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Two derivatives of adamantane benzenesulfamide have been synthesized and studied: N-adamantane-1-yl-2,4,6-trimethyl-benzenesulfamide (1) and N-adamantane-1-yl-4-methoxy-benzenesulfamide (2). Crystal structures 1 and 2 are solved using X-ray diffraction (XRD) analysis. The solubilities of compounds in a phosphate buffer solution with pH 7.4, 1-octanol, and n-hexane are determined at several temperature points using isothermal saturation. The values of Gibbs energy, enthalpy, and entropy of solubility of the compounds at 298 K are determined.

New 3,5-disubstituted-1,2,4-thiadiazoles were synthesized and together with a series of their analogs obtained earlier were tested for cytotoxic activity to breast adenocarcinoma MCF-7 and lung carcinoma A 549 cells. The selectivity of cytotoxic action was determined in comparison to etiologically noncancerous breast epithelial cells MCF-10A and lung fibroblasts VA13. From five- to six-fold selectivity of cytotoxic action was revealed for 3,4-dichlorophenyl-{3-[2-(2-morpholin-4-ylethylamino)propyl]-[1,2,4]thiadiazol-5-yl}amine and (2-{5-[(4-diethylami-nobenzyl)pyridin-3-ylmethylamino]-[1,2,4]thiadiazol-3-yl}-1-methylvinyl)-(2,2,6,6-tetra-methylpiperidin-4-yl)amine in the pairs A 549/VA13 and MCF-7/MCF-10A, respectively. Some structure—property relationships for the compounds under study were discussed.

A series of novel conjugates of 4-amino-2,3-polymethylene quinolines and phenolic antioxidant vanillin was synthesized by the condensation of aminoquinolines with vanillin followed by reduction of imines with sodium borohydride. The conjugates effectively inhibit AChE and BChE with preferable BChE inhibition and displace propidium from the PAS AChE. Compounds with aminoalkyl spacer have preferable esterase profile being more potent cholinesterases inhibitors with lower anti-CES activity and are the most potent antioxidants in ABTS and FRAP tests.

Crystals of two copper complexes with N-(5,6-dihydro-4H- +1,3-thiazin-2-yl)benzamide were obtained and characterized by X-ray diffraction analysis. LETDI studies have shown that the composition of the complex is inhomogeneous, and the precipitated crystals can have different structures being of Cuii or Cui–Cuii types. The complexes are significantly more cytotoxic toward the leukemic Jurkat cell line than to healthy lymphocytes.

A specific number of structures described in this paper with adamantane and memantine fragments have been synthesised and characterised. Their single crystals have been grown and their crystal structures have been determined. XPac analysis has shown that there are four sets of isostructural crystals based on adamantane/memantine-specific hydrogen bond patterns and packing of bulky substituents. The use of packing density analysis, QTAIMC and Hirshfeld surface analyses has allowed the elucidation of the influence of the nature and position of functional groups and molecular arrangement on the strength of non-covalent interactions in crystals and overall packing efficiency. The nature and size of a fragment in the para-position of the phenyl ring have been found to have the highest influence on the packing architecture.

Using two ways of functionalizing amiridine-acylation with chloroacetic acid chloride and reaction with thiophosgene-we have synthesized new homobivalent bis-amiridines joined by two different spacers-bis

Complexes of Bi iii with 2-aminopyrimidine cations with metal-to-ligand ratios of 1:3 or 2:4 (depending on reaction conditions) were synthesized and characterized by elemental analysis, 1H NMR spectroscopy, and single crystal X-ray crystallography. The possibility of conversion of the latter complex into the former one was demonstrated. The determined cytotoxicity depended on the structure of these complexes.

A series of eight novel 5-N,N-disubstituted-5-amino-3-(2-oxopropyl)-1,2,4-thiadiazoles with diverse lipophilic groups was obtained by reaction of 3-isothiocyanato-5-methylisoxazole with secondary amines. All the compounds of the series (independently on the type of the substituents) were found to be ineffective as inhibitors of calcium ions uptake in synaptosomes of rat cerebral cortex. Screening of the cytotoxicity to four cell lines (breast adenocarcinoma MCF-7, conditionnally normal breast epithelial cells MCF-10A, lung carcinoma A549, non-cancer lung fibroblasts VA13) revealed three compounds with good selectivity to cancer cells MCF-7 in comparison with non-cancer cell line MCF- 10A. These 1,2,4-thiadiazoles can serve as new leads for further study of their antitumor properties.

