Search

The geometry of the channel formed by nontoxic derivative of diphtheria toxin CRM197 in lipid bilayer was determined using the dependence of single-channel conductance upon the hydrodynamic radii of different nonelectrolytes. It was found that the cis entrance of CRM197 channel on the side of membrane to which the toxoid was added at pH 4.8 and the trans entrance on the opposite side at pH 6.0 had effective radii of 3.90 and 3.48 A, respectively. The 3-alkyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium salts reversibly reduced current via CRM197 channels. The potency of the blockers increased with increasing length of alkyl chain at symmetric pH 6.0 and remained high and stable at pH 4.8 on the cis side. Comparative analysis of CRM197 and amphotericin B pore size with the inhibitory action of thiazolium salts revealed a significant increase in CRM197 pore dimension at pH 6.0. Addition of thiazolium salt with nine carbons alkyl tail increased by ∼30% the viability of human carcinoma cells A431 treated with diphtheria toxin.

Thiazole-containing derivatives of rhodanine-3-alkanoic acids with propanoic or undecanoic acid groups were synthesized and evaluated as inhibitors of some protein tyrosine phosphatases and glutathione S-transferases. The rhodanines bearing longer carboxylated N-alkyl chain were found to inhibit PTP1B, MEG1, MEG2, and VE-PTP as well as GST from equine liver and GSTA1-1 with IC50 values in the low micromolar range. The inhibitory effect on protein tyrosine phosphatase activity depends on substituent at position 2 of the thiazole ring. The best compound showed a competitive type of VE-PTP inhibition. In case of GST from equine liver, the inhibition was of mixed or non-competitive type with respect to glutathione or CDNB substrate, respectively. Possible binding modes of the inhibitors were discussed based on molecular docking calculations.

Background: Currently, a study on the relationship between candidiasis and cancer has been conducted. Until recent years, the opportunistic fungus C. albicans is mainly associated with cancer processes and is able to stimulate carcinogenesis and metastasis. Methods: A number of ionic liquids as potential anticancer and anti-Candida agents have been investigated based on modern theoretical and experimental data about the relationship between oncopathology and candida infection. Results: The analysis of the received experimental results demonstrates that ionic liquid with alkyl chain length of 6 carbon atoms (C6) has not shown anti-Candida activity. The indicators of its cytotoxicity ІС50 (28,617μМ) and MTC (9,050 μМ) against HEP-2 tumor cell line were also very low. Compounds with alkyl chain length C12 have shown high potential of anti-Candida activity and anticancer properties. Conclusion: Based on the obtained results, сompound 4 (C12C1IM-Cl) is proposed for further study as a potential double-acting agent with high anticancer and anti-Candida activities. N-myristoyltransferase is presented and used for docking as a potential molecular target responsible for the dual anti-Сandidа and anticancer activities of studied ionic liquids.

A series of long-chain imidazolium-based ionic liquids (ILs) 1-dodecyl-3-methylimidazolium chloride (1), 1,3-bis(octyloxycarbonylmethyl)imidazolium chloride (2) and 1-dodecyloxycarbonylmethyl-3-methyloxycarbonylmethylimidazolium chloride (3), were synthesized and evaluated as antimicrobials against a wide range of bacteria and fungi. Toxicological risks of selected compounds were assessed using the biomodels of various organizational and functional levels. All compounds demonstrated significant antibacterial and antifungal activity. The toxicity results indicate that ILs containing an ester functional group in the alkyl side chain exhibited much lower toxicity to D. magna and acetylcholinesterase inhibition than ILs with long alkyl chain without polar substituents, while toxicity toward Danio rerio was on a par. The HSA-binding properties of ILs have been investigated by FT-IR spectroscopy technique and the evidences have suggested that the test compounds could induce the protein unfolding and changes in the secondary structure of HSA. The docking studies were carried out to provide structural insights of the ILs–HSA-binding interactions. The docked compounds exhibit a high binding affinity to HSA and the hydrogen bonding, hydrophobic and electrostatic interactions played a major role in the process. ILs 2 and 3 may be perspective for further investigation as potential low-toxic biocides with high antimicrobial activity against reference and clinical multidrug-resistant strains.

