Supplementary data for the article: Vitorović-Todorović, M. D.; Koukoulitsa, C.; Juranić, I. O.; Mandić, L. M.; Drakulić, B. J. 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. European Journal of Medicinal Chemistry 2014, 81, 158–175. https://doi.org/10.1016/j.ejmech.2014.05.008

Supplementary material for: [https://doi.org/10.1016/j.ejmech.2014.05.008]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1808]Related to accepted version:[http://cherry.chem.bg.ac.rs/handle/123456789/2907

Supplementary data for the article: Vitorović-Todorović, M. D.; Koukoulitsa, C.; Juranić, I. O.; Mandić, L. M.; Drakulić, B. J. 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. European Journal of Medicinal Chemistry 2014, 81, 158–175. https://doi.org/10.1016/j.ejmech.2014.05.008

Supplementary material for: [https://doi.org/10.1016/j.ejmech.2014.05.008]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1808]Related to accepted version:[http://cherry.chem.bg.ac.rs/handle/123456789/2907

Rational design, efficient syntheses and biological evaluation of N,N′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

A series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA2 values) and binding affinities (–logIC50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (–logIC50 = 9.04) and the sodium (–logIC50 = 8.54) salts of 4-butyl-N,N′-bis{[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (–logIC50 = 9.46) and the 4-butyl-2-hydroxymethyl-N,N′-bis{[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (–logIC50 = 8.37, pA2 = 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (–logIC50 = 8.25, pA2 = 8.25). On the contrary, 2-butyl-N,N′-bis{[2′-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (–logIC50 = 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N′-bis{[2′-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (30) (–logIC50 = 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the headgroup, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC).Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the headgroup. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phasetransition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discusse

A Journey to the Conformational Analysis of T-Cell Epitope Peptides Involved in Multiple Sclerosis

Multiple sclerosis (MS) is a serious central nervous system (CNS) disease responsible for disability problems and deterioration of the quality of life. Several approaches have been applied to medications entering the market to treat this disease. However, no effective therapy currently exists, and the available drugs simply ameliorate the destructive disability effects of the disease. In this review article, we report on the efforts that have been conducted towards establishing the conformational properties of wild-type myelin basic protein (MBP), myelin proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) epitopes or altered peptide ligands (ALPs). These efforts have led to the aim of discovering some non-peptide mimetics possessing considerable activity against the disease. These efforts have contributed also to unveiling the molecular basis of the molecular interactions implicated in the trimolecular complex, T-cell receptor (TCR)-peptide-major histocompatibility complex (MHC) or human leucocyte antigen (HLA)

Comparative docking studies of labdane-type diterpenes with forskolin at the active site of adenylyl cyclase

Diterpen labd-13(E)-ene-8a,15-diol (1) is a natural product found to possess potential cytotoxic and cytostatic effects against human cancer cell lines. Adenylyl cyclases (ACs) are promising pharmacological targets for treating heart failure, cancer, and psychosis. It has been demonstrated that forskolin is a potent adenylyl cyclase activator. Labdane 1 belongs to same family as forskolin. Its conformational properties are explored using a combination of 1D, 2D NMR spectroscopy, and molecular modeling techniques. The derived low energy conformers are subjected to docking calculations aiming to reveal similarities and differences in the binding mode between 1 and forskolin. Additionally, docking calculations performed on the 1a,9a-OH and 1a-OH derivatives of 1 suggest major contribution of 1a position in increasing binding affinity. This information may be of paramount importance to medicinal chemists who are interested in the synthesis of proposed analogs and test the docking results through in vitro experiment

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

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. (C) 2014 Elsevier Masson SAS. All rights reserved.Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/2906]Peer reviewed manuscript: [http://cherry.chem.bg.ac.rs/handle/123456789/2907

Sesquiterpene Lactones from Anthemis melanolepis and Their Antibacterial and Cytotoxic Activities. Prediction of Their Pharmacokinetic Profile

Nine sesquiterpene lactones, anthemin A (1), 1 alpha-hydroxydeacetylirinol-4 alpha,5 beta-epoxide (2), anthemin C (3), tatridin A (4), 1-epi-tatridin B (5), anthemin B (6), 6-deacetyl-beta-cyclopyrethrosin (7), elegalactone A (8), and 1 beta,4 alpha,6 alpha-trihydroxyeudesm-11-en-8 alpha-12-olide (9), were isolated front the aerial parts of A. melanolepis in addition to eight known flavonoids and three phenolic acids. Compounds 1, 3, and 6 are new natural products. The structures of the compounds were deduced by spectroscopic methods. The in vitro antimicrobial potential of the isolated sesquiterpene lactones four Gram-positive and five Gram-negative bacteria and One fungus was evaluated using the against microdilution method, and their in vitro cytotoxic activity was determined against a panel of human tumor cell lines. Furthermore. The pharmacokinetic profile Of the sesquiterpene lactones was investigated using computational methods.ESF (European Social Fund); National Resources [70/3/7171

Sesquiterpene Lactones from Anthemis melanolepis and Their Antibacterial and Cytotoxic Activities. Prediction of Their Pharmacokinetic Profile

Nine sesquiterpene lactones, anthemin A (1), 1 alpha-hydroxydeacetylirinol-4 alpha,5 beta-epoxide (2), anthemin C (3), tatridin A (4), 1-epi-tatridin B (5), anthemin B (6), 6-deacetyl-beta-cyclopyrethrosin (7), elegalactone A (8), and 1 beta,4 alpha,6 alpha-trihydroxyeudesm-11-en-8 alpha-12-olide (9), were isolated front the aerial parts of A. melanolepis in addition to eight known flavonoids and three phenolic acids. Compounds 1, 3, and 6 are new natural products. The structures of the compounds were deduced by spectroscopic methods. The in vitro antimicrobial potential of the isolated sesquiterpene lactones four Gram-positive and five Gram-negative bacteria and One fungus was evaluated using the against microdilution method, and their in vitro cytotoxic activity was determined against a panel of human tumor cell lines. Furthermore. The pharmacokinetic profile Of the sesquiterpene lactones was investigated using computational methods.ESF (European Social Fund); National Resources [70/3/7171

Facile and Efficient Syntheses of a Series of N-Benzyl and N-Biphenylmethyl Substituted Imidazole Derivatives Based on (E)-Urocanic acid, as Angiotensin II AT1 Receptor Blockers

molecule