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A new Au(III) complex was synthesized from an amidrazone derivative and HAuCl4. Cyclization of amidrazone moiety lead to the 1,2,4-triazolo[1,5a]pyridine ring system, followed by Au(III) chelation. The crystal and molecular structure of the final compound was studied by single crystal X-ray diffraction as well as by 1H 13C and 1H 15N HMQC- and HMBC-NMR spectroscopy, which resulted in the assignment of all detected signals. This species was tested in vitro as an antibacterial and antiproliferative agent. It exhibited good antibacterial activity against Staphylococcus aureus and was proved to be more potent than amoxicillin against Bacillus subtilis and the drug resistant strain of Klebsiella pneumoniae. In contrast, its antiproliferative properties against cancer cell lines A549, HT-29, MV-4-11 and MCF-7 were relatively low.

A series of new linear trisubstituted N1-acylamidrazones have been investigated using a variety of analytical techniques and theoretical calculations to check the influence of the type of N1-acyl substituent on the resonance forms and conformational behavior in the solid state and in solution. The 1D- and 2D-NMR experiments, supported by computational studies, revealed that in solution all amidrazones exhibit conformational syn/anti isomerism that results from the hindered rotation around the amide bond. In the case of the propenoic acid derivative, the ROESY, HSQC, and HMBC experiments proved a third equilibrium structure that corresponds to the planar ylide form. The SC XRD data confirmed that the compounds tend to exist as Z-anti conformers of their hydrazone-amide tautomeric species in the solid state. The carboxyl-amide heterosynthon is favoured provided that the carboxyl group is not involved in the intramolecular hydrogen bonding. Interestingly, after replacement of the cyclic C1-substituent by the smaller propanoic acid unit, which results in lower steric hindrance, both syn and anti conformers can exist. Furthermore, in the former case both the neutral molecules and zwitterions are present in the single crystal. The relative stability of the distinct crystal forms was examined using TG-DSC methods supplemented with cohesive energy calculations (CRYSTAL). The results indicate that the unsolvated forms are stable in a wide range of temperatures; however, inclusion of solvent molecules makes them prone to cyclization at higher temperatures. This paper reports the first observation of temperature-induced cyclization of N1-acylamidrazone to its cyclic triazole derivative in the solid state.

Polymorphism of four biologically active 3-(4,5-diaryl-4H-1,2,4-triazole-3-yl)propenoic acid derivatives has been investigated. Traditional solution-based solid-state forms screening revealed three anhydrous forms of 3-[4-phenyl-5-(2-pyridyl)-4H-1,2,4-triazole-3-yl]propenoic acid. Noteworthy, two pairs of concomitant polymorphs were detected for this system. Two other compounds were found to be dimorphic. The molecular and crystal structures of all obtained crystal forms were established by single-crystal X-ray diffraction. The resulting crystal structures were analyzed in terms of molecular conformation, intermolecular interaction patterns, and crystal packing motifs. The experimental studies were supported by extended lattice and interaction energy calculations. It was found that the carboxylic group adopts the anti conformation in all studied forms and is involved in the intramolecular O–H···Ntriazole hydrogen bonding. In consequence, the association modes are dominated by the weak C–H···O, C–H···N hyd...

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that affects the body's cortisol levels. The inhibition of its activity can be used in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes. In this study, we synthesized new derivatives of 2-(methylamino)thiazol-4(5H)-one and tested their activity towards inhibition of 11β-HSD1 and its isoform - 11β-HSD2. The results were compared with the previously tested allyl derivatives. We found out that methyl derivatives are weaker inhibitors of 11β-HSD1 in comparison to their allyl analogs. Due to significant differences in the activity of the compounds, molecular modeling was performed, which was aimed at comparing the interactions between 11β-HSD1 and ligands differing by substituent at the amine group (allyl vs. methyl). Modeling showed that the absence of the allyl group can lead to the rotation of whole ligand molecule which affects its interaction with the enzyme.

11β-hydroxysteroid type 1 dehydrogenase (11β-HSD1) is an enzyme that increases tissue concentrations of cortisol. Selective inhibitors of this enzyme regulate the level of cortisol and thus play a key role in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes. In this study the inhibitory activity of 29 thiazolo[3,2-a]pyrimidin-5-one derivatives on 11β-HSD1 were investigated. Studies were carried out with pooled human liver microsomes. A lot of analyzed compounds show activity for inhibiting 11β-HSD1 (up to 59.15% at concentration 10 µmol/l). Molecular docking simulation show that the molecule of the most active compound: 7-(cyclohexylmethyl)-2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one forms hydrogen bonds with Ala172, Leu171, Leu215 or Tyr177. In addition, the cycloalkane moiety can create the hydrophobic contacts with NADP+. For this compound also the most favourable Docking Score value was obtained. The most active compound only in the slight degree inhibits 11β-HSD2 activity and is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1. Consequently it can have a real effect on the regulation of the cortisol level in the body.