O-Acyl substituted derivatives of 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride which is a structural analog of vitamin B1 were synthesized and evaluated towards acetylcholinesterase and butyrylcholinesterase in vitro. The inhibition properties of the O-substituted compounds depend on nature of substituents at position 3 and 5 of the thiazolium ring. Some of the thiazolium salts showed high potency in the inhibition of only one of the two enzymes. The selective effects of these inhibitors are governed by substituent at position 5. Kinetic studies and molecular docking simulation were performed for elucidating mechanisms of enzyme-inhibitor complex formation.

Background: The incidence of invasive fungal infections caused by Candida spp. has increased continuously in recent decades, especially in populations of immunocompromised patients or individuals hospitalized with serious underlying diseases. Therefore, the goal of our study was the search for new potent Candida albicans inhibitors via the development of QSAR models that could speed up this search process. A number of the most promising 1,3-oxazol-4-yltriphenylphosphonium derivatives with predicted activities were synthesized and experimentally tested. Furthermore, the toxicity of the studied compounds was determined in vitro using acetylcholinesterase enzyme as a biological marker. Methods: The classification QSAR models were created using Random Forests (WEKA-RF), k-Nearest Neighbors and Associative Neural Networks methods and different combinations of descriptors on the Online Chemical Modeling Environment (OCHEM) platform. Аntifungal properties of the investigated compounds were performed using standard disk diffusion method. The enzyme inhibitory action of the compounds was determined by modified Ellman's method using acetylcholinesterase from the electric organ of Electrophorus electricus. Results: Three classification QSAR models were developed by the WEKA-RF, k-NN and ASNN methods using the ALogPS, E-State indices and Dragon v.7 descriptors. The predictive ability of the models was tested through cross-validation, giving a balanced accuracy BA = 80-91%. All compounds demonstrated good antifungal properties against Candida spp. and slight inhibition of the acetylcholinesterase activity. Conclusion: The high percentage of coincidence between the QSAR predictions and the experimental results confirmed the high predictive power of the developed QSAR models that can be applied as tools for finding new potential inhibitors against Candida spp. Furthermore, 1,3-oxazol-4- yl(triphenyl)phosphonium salts could be considered as promising candidates for the treatment of candidiasis and the disinfection of medical equipment.

In our previous work, a number of new nitrogen-containing bisphosphonates (N-BPs) with high predicted and experimental antifungal activity were presented as potential Candida albicans farnesyl pyrophos­phate synthase (FPPS) inhibitors. To confirm this hypothesis, a homologous C. albicans FPPS model with high-quality scores has been developed and used in present work to study the molecular mechanism of nit­rogen-containing bisphosphonates action as anti-Candida agents. The known FPPS inhibitors ammonium 2-(Pyridin-2-ylamino)ethylidene-1,1-bisphosphonate, risedronate and alendronate were used in molecular docking analysis. The molecular docking analysis of the new N-BPs demonstrated a number of common features of all ligand’s interaction in the active center of FPPS C. albicans. It is established that the ligands phosphonate groups are the key elements in the formation of the stable ligand-protein complexes with binding energy in a range (ΔG) from –6.6 to –7.1 kcal/mol due to a significant number of electrostatic, hydrogen and metal-acceptor bonds. It is confirmed that the new studied N-BPs 1 and 3 with high anti-Candida activity are FPPS inhibitors.

Background: Due to the increase of multidrug-resistant microorganisms, the search for biologically active molecules does not stop. In the present study, we developed the effective QSAR model which allows a quick search of new potential Staphylococcus aureus inhibitors in the series of quaternary phosphonium salts. A number of the most promising 1,3-oxazol-4-yltriphenylphosphonium derivatives with predicted activities were synthesized and examined to confirm their antibacterial properties and the accuracy of the forecast. Furthermore, the toxicity of the investigated compounds was evaluated. Methods: The predictive QSAR model was developed using Artificial Neural Network approach. Antibacterial properties of the investigated compounds were performed using standard disk diffusion method. The toxicity of the compounds was determined in vivo using zebrafish (Danio rerio) and in vitro on acetylcholinesterase (AChE) enzyme as the test models. Results: The predictive ability of the regression model was tested by cross-validation, giving the cross-validated coefficient q2=0.82. Derivatives of 1,3-oxazol-4-yltriphenylphosphonium salts predicted as active were synthesized and screened for their antibacterial activities. All compounds demonstrated antibacterial activity according to the prediction. The toxicity tests indicated that all investigated samples were less toxic than well-known cationic surfactants. Conclusion: The most promising compound 2b exhibited strong antibacterial activity together with low toxicity and can be considered as a new efficient biocidal agent for future investigation. In addition, the proposed QSAR model can be used for predicting and designing novel potential S. aureus inhibitors among ionic liquids/salts.