The derivative of 1,2,4-thiadiazole (TDZ) can be considered as a perspective agent for the Alzheimer’s disease prevention. Due to a highly lipophilic character, the compound reveals good membrane permeability properties and poor solubility in aqueous media. In order to solve this problem, water-soluble biodegradable polymers: PEG 6000 (PEG), PVP K29-30 (PVP) and linear (A–B–A type) ethylene oxide-propylene oxide block copolymer Pluronic F127 (F127) were used in the present investigation to obtain binary and ternary TDZ composites (solid dispersions) with improved solubility and dissolution rate. Composites were prepared by a mechanical grinding procedure. Differential scanning calorimetry and FTIR spectroscopy were used to characterize the obtained samples. The interaction of TDZ with PVP after the grinding procedure was revealed. Shake-flask method was applied to measure the solubility of the composites. A dramatical increase in the solubility was shown for the solid dispersion with F127 above the critical micelle concentration. The dissolution behavior was studied with the help of the basket method at pH 1.2 and pH 6.8. The dissolution of TDZ/polymer solid dispersions was substantially accelerated as compared to pure TDZ and physical mixtures. The dissolution mechanism was estimated through the Korsmeyer–Peppas model equation. Franz diffusion cell and new Permeapad™ barrier were applied for the permeability assay. The permeability of TDZ in solid dispersions through the Permeapad™ barrier was shown to decrease in comparison with the pure TDZ. It was concluded that composites with PEG, PVP and F127 are an effective tool for increasing the solubility and dissolution of 1,2,4-thiadiazole derivative.

A copper complex with N-(5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide was synthesized for the first time and characterized by 1H NMR spectroscopy, LETDY mass spectrometry, and elemental analysis. A comparative study of the obtained complex and copper 2-aminopyrimidine complex was performed by flow cytometry on normal lymphocytes and Jurkat cells. Complexes with radionuclides 64,67Cu (with and wihout a carrier) were prepared, and distribution of the labeled complexes in the organs of mice was considered. Packing in carboxymethylcellulose-based microgels was proposed as a transport form for the complexes. The results show a promise of the obtained materials as potential radiopharmaceutical agents.

Literature data and authors’ own results on the role of serine hydrolases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as drug targets for treatment of neurodegenerative diseases and carboxylesterase (CaE) inhibitors as modulators of CaE-hydrolysis of ester-containing drugs are analyzed. Today, a promising approach is the development of cholinesterase inhibitors with additional neuroprotective and disease-modifying properties. The developed esterase profile approach, that is, comparative assessment of the inhibitory activity against AChE, BChE, and CaE, can be used to evaluate both the main potential pharmacological effect and possible side effects of a new compound. Analysis of the esterase profile, in combination with computer modeling and assessment of radical-scavenging ability of the synthesized compounds and their potential ability to block AChE-induced β-amyloid aggregation revealed highly active multifunctional compounds for the treatment of Alzheimer’s disease: selective inhibitors of BChE and inhibitors of both cholinesterases without potential side effects associated with CaE inhibition. A number of effective and selective inhibitors of CaE, free from cholinergic side effects, were also found for modulation of the rate of hydrolytic metabolism and for rational use of ester-containing drugs.

The synthesized 1,2,4-thiadiazole derivative displaying biological activity has low aqueous solubility and dissolution rate. Novel oral formulations of thiadiazole with β- and hydroxypropyl-β-cyclodextrins were obtained by grinding and freeze-drying methods with the purpose to improve the aqueous solubility. Complex formation of 1,2,4-thiadiazole derivative with cyclodextrins was confirmed by means of solid-state 13C MAS CP/TOSS NMR. Solubility, dissolution rate and permeability of the solid inclusion complexes were evaluated in different biorelevant media (SGF, FaSSGF, FaSSIF) simulating the conditions in the gastrointestinal tract. It was demonstrated that the content of biorelevant media affects the properties of the inclusion complexes. In particular, solubilizing effect of cyclodextrins became less pronounced when the micelles of taurocholic acid and lecithin are formed in the dissolution media. The inclusion of thiadiazole into cyclodextrin cavity is in competition with its partitioning into the mic...

