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 MD, Worek F, Perdih A, Bauk SD, Vujatovic TB, Cvijetic IN Ref: Chemico-Biological Interactions, 309:108714, 2019 : PubMed
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.
Title: Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE-ligand interactions by docking calculations and molecular dynamics simulations Vitorovic-Todorovic MD, Koukoulitsa C, Juranic IO, Mandic LM, Drakulic BJ Ref: Eur Journal of Medicinal Chemistry, 81C:158, 2014 : PubMed
Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl- and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzyme-substrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide -NH- moiety of compounds and -OH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChE-compound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding.
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 MD, Cvijetic IN, Juranic IO, Drakulic BJ Ref: J Mol Graph Model, 38C:194, 2012 : PubMed
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.
Title: 4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure-activity relationship based on molecular interaction fields Vitorovic-Todorovic MD, Juranic IO, Mandic LM, Drakulic BJ Ref: Bioorganic & Medicinal Chemistry, 18:1181, 2010 : PubMed
Synthesis and anticholinesterase activity of 4-aryl-4-oxo-N-phenyl-2-aminylbutyramides, novel class of reversible, moderately potent cholinesterase inhibitors, are reported. Simple substituent variation on aroyl moiety changes anti-AChE activity for two orders of magnitude; also substitution and type of hetero(ali)cycle in position 2 of butanoic moiety govern AChE/BChE selectivity. The most potent compounds showed mixed-type inhibition, indicating their binding to free enzyme and enzyme-substrate complex. Alignment-independent 3D QSAR study on reported compounds, and compounds having similar potencies obtained from the literature, confirmed that alkyl substitution on aroyl moiety of molecules is requisite for inhibition activity. The presence of hydrophobic moiety at close distance from hydrogen bond acceptor has favorable influence on inhibition potency. Docking studies show that compounds probably bind in the middle of the AChE active site gorge, but are buried deeper inside BChE active site gorge, as a consequence of larger BChE gorge void.
The title compound, C(14)H(14)ClN, is a chloro analogue of tacrine, an acetylcholinesterase inhibitor. The compound comprises a seven-membered alicyclic ring whose CH donor groups are engaged in extensive intermolecular interactions. The important feature of this crystal structure is that, regardless of the presence of two typical hydrogen-bonding acceptors, viz. chlorine and nitrogen, the corresponding C-H...Cl and C-H...N interactions take no significant role in crystal stabilization. The molecules form dimers through pi-pi interactions with an interplanar distance between interacting pyridine rings of 3.576 (1) A. Within the dimers, the molecules are additionally interconnected by four C-H...pi interactions. The dimers arrange into regular columns via further intermolecular C-H...pi interactions.