Мета роботи. Порівняння похідних сульфонілкалікс[4]арену, які містять здатні та нездатні до іонізації залишки на верхньому вінці макроциклу, як інгібіторів РТР1В та інших протеїнотирозинфосфатаз. Результати та їх обговорення. Властивості сульфонілкалікс[4]арену з чотирма фосфонатними групами, приєднаними до верхнього вінця макроциклу, порівнювалися з властивостями сполук, які містять чотири трет-бутильні або трифторацетамідні замісники. Було встановлено, що сульфонілкалікс[4]арентетракіс-метилфосфонова кислота інгібує PTP1B зі значенням IC50 в низькомікромолярному діапазоні без селективності стосовно інших PTPаз, таких як TC-PTP, MEG1, MEG2, SHP2 та PTPβ. Модифікація сульфонілкалікс[4]арену залишками трифторацетаміду забезпечила інгібування PTP1B зі значенням IC50 1,4 мкМ з 4-28-кратною селективністю відносно інших PTPаз. Для з’ясування інгібувальної здатності похідної сульфонілкалікс[4]арену з трифторацетамідними замісниками відносно PTP1B було застосовано молекулярний докінг та моделювання методом молекулярної динаміки. Обговорюється можливий механізм інгібування. Експериментальна частина. Активність сполук досліджували спектрофотометрично, вимірюючи швидкість ферментативного гідролізу п-нітрофенілфосфату як субстрату протеїнотирозинфосфатаз. Молекулярний докінг було виконано за допомогою AutoDock Vina. Висновки. Це дослідження може бути основою нового підходу до розробки інгібіторів PTPаз шляхом модифікації верхнього вінця сульфонілкалікс[4]аренового каркасу неіоногенними замісниками.

Cholinesterase inhibitors can be used for treatment of neuropsychiatric symptoms and functional impairments in neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases. Aim. To synthesize and assess the inhibitory activity of adamantyl-containing 5-substituted N-benzyl and N-phenacylthiazolium salts against butyrylcholinesterase and acetylcholinesterase. Results and discussion. The synthesis of 3-aroylmethyl- and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts included preparation of 5-acyloxyethyl thiazole derivatives by the reaction of 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole with the corresponding adamantoyl- or adamantylacetyl chlorides. The derivatives of 5-acyloxyethyl thiazole were quaternized in the reaction with benzyl or phenacyl halides. The studies in vitro have shown that the compounds synthesized inhibit butyrylcholinesterase with IC50 values in the micromolar range. Some of them exhibited selectivity over acetylcholinesterase. The molecular docking was performed for understanding the mechanisms of the enzyme-inhibitor complex formation. Experimental part. The synthesis of the intermediate and target compounds was carried out by the classical methods. The structures of compounds were proven by NMR 1H-spectroscopy and elemental analysis. The methods of enzymatic kinetics were used for determination of the inhibitory effects of the compounds synthesized. Calculations by molecular docking were carried out using Autodock 4.2 program. Conclusions. 3-Aroylmethyl- and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts with adamantylcontaining substituents in position 5 can selectively inhibit butyrylcholinesterase compared to their effect on acetylcholinesterase.