New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer&rsquo, s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 &plusmn, 0.16 &micro, M, IC50(BChE) = 0.084 &plusmn, 0.008 &micro, M, and 13.6 &plusmn, 1.2% propidium displacement at 20 &mu, M. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites, peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced &beta, amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics.

New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes of the aliphatic ring and linked to p-tolylsulfonamide with alkylene spacers of increasing length were synthesized as potential drugs for treatment of Alzheimer&rsquo, s disease (AD). All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide (7h) exhibited an IC50 (AChE) = 0.131 &plusmn, 0.01 &micro, M (five times more potent than tacrine), IC50(BChE) = 0.0680 &plusmn, 0.0014 &micro, M, and 17.5 &plusmn, 1.5% propidium displacement at 20 &micro, M. The compounds possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. Kinetics studies were consistent with mixed-type reversible inhibition of both cholinesterases. Molecular docking demonstrated dual binding sites of the conjugates in AChE and clarified the differences in the structure-activity relationships for AChE and BChE inhibition. The conjugates could bind to the AChE peripheral anionic site and displace propidium, indicating their potential to block AChE-induced &beta, amyloid aggregation, thereby exerting a disease-modifying effect. All compounds demonstrated low antioxidant activity. Computational ADMET profiles predicted that all compounds would have good intestinal absorption, medium blood-brain barrier permeability, and medium cardiac toxicity risk. Overall, the results indicate that the novel conjugates show promise for further development and optimization as multitarget anti-AD agents.

Solubility and permeability are the main parameters determining the bioavailability of drugs. In this study the increased solubility of novel 1,2,4-thiadiazole derivative (TDZ) proposed for the prevention and treatment of Alzheimer's disease was achieved in the solutions of polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and pluronic F127 (F127). It was found that solubilizing power of polymers follows the order F127 > PVP > PEG. The mechanism of TDZ solubilization was proposed on the basis of 1H NMR and UV-spectroscopy studies. It was suggested that PEG enhances the TDZ solubility by acting mainly as cosolvent, whereas PVP can be considered as cosolvent and complexing agent. In case of F127, the insertion of TDZ into micelles was detected. The solubilization capacity of pluronic was quantified in terms of average number of TDZ and F127 per micelle and binding constant. In order to reveal the effect of polymers on the TDZ membrane permeability, the distribution coefficients in the 1-octanol/buffer system and permeability coefficients through the novel Permeapad™ barrier were determined. The solubility-permeability and solubility-distribution relationships were discussed.

The apparent distribution coefficients of the potential bioactive compounds of the N-aryl-(3-sulfur-1-azabicyclo[3,3,1] non-2-ylidene) amine series in organic solvent/buffer pH 7.4 systems at five temperatures from 293.15 to 315.15 K have been determined by the shake-flask method. The logDO/B values of substances between 1-octanol and the aqueous phase range from 1.76 to 2.06 and at 298 K decrease depending on the chemical nature of the substituents of the phenyl fragment in the following order: cyan- > ethyl- > acetyl- > methyl-, chloro- > isopropyl-. The replacement of 1-octanol by hexane shifts the equilibrium of the substances from the organic phase to the buffer and the resulting values logDH/B

A complex of zinc with N-(5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide (L) ligand, LZnCl2, was synthesized for subsequent medical trials. The molar extinction coefficients were determined for LHBr solutions in water and physiological saline, and for LZnCl2 ethanol solution. The ligand stability in various solvents was evaluated and the value of its protonation constant was found for the physiological saline solution, logK = 5.3±0.2. The impossibility of determination of the complex stability constant by the potentiometric titration method was demonstrated. The complex exhibited an insufficient stability in aqueous and physiological saline solutions, but was stable as the solution in alcohol. There was no sorption observed upon the treatment of ligand with hydroxyapatite nanoparticles, which could be a potential carrier for the therapeutic form of LZnCl2, providing additional degrees of freedom for the interaction of ligand with cell membranes and a prolonged action of zinc ions.

