Alicja Skrzypek

Synthesis and biological evaluation of 1,3,4-thiadiazole analogues as novel AChE and BuChE inhibitors

In this paper a series of new 1,3,4-thiadiazole derivatives has been designed, synthesized and evaluated as the acetyl- and butyrylcholinesterase inhibitors. Some analogues showed promising inhibition of both enzymes in vitro in the nM range. Generally, inhibitory potency of compounds was stronger against AChE than BuChE, and one of them was 1154-fold more active inhibiting AChE (IC50 = 0.17 μM) than BuChE. The kinetic studies showed that one of the most active analogues 8 (IC50 = 0.09 μM, AChE) acted as a non-competitive AChE inhibitor and was characterized by the high selectivity index (300). The other derivative (1) exhibited a mixed-type of AChE inhibition. Docking simulations enabled the detection of key binding interactions of the compounds with AChE and revealed that they occupied mainly the catalytic active site. The scoring function for the novel compounds was similar or higher than for the reference inhibitor. Additionally, based on Lipinski and other filters, the drug-likeness of compounds was assessed. They revealed that the compounds possess properties which can suggest the favourable pharmacokinetics in the human body after oral admission.

Synthesis and anticholinesterase activities of novel 1,3,4-thiadiazole based compounds

In the present study, new (1,3,4-thiadiazol-2-yl)benzene-1,3-diol based compounds have been synthesized and their potential anticholinesterases properties have been investigated using the modified of Ellman’s spectrophotometric method. The compounds were obtained by the reaction of hydrazides or thiosemicarbazides with aryl-modified sulfinylbis[(2,4-dihydroxyphenyl)methanethione]s. Their chemical structures were elucidated by IR, 1H-NMR, 13C-NMR and EI-MS spectral data and elemental analyses. Most of the compounds acted as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors in vitro, with IC50 values ranging from >500 to 0.053 μM and from >500 to 0.105 μM, respectively. The most potent compound 9 (IC50 = 0.053 μM) proved to be selective toward AChE, exhibiting selectivity ratios versus BuChE of ca. 950. The kinetic studies showed that it is a mixed-type of AChE inhibitor. Another compound (2) was active against both enzymes with IC50 values in the low nM range. The structure-activity relationships (SARs) of the compounds under consideration were discussed.

Synthesis of 4-(4-methylidene-4H-3,1-benzothiazin-2-yl)benzene1,3-diols and their antiproliferative activity against human cancer cell lines

One-step synthesis of novel biologically active 4- or 6-(4-methylidene-4H-3,1-benzothiazin-2yl)benzene-1,3-diols is described. The target compounds were prepared by the reaction of aryl-modified sulfinylbis[(2,4-dihydroxyphenyl)methanethione]s with 1-(2-aminophenyl)ethanones. Newly synthesized compounds were characterized by IR, 1H NMR, and mass spectral data. Their antiproliferative potency against human cancer cell lines was determined. Some descriptors were calculated to find the relationship between the structure and activity. It is revealed that the presence of hydrophobic substituents in the benzenediol ring intensifies the biological potency.

EFFECT OF ORGANIC MODIFIER ON THE LIPOPHILICITY OF ANTIPROLIFERATIVE ACTIVE 4-(5-AMINO-1,3,4-THIADIAZOL-2-YL/BENZENE-1,3-DIOLS BY REVERSED-PHASE OVERPRESSURED LAYER CHROMATOGRAPHY

The retention behavior of compounds of antiproliferative activity from the 4-(5-amino-1,3,4-thiadiazol-2-yl)benzene-1,3-diols group by OPLC was investigated. RP-18 stationary phase and five different organic modifiers were used. In the case of ethanol as an organic solvent the highest concentration of water in the eluent can be applied. On the base of the linear relationship between the retention and the concentration of organic solvent, various lipophilicity descriptors were determined. Moderate correlations between the chromatographic parameters and the calculated log P values according to the Villar approach were found. The RMw parameters were compared with the antiproliferative activity of compounds against human cancer cell T47D (breast cancer) to find QSAR equations. The best results for ethanol as the organic solvent were found.

Synthesis and biological activity of novel benzoazoles, benzoazines and other analogs functionalized by 2,4-dihydroxyphenyl moiety

Novel benzoazoles, benzoazines, benzothiazoles, benzothiazines and other related compounds possessing a 2,4-dihydroxyphenyl moiety were prepared. The compounds were obtained by the reaction of sulfinylbis[(2,4-dihydroxyphenyl)methanethione]s with the appropriate heterocyclic amines or hydrazines. The structures of the compounds were proved by IR, 1H NMR, and mass spectral data. Human cancer lines, Candida species and phytopathogenic fungi were used for the evaluation of biological potency of compounds. Additionally, drug-like properties were estimated in silico.

Spectroscopic and Theoretical Studies of Fluorescence Effects in 2-Methylamino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole Induced by Molecular Aggregation

The article presents the results of fluorescence analyses of 2-methylamino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (MDFT) in an aqueous environment. MDFT dissolved in aqueous solutions with a pH value in the range from 1 to 4.5 yielded an interesting effect of two clearly separated fluorescence emissions. In turn, a single fluorescence was observed in MDFT dissolved in water solutions with a pH value from 4.5 to 12. As it was suggested in the previous investigations of other 1,3,4-thiadiazole compounds, these effects may be associated with conformational changes in the structure of the analysed molecule accompanied by aggregation effects. Crystallographic data showed that the effect of the two separated fluorescence emissions occurred in a conformation with the –OH group in the resorcyl ring bound on the side of the sulphur atom from the 1,3,4-thiadiazole ring. The hypothesis of aggregation as the mechanism involved in the change in the spectral properties at low pH is supported by the results of (Time-Dependent) Density Functional Theory calculations. The possibility of rapid analysis of conformational changes with the fluorescence spectroscopy technique may be rather important outcome obtained from the spectroscopic studies presented in this article. Additionally, the presented results seem to be highly important as they can be easily observed in solutions and biologically important samples.

QSAR study of pyrazolo[4,3-e][1,2,4]triazine sulfonamides against tumor-associated human carbonic anhydrase isoforms IX and XII

The QSAR models for a set of pyrazolo[4,3-e][1,2,4]triazines incorporating benzenesulfonamide moiety combined directly with the heterocyclic ring or by NH linkage were generated. The inhibitory potency of compounds against human carbonic anhydrase isoforms IX and XII and antiproliferative activity against human MCF-7 cells were used as the dependent variables. The Codessa pro software was used for the descriptors calculation and the Best Multi-Linear Regression (BMLR) algorithm was employed to build the QSAR models. It was found that quantum descriptors are critical of the compounds activities. The selected models have good predictive accuracy confirmed by a set of the statistical quantities recommended by OECD.