It has been previously shown that phosphonic acids covalently attached to the macrocyclic platform of calix[4]arenes are capable of inhibiting alkaline phosphatases. In this paper the effects of the upper-rim functionalized calix[4]arenes on the activity of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) have been examined. Aim. To assess the inhibitory potential of calix[4]arene, thiacalix[4]arene and sulfonylcalix[4]arene derivatives against NPP1. Results and discussion. It has been found that calix[4]arene, thiacalix[4]arene, and sulfonylcalix[4]arene tetrakismethylphosphonic acids inhibit NPP1 with the IC50 values in the micromolar range. The derivatives of sulfonylcalix[4]arene demonstrated the selectivity of inhibition of NPP1 over alkaline phosphatases. In addition, sulfonylcalix[4]arene tetrakismethylphosphonic acid was able to inhibit the nucleotide pyrophosphatase/phosphodiesterase activity of the human serum. The possible mechanism of the inhibition has been discussed. Experimental part. The activity of NPP1 was monitored by spectrophotometry measuring the rate of hydrolysis of bis-p-nitrophenyl phosphate. The phosphodiesterase activity of the human serum was assessed in the presence of p-nitrophenyl ester of thymidine-5-monophosphate as a substrate. The homology model of the human NPP1 was generated based on the crystal structure of the murine enzyme. The molecular docking was performed using AutoDock 4.2. Conclusions. The results obtained have shown the ability of sulfonylcalix[4]arene derivatives to inhibit the activity of NPP1 in vitro, including the nucleotide pyrophosphatase/phosphodiesterase activity in the human blood serum.

Synthetic approaches for the preparation of 6-amino-5-hetarylpyrimidine derivatives by the ring transformation reaction of 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles with amidines have been developed. Some of 2,6-diamino-5-(1,3-benzothiazol-2-yl)pyrimidines were found to exhibit modest inhibitory activity against human dihydrofolate reductase. Molecular docking was performed to evaluate the binding mode of compounds of this series in the enzyme’s active site.

Xanthine oxidase is a potential target for treatment of hyperuricemia and gout. In this study, a number of A- and B-ring carboxylated aurone derivatives were synthesized and evaluated for their ability to inhibit xanthine oxidase in vitro . According to the results obtained, two different ranges of inhibitory activity were observed. The aurones with carboxylic acid group at the 4′-position of B-ring were found to be potent inhibitors of the enzyme with IC 50 values in the low micromolar range. The effects of these compounds were about 50 fold higher than of A-ring modified aurones with carboxymethoxy group at the 6-position. The binding modes of the carboxylated aurones in the active site of xanthine oxidase were explained using molecular docking calculations.

Previously, phosphonic acid derivatives of calix[4]arene and thiacalix[4]arene were found to be potential inhibitors of protein tyrosine phosphatase 1B. In the present paper, the inhibitory activity of unsubstituted sulfonyl-bridget calix[4]arene towards some of the therapeutically important protein tyrosine phosphatases has been established. The obtained results showed that the sulfonylcalix[4]arene is able to inhibit protein tyrosine phosphatase MEG2 with IC50 value in the micromolar range. At the same time, the inhibitor demonstrated lower activity in case of other protein tyrosine phosphatases such as PTP1B, MEG1, TC-PTP, SHP2, and PTPβ. The performed molecular docking indicated that the inhibitor binds to the active site region of MEG2 and PTP1B with WPD-loop in the open conformation.

Inhibition of acetylcholinesterase is considered as a promising approach for treatment of neurodegenerative disorders including Alzheimer's disease. In this study, we demonstrated that 5-substituted N-phenacylthiazolium derivatives are capable of inhibiting acetylcholinesterase and butyrylcholinesterase activities with IC50 values in the micromolar range. Some of the new thiazolium-based inhibitiors showed more than 10-fold selectivity for butyrylcholinesterase. Kinetic experiments and molecular docking were performed for understanding the inhibition mechanisms.

In this study, the synthesis, in vitro anti-Candida activity and molecular modeling of 4-phosphorylated derivatives of 1,3-oxazole as inhibitors of Candida albicans fructose-1,6-bisphosphate aldolase (FBA-II) are demonstrated and discussed. Significant similarity of the primary and secondary structure, binding sites and active sites of FBA-II C. albicans and Mycobacterium tuberculosis are established. FBA-II C. albicans inhibitors contained 1,3-oxazole-4-phosphonates moiety are created by analogy to inhibitors FBA-II M. tuberculosis. The experimental studies of the anti-Candida activity of the designed and synthesized compounds have shown their high activity against standard strain and its C. albicans fluconazole resistant clinical isolate. It was hypothesized that the growth suppression of fluconazole-resistant С. albicans strain may be due to the inhibition of aldolase fructose-1,6-bisphosphate. A qualitative homology 3D model of the C. albicans FBA-II was created using SWISS-MODEL server. The probable mechanism of FBA-II inhibition by studied 4-phosphorylated derivatives was shown using molecular docking. The main role of amino acid residues His110, His226, Gly227, Leu248, Val238, Asp144, Lys230, Glu147, Gly227, Ala112, Leu145 and catalytic zinc atom in the formation of stable ligand-protein complexes with ΔG = –6.89, –7.2, –7.16, –7.5, –8.0, –7.9 kcal/mol was shown. Thus, the positive results obtained in the work were demonstrated the promise of using the proposed homology 3D model of the C. albicans FBA-II as the target for the search and development of new anti-Candida agents against azole-resistant fungal pathogens. Designed and studied 4-phosphorylated derivatives of 1,3-oxazole having a direct inhibiting FBA-II molecular mechanism of action can be used as perspective drug-candidates against resistant C. albicans strains.