Three distinct solid forms, namely anhydrous cocrystals with 2 : 1 and 1 : 1 drug/acid ratios ([TDZ : GA] (2 : 1), [TDZ : GA] (1 : 1)), and a hydrated one having 1 : 1 : 1 drug/acid/water stoichiometry ([TDZ : GA : H2O] (1 : 1 : 1)), have been formed by cocrystallization of the biologically active 1,2,4-thiadiazole derivative (TDZ) with gallic acid (GA). The thermodynamic stability relationships between the cocrystals were rationalized in terms of Gibbs energies of the formation reactions and further verified by performing a set of competitive and exchange mechanochemical reactions. Interestingly, competitive grinding in the presence of the structurally related vanillic acid led to the formation of a new polymorphic form of the [TDZ : Vanillic acid] (1 : 1) cocrystal, which was promoted by gallic acid. The mechanochemical method was also applied to elucidate the alternative pathways of the [TDZ : GA : H2O] (1 : 1 : 1) cocrystal formation. Direct cocrystallization of TDZ with GA monohydrate was found to proceed much faster than the reaction of TDZ and anhydrous GA in the presence of an acetonitrile/water mixture, which may indicate the presence of a transitional stage. According to dissolution studies, the [TDZ : GA : H2O] (1 : 1 : 1) cocrystal was ca. 6.6 times more soluble than the parent 1,2,4-thiadiazole at pH 2.0 and 25.0 °C. The apparent two-step dehydration behavior of the [TDZ : GA : H2O] (1 : 1 : 1) cocrystal monohydrate was clarified by analyzing the intermolecular interactions of water molecules with the crystalline environment derived from solid state DFT calculations.

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC50 for AChE = 1.83 ± 0.03 μM (Ki = 1.50 ± 0.12 and αKi = 2.58 ± 0.23 μM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pKa values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.

Three biologically active selenium bicyclic compounds – N-aryl-(3-seleno-azabicyclo[3.3.1]non-2-ylidene)amines were synthesized. The effect of the substances structure on their protolytic properties was investigated. The substance solubility in hexane and pharmaceutically relevant buffer solutions (pH 2.0 and pH 7.4) was measured in the temperature range of 293.15–313.15 K by the saturation shake-flask method. Temperature dependences of the distribution coefficients of the compounds in the two-phase systems “organic solvent (octanol, hexane)/buffer solution” were obtained. Thermodynamic parameters of distribution process were calculated.

Pharmacologically important properties of two structurally related biologically active 1,2,4-thiadiazole derivatives were investigated in phosphate buffer and biorelevant media FaSSIF simulating the intestinal fluid. Solubility and distribution coefficients of thiadiazoles were found to be substantially higher in FaSSIF than in blank buffer. On the contrary, permeability coefficients decreased and dissolution rate was not changed in FaSSIF. Mechanism of FaSSIF components action on thiadiazoles behavior was revealed using 1H NMR and UV-spectroscopy.

The solubility of eight biologically active nonaromatic compounds with a common 3-thia-1-aza-bicyclo fragment in 1-octanol and hexane was determined in the temperature range of T = 293.15–315.15 K. The solubility of the substances in alcohol is approximately 2 orders of magnitude higher than in alkane and varies within 3.0 × 10–3 to 2.1 × 10–1 and 7.1 × 10–5to 13.5 × 10–3 mol. fractions, respectively. In accordance with the structure of the substituent at the para position of the phenyl ring, the studied compounds are arranged in the following order of decreasing solubility in both solvents: methyl- > fluoro- > ethyl- > trifluoromethyl- > cyano- > acetyl-. The ideal solubility of the substances in 1-octanol, calculated from thermophysical parameters was found to correlate with the reported experimental data. The activity coefficients of the substances in saturated solutions of organic solvents are determined by the method of distribution between two liquid phases. The thermodynamic aspects of the relation...

