID: 31228470

Title : The 3D-QSAR study of 110 diverse, dual binding, acetylcholinesterase inhibitors based on alignment independent descriptors (GRIND-2). The effects of conformation on predictive power and interpretability of the models - Vitorovic-Todorovic_2012_J.Mol.Graph.Model_38C_194
Author(s) : Vitorovic-Todorovic MD , Cvijetic IN , Juranic IO , Drakulic BJ
Ref : J Mol Graph Model , 38C :194 , 2012
Abstract : The 3D-QSAR analysis based on alignment independent descriptors GRIND-2 was performed on the set of 110 structurally diverse dual binding AChE reversible inhibitors Three separate models were built based on different conformations generated following next criteria i minimum energy conformations ii conformation most similar to the co-crystalized ligand conformation and iii docked conformation We found that regardless on conformation used all the three models had good statistic and predictivity The models revealed the importance of protonated pyridine nitrogen of tacrine moiety for anti AChE activity and recognized HBA and HBD interactions as highly important for the potency This was revealed by the variables associated with protonated pyridinium nitrogen and the two amino groups of the linker MIFs calculated with the N1 pyridinium nitrogen and the DRY GRID probes in the AChE active site enabled us to establish the relationship between amino acid residues within AChE active site and the variables having high impact on models External predictive power of the models was tested on the set of 40 AChE reversible inhibitors most of them structurally different from the training set Some of those compounds were tested on the different enzyme source We found that external predictivity was highly sensitive on conformations used Model based on docked conformations had superior predictive ability emphasizing the need for the employment of conformations built by taking into account geometrical restrictions of AChE active site gorge.
ESTHER : Vitorovic-Todorovic_2012_J.Mol.Graph.Model_38C_194
PubMedSearch : Vitorovic-Todorovic_2012_J.Mol.Graph.Model_38C_194
PubMedID: 23073222