In the present work, the derivatives of calix[4]arene, thiacalix[4]arene, and sulfonylcalix[4]arene bearing four methylene(phenyl)phosphinic acid groups on the upper rim of the macrocycle were synthesized and studied as inhibitors of human protein tyrosine phosphatases. The inhibitory capacities of the three compounds towards PTP1B were higher than those for protein tyrosine phosphatases TC–PTP, MEG1, MEG2, and SHP2. The most potent sulfonylcalix[4]arene phosphinic acid displayed Ki value of 32 nM. The thiacalix[4]arene phosphinic acid was found to be a low micromolar inhibitor of PTP1B with selectivity over the other PTPs. The kinetic experiments showed that the inhibitors compete with the substrate for the active site of the enzyme. Molecular docking was performed to explain possible binding modes of the calixarene-based phosphinic inhibitors of PTP1B.

The study of effects caused by the conjugated bridge binding of heterocycles (forming of $\alpha,\omega$ -disubstituted polyenes) was performed by quantum-chemical and spectral methods. It is shown that such modification of chemical constitution is accompanied by essential changes in the donor-acceptor property and energy gap. For the quantitative estimation of the influence of substituents on the donor-acceptor characteristic, the topological index $\varphi_{0}$ is used. Also, the spectral effects of the substituents on the energy gap were studied; they were experimentally observed in the spectra of the heterocycles and their bridged derivatives.

In this study, we identified water-soluble C60 and C70 fullerene derivatives as a novel class of protein tyrosine phosphatase inhibitors. The evaluated compounds were found to inhibit CD45, PTP1B, TC-PTP, SHP2, and PTPβ with IC50 values in the low micromolar to high nanomolar range. These results demonstrate a new strategy for designing effective nanoscale protein tyrosine phosphatase inhibitors.

The study of the inhibition of human protein tyrosine phosphatases by water-soluble [60]fullerene derivatives bearing five organic addends loaded with carboxylic groups demonstrated that a fullerene core is responsible for interactions with the enzymes while organic addends play a minor role modifying the selectivity of the inhibition.

α,α-Difluoro-β-ketophosphonated derivatives of tetraazamacrocycles were synthesized and found to be potential inhibitors of protein tyrosine phosphatases. N-Substituted conjugates of cyclam and cyclen with bioisosteric phosphonate groups displayed good activities toward T-cell protein tyrosine phosphatase with IC50 values in the micromolar to nanomolar range and showed selectivity over PTP1B, CD45, SHP2, and PTPβ. Kinetic studies indicated that the inhibitors can occupy the region of the active site of TC-PTP. This study demonstrates a new approach which employs tetraazamacrocycles as a molecular platform for designing inhibitors of protein tyrosine phosphatases.

Inhibition of PTP1B by polyhydroxylated fullerenes was studied in silico and in vitro. The enzyme kinetics in the presence of polyhydroxy small gap fullerenes showed that reciprocal value of maximum velocity non-linearly increases with increasing the inhibitor concentration. Analysis of the dose-dependent curve of PTP1B inhibition suggests an apparent positive cooperativity with involvement of at least two binding sites for the hydroxylated fullerene cages. Molecular docking calculations indicated that highly hydroxylated fullerene C60 may occupy the active site and additional allosteric binding site with similar affinity. In silico analysis of a number of fullerenols with 6, 12, 18, 24, 30, and 36 hydroxyl groups showed that the inhibitory activity may depend on the degree of hydroxylation of the nanoparticles surface. These data provide some understanding of the mechanisms of inhibitory action of fullerenols on activity of protein tyrosine phosphatases.