The cocrystallization approach has been applied to modify the poor solubility profile of the biologically active 1,2,4-thiadiazole derivative (TDZ). Extensive cocrystal screening with a library of coformers resulted in formation of a new solid form of TDZ with vanillic acid in a 1:1 molar ratio. The cocrystalline phase was identified and characterized by thermal and diffraction analyses including single-crystal X-ray diffraction. The energies of intermolecular interactions in the crystal were calculated by solid-state DFT and PIXEL methods. Both calculation schemes show good consistency in terms of total energy of the intermolecular interactions and suggest that the cocrystal is mainly stabilized via hydrogen bonds, which provide ca. 44% of the lattice energy. Since the cocrystal contained the hydroxybenzoic acid derivative as a coformer, the solubility profile of the cocrystal was investigated at different pHs using eutectic concentrations of the components. Furthermore, the influence of the cocrystallization on the permeability performance of the 1,2,4-thiadiazole through an artificial regenerated cellulose membrane was also evaluated. In addition, the thermodynamic functions of the cocrystal formation were estimated from the solubility of the cocrystal and the corresponding solubility of the pure compounds at various temperatures. The cocrystal formation process was found to have a relatively small value of the driving force (-5.3kJ·mol-1). The most significant contribution to the Gibbs energy was provided by the exothermic enthalpy of formation.

Complex formation of α-, β- and γ-cyclodextrins with 1,2,4-thiadiazole derivatives, which are structural isomers displaying an activity in the treatment of Alzheimer’s disease, was examined by the use of 1H NMR and UV-spectroscopy. Stability constants of the complexes formed between cyclodextrins and thiadiazoles in two different buffers (pH 1.2 and 7.4) were calculated and analyzed. The temperature dependences of the stability constants were used to evaluate the enthalpy and entropy changes of complex formation. It was demonstrated that selectivity of the interactions between cyclodextrins and isometric 1,2,4-thiadiazole derivatives is determined by the size of macrocyclic cavity and relative position of the side groups in the benzene ring of the guest molecules. Higher stability of the complexes in the acidic medium (pH 1.2) in comparison with the slightly alkaline solution (pH 7.4) is caused by the important role of surface interactions.

The saturated vapor pressures of 4 nonaromatic bicyclic 1,3-thiazine and 1,3-selenazine derivatives have been measured by the method of transpiration by inert gas-carrier in the temperature range of 308–392 K. Based on the experimental data the thermodynamic functions of sublimation have been calculated. The sublimation enthalpies of the compounds vary from 104 to 150 kJ mol −1 depending on the chemical nature of the substituent in the aryl moiety and the heteroatom in the bicyclic fragment. The crystal lattice energy of thiazines decreases with the introduction of substituents in the following order: cyano > acetyl > isopropyl. New approach has been suggested to evaluating sublimation enthalpy of the studied and structurally related compounds by using clusterization of the space of experimental points.

A platform containing three anticancer components is proposed. The components are a radioactive 69mZn isotope and zinc complexes, where both zinc and ligand exhibit anticancer properties. Two zinc-containing complexes, namely (2-AP)2ZnCl2 and (2-AP)2Zn(Sal)2 (AP is 2-aminopyrimidine, Sal is salicylate) were synthesized and characterized. Their cytotoxicity with respect to some leukemia cell lines is demonstrated. Their stability in physiological solution and percentage of apoptosis (by flow cytometry) are investigated. Stable complexes of compounds with the isotope 69mZn were characterized by TLC and autoradiography.

New N-(pyridin-3-ylmethyl)-2-aminothiazolines containing various substituents at the 5 position of the thiazoline ring and the 4-tert-butylbenzyl, 4-isopropylbenzyl, or 4-fluorobenzyl moiety at the nitrogen atom of the amino group were synthesized. The inhibitory activity of the synthesized compounds against human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), equine serum butyrylcholinesterase (BChE, EC 3.1.1.8), and porcine liver carboxylesterase (CaE, EC 3.1.1.1) was evaluated and their antioxidant properties were studied by ABTS assay. N-(Pyridin-3-ylmethyl)-2-aminothiazolines proveded to be very weak AChE inhibitors, while their inhibitory activity against BChE and CaE was structure-dependent. 2-Aminothiazolines containing the 4-tert-butylbenzyl moiety are more efficient BChE inhibitors compared to the derivatives containing the 4-isopropylbenzyl or 4-fluorobenzyl substituent. An analysis of the dependence of the esterase profile of N-(pyridin-3-ylmethyl)-2-aminothiazolines on the structure of the substituent at the 5 position of the thiazoline ring of these compounds demonstrated that the derivatives containing the iodomethyl substituent possess the highest anti-BChE activity, the compounds with R2 = H and R3 = CH2I have the optimal esterase profile. Regardless of the structure of the substituents in the benzyl moiety, all N-(pyridin-3-ylmethyl)-2-aminothiazolines containing the iodomethyl substituent at the 5 position of the thiazoline ring exhibited high radical scavenging activity comparable with that of the standard antioxidant Trolox. N-(Pyridin-3-ylmethyl)-2-aminothiazolines were shown to be a new promising class of compounds for the design of multifunctional agents for the treatment of neurodegenerative diseases.

New 5-anilino-1,2,4-thiadiazole derivatives with different substituents at position 3 were synthesized and their influence on the key binding sites of NMDA receptors, inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and carboxylesterase, as well as antioxidant properties were studied. The compounds with a 2-aminopropyl fragment were found to be efficient blockers of allosteric modulator [3H]ifenprodil binding site of the NR2B-containing NMDA receptors and moderate butyrylcholinesterase inhibitors. Some compounds were found to be able to simultaneously block the [3H]ifenprodil and intrachannel [3H]MК-801 binding sites of NMDA receptors. Compounds containing a 2-aminopropenyl fragment did not exhibit activity against NMDA receptors and butyrylcholinesterase, but showed high radical-scavenging activity.

A database of some S,N,N,N′-tetrasubstituted isothiourea derivatives possessing neuroprotective properties was successfully clustered in order to study the quantitative structure – activity relationship. Clustering by k-means was carried out in the factor space of topological descriptors. The identified clusters were combined according to analyses of intra- and intercluster distances. The initial number of clusters in the k-means clustering was determined from the number of iterations for which a solution was obtained. The homogeneity of the database and the identified clusters was estimated by using a coefficient of molecular diversity. A plot of the database compounds as points in factor space led to a conclusion about the successful applicability of the proposed clustering approach.

New 1,2,4-thiadiazole derivative displaying neuroprotective potential and high activity in the treatment of Alzheimer’s disease has been synthesized. The objective of this study was to improve the aqueous solubility of this drug-like compound by means of complex formation with native and hydroxypropylated β-cyclodextrins. To this end, aqueous solubility of 1,2,4-thiadiazole derivative was investigated in the presence of β-cyclodextrins. It was shown that the phase solubility diagrams are of Bs type demonstrating the initial increase in thiadiazole solubility in solutions of cyclodextrins (concentration up to 0.01 mol kg−1) followed by a solubility decrease due to the precipitation of the complexes formed. In comparison with β-cyclodextrin, hydroxypropyl-β-cyclodextrin displays more pronounced solubilizing action since it forms more stable complexes with thiadiazole. Solid complexes of 1,2,4-thiadiazole derivative with β-cyclodextrins were prepared by grinding and freeze-drying methods. DSC, TG, hot-stage microscopy, solid-state 13C MAS CP/TOSS NMR, powder X-ray diffractometry and FTIR spectroscopy were used to prove the existence of complexes in the solid state. Solubility of the obtained formulations was also examined. It was found that complexes of thiadiazole with hydroxypropyl-β-cyclodextrin exhibited higher solubility in phosphate buffer (pH 7.4) compared with pure thiadiazole and its complexes with β-cyclodextrin.

Study of complex formation of cyclodextrins with 1,2,4-thiadiazole derivatives intended for Alzheimer's disease treatment was carried out using 1H NMR, ITC and phase solubility methods. Structure of cyclodextrins and thiadiazoles affects the binding mode and thermodynamics of complexation. The larger cavity of β- and γ-cyclodextrins is more appropriate for deeper insertion of 1,2,4-thiadiazole derivatives which is accompanied by intensive dehydration and solvent reorganization. Benzene ring of the thiadiazoles is located inside macrocyclic cavity while piperidine ring is placed outside the cavity and can form H-bonds with cyclodextrin exterior. Complexation with cyclodextrins induces the enhancement of aqueous solubility of 1,2,4-thiadiazole derivatives.

New 2H,3′H-3,4′-bipyrazol-3′-ones were obtained by reaction of hydrazines with difluoroboron chelate of 4-acetyl-5-hydroxy-3-methyl-1-phenyl-1H-pyrazole. Relative isoxazolyl pyrazolone derivative was synthesized from this chelate and hydroxylamine.

In a search of nitric oxide synthase inhibitors with prolonged vasoconstrictive activity, a series of lipophilic cyclohexafused 2-amino-2-thiazolines was obtained via cyclization of tert-butyl- or benzoyl-substituted N-(cyclohex-2-en-1-yl)thioureas. The crystal structure of intermediate N-[(3aRS,7aSR)-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazol-2-yl]benzamide hydrobromide was determined by X-ray analysis. One compound was found to cause pronounced and prolonged vasoconstrictive effect after single injection to the Wystar rats with lipopolysaccharide induced acute endotoxic (vasodilatation) shock.

An approach to the synthesis of adamantane derivatives with NO-generating fragment containing nitroxy group has been developed. 1-Aminoadamantane, memantine, and adamantanecarboxylic acid have been used as initial compounds. The prepared compounds have shown ability to generate nitric oxide in a system mimicking biological reactions of nitro group reduction.

Effect of cyclodextrins on aqueous solubility of 1-[5-(3-chloro-phenylamino)-1,2,4-thiadiazol-3-yl]-propan-2-ol (I), which was synthesized and proposed for the treatment of Alzheimer’s disease, was studied. First of all, inclusion complex formation of I with different cyclodextrins was studied in aqueous solutions. Formation of more stable complexes with β- and hydroxypropyl-β-cyclodextrins was revealed. Next, solid inclusion complexes of I with β- and hydroxypropyl-β-cyclodextrins were prepared by the mechanical grinding, and their existence in the solid state was confirmed by powder X-ray diffraction, FTIR spectroscopy, microscopy, and thermochemical methods. Dissolution testing of the tablets of pure I and its complexes with β- and hydroxypropyl-β-cyclodextrins in the aqueous buffered solutions simulated the biological environment was carried out. The observed drastic enhancement of dissolution extent and dissolution rate of the complexes was attributed to the inclusion complex formation.

Previously synthesized 1,2,4-thiadiazole derivatives displayed an activity in the treatment of Alzheimer’s disease; however, these compounds are poorly soluble in aqueous solutions. Inclusion complex formation with cyclodextrins is proposed for the development of water-soluble dosage forms of 1,2,4-thiadiazoles under study. To this end, binding of 1,2,4-thiadiazole derivatives with α-, β- and γ-cyclodextrins as well as with modified β-cyclodextrins was investigated by isothermal titration calorimetry, 1H NMR and UV–Vis spectroscopy in aqueous buffered solution (pH = 7.4) at 298.15 K. The detailed analysis of the thermodynamic parameters of complex formation is presented. The structure of 1,2,4-thiadiazole/cyclodextrin complexes was evaluated on the basis of 2D 1NMR (ROESY) experiments. The influence of structural factor (dimensions of macrocyclic cavity, modification of the host external surface, structure of guest molecules) on the thermodynamics and binding mode was discussed.

Hybrid γ-carboline-based compounds containing a nitrooxy group as an NO-donor were prepared. It was shown that the introduction of this group did not affect the inhibitory activity of γ-carboline pharmacophore against acetyl- and butyrylcholinesterase.

69mZn was produced and separated for medical applications. Possibilities and perspectives for production of radiopharmaceuticals based on 69mZn containing derivatives of thiazine, thiazoline and thiourea are considered. Each one of the latters is a zinc chelator and a nitric oxide synthase (NOS) effector at the same time. Cytotoxic effect of NOS activator and NOS inhibitors are shown in experiments with HL-60, K-562 and MOLT-4 cell lines and in bone marrow cells of the acute B-lymphoblastic leukemia patients. Some of those compounds are worthy to get selected for further application as radiopharmaceuticals including their antitumor speciements.

Detailed studies of properties of new 3-substituted 5-anilino-1,2,4-thiadiazoles containing different substituents at position 3 of the thiadiazole ring were carried out, in particular, their esterase profile and antioxidant properties. It was found that the presence in the molecule of 2-aminopropyl fragment determines an efficient and selective inhibition of butyrylcholinesterase as compared to acetylcholinesterase and carboxylesterase, with radical-scavenging activity being weak. The compounds containing a 2-aminopropenyl fragment possess a high radicalscavenging activity, weakly inhibit cholinesterases, and exhibit anticarboxylesterase activity. A wide spectrum of activity of 3-substituted 5-anilino-1,2,4-thiadiazoles as inhibitors of cholinesterases and highly efficient scavengers of free radicals gives a basis for the optimization of structure and development in this series of original agents for therapy of neurodegenerative diseases.

Thiosemicarbazones of ketones from 3,6-diazahomoadamantane series were prepared by two procedures: by treating 3,6-diazahomoadamantan-9-ones with thiosemicarbazide and by a reaction of substituted (3,6-diazahomoadamantan-9-ylidene)hydrazines with versatile isothiocyanates.

Influence of a structural modification on thermodynamic aspects of solubility and solvation processes of the 1,2,4-thiadiazole drug-like compounds in pharmaceutically relevant solvents n -hexane and 1-octanol was investigated. The solubility of the compounds in 1-octanol does not substantially depend on the nature and position of the substituent in the phenyl moiety. In n -hexane, however, the introduction of any substituent in the phenyl ring of the 1,2,4-thiadiazole molecule reduces the solubility in the solvent. In order to rationalize the relationships between the structure of 1,2,4-thiadiazoles and their solubility, the latter was considered in terms of two fundamental processes: sublimation and solvation. It was found that for the most of the compounds the solubility change in both solvents is a consequence of competition between the sublimation and solvation contributions, i.e. the introduction of substituents leads to growth of the sublimation Gibbs energy and increase in the solvation Gibbs energy. Thermodynamic parameters of the transfer process of the compounds from n -hexane to 1-octanol, which is a model of the blood–brain barrier (BBB), were also analyzed.

A series of 31 N,N-disubstituted 2-amino-5-halomethyl-2-thiazolines was designed, synthesized, and evaluated for inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE). The compounds did not inhibit AChE; the most active compounds inhibited BChE and CaE with IC50 values of 0.22-2.3μM. Pyridine-containing compounds were more selective toward BChE; compounds with the para-OMe substituent in one of the two dibenzyl fragments were more selective toward CaE. Iodinated derivatives were more effective BChE inhibitors than brominated ones, while there was no influence of halogen type on CaE inhibition. Inhibition kinetics for the 9 most active compounds indicated non-competitive inhibition of CaE and varied mechanisms (competitive, non-competitive, or mixed-type) for inhibition of BChE. Docking simulations predicted key binding interactions of compounds with BChE and CaE and revealed that the best docked positions in BChE were at the bottom of the gorge in close proximity to the catalytic residues in the active site. In contrast, the best binding positions for CaE were clustered rather far from the active site at the top of the gorge. Thus, the docking results provided insight into differences in kinetic mechanisms and inhibitor activities of the tested compounds. A cytotoxicity test using the MTT assay showed that within solubility limits (

Selective carboxylesterase inhibitors are employed as modulators of hydrolytic metabolism of ester or amide-containing drugs. Using the Molecular Field Topology Analysis (MFTA), the models for the relationships between the structures and inhibitory activities of 5-halomethyl-2-aminothiazolines against acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were built, the molecular design was performed, and a focused library of potentially active and selective carboxylesterase inhibitors was proposed.

The antileukemic activities of some thiadiazole derivatives in the forms of hydrochlorides and salicylates have been determined. The insertion of salicylate ion in the compound increases the therapeutic index, mainly due to the reduction of cytotoxicity against healthy cells.