In this study, we present a convenient method for the synthesis of oxime ethers by reacting oximes with various chlorides (alkyl, functionalized alkyl, and benzyl) and with the subsequent use of a super base—pulverized potassium hydroxide in DMSO. The reactions take place at room temperature and the products are obtained in high yields. The final products were received within 2 min to 3 h. In addition, the compounds do not require chromatographic separation. The structure elucidation of the titled compounds was performed by using 1H NMR and 13C NMR spectroscopy as well as mass spectrometry. The presented method of synthesis for oxime ethers is environmentally friendly, because neither water cooling or heating of the reaction mixture/solvents (necessary for chromatographic purification) is required. The synthesis can be carried out very easily on a large scale.

Optically pure (R)-2-(anthracen-9-yl)-2-methoxyacetic acid ((R)-9-AMA) was obtained. The most important stage of the synthesis generating chirality and ensuring high enantioselectivity was the stage of desymmetrization of prochiral α-ketoester. Enzymatic biotransformation was used in the presence of Saccharomyces cerevisiae and Aureobasidium pullulans. Biotransformation using S. cerevisiae leads to 65–70% enantiomeric excess (R-isomer). The antimycotic agent Boni Protect containing live cells of A. pullulans allowed to obtain enantiomerically pure (R)-9-AMA.

Some reactions of selected chlorooxoesters and haloesters with a 1-allylthiourea under various conditions have been performed. The reactions have been performed in methanol in alkaline and neutral environment. Condensation of 1-allylthiourea with chlorooxoesters has been further led via acetal as intermediate compound. As a result, the compounds containing thiazole and a 4,5-dihydrothiazole ring with a good yield have been obtained. The structures of the compounds were verified by 1H NMR, 13C NMR as well as X-ray diffraction analysis. Due to the potential biological activity of the synthesized compounds, the parameters of their bioavailability have been determined, and the probability of pharmacological action has been defined. All of the obtained compounds fulfilled the rule of five, which indicate their good absorption after oral intake. The probability of pharmacological action and potential targets calculated for the obtained compounds show that they can be potential drugs. Graphical abstract

The series of new 1,2,4-triazole derivatives with methacrylic acid moiety were synthesized and characterized by NMR and IR spectroscopy as well as X-ray crystallography. The influence of newly synthesized compounds on the inflammation on the level of cytokine production and the proliferation of human peripheral blood mononuclear cells (PBMC) were experimentally evaluated. Obtained triazoles showed antiproliferative activity and diverse effects on cytokine production. Two compounds demonstrated potentially anti-inflammatory activity and comparable effects with ibuprofen.

Heterocyclic oxime ethers play a significant role in organisms due to their biological activity. Lipophilicity is an important parameter that may affect biological activity of the compounds 1-(benzofuran-2-yl)ethan-1-one oxime and its nine biologically active ethers. The relationship between the structure and lipophilicity parameters (log kw values) of the ten compounds is here described. Reversed phase high performance liquid chromatography (RP-HPLC) method was used having methanol, 2-propanol and acetonitrile as organic modifiers of the mobile phases. Both experimental (log kw) and calculated (log P) parameters showed to be strongly positively correlated. The weakest correlation with all the data was for the log kw methanol. For all of analyzed compounds, log kw values are smaller than 5 (except for analyses carried out in methanol), and this result corresponds to the Lipinski’s rule in the range of lipophilicity. Therefore, in the case of their use as drugs, they will be probably active after oral application.

2-Allylaminodihydrothiazole derivatives (III) are synthesized by condensation of allylthiourea (I) with haloesters (II) in alkaline medium, whereas 2-allylaminothiazole derivatives (V) are obtained by condensation of (I) with chlorooxoesters (IV) via acetal as intermediate compound, both of them with good yields.

Systems containing fused thiazole and pyrimidine rings play a significant role in organisms due to their biological activity. Lipophilicity, as important parameter to expect biological activity of the compounds, was evaluated for 27 potentially active thiazolo[3,2-a]pyrimidine derivatives using chromatographic methods: reversed phase thin layer chromatography (RP-TLC) and reversed phase high performance liquid chromatography (RP-HPLC) methods. Methanol was used as the organic modifier of the mobile phases. The corresponding relationship between compound's structure and lipophilicity parameters (RM0 and log kw) values were observed and featured. RM0 and log kw parameters were compared with computed log P values. For all of analyzed compounds, determined lipophilicity's parameters values are > 0 which means that there are hydrophobic substances, soluble in the lipid phase. Simultaneously, these values are < 5, i.e., are in accordance with Lipinski's rule in the range of lipophilicity. In the case of the possibility of their use as drugs, they will be active after oral application.

A new linear amidrazone derivative, 6-acetyl-cyclohex-3-enecarboxylic acid [1-pyridin-2-yl-1-(pyridyn-2-yloamin)meth-(Z)-ylidene] hydrazide, H(2)L (2) and its Cu(II) complex, [Cu(2)L(2)]·4H(2)O (3) were synthesized and characterized by elemental analysis, IR and (1)H NMR spectroscopy and cyclic voltammetry. Compound 2 was synthesized in the equimolar reaction of N(3)-substituted amidrazone with cis-1,2,3,6-tetrahydrophthalic anhydride. The Cu complex of 2 was obtained in the reaction with copper(II) acetate. The molecular structures of 2 and 3 were determined by X-ray crystallography. The parent ligand exists in its amide-hydrazone form in the solid state. The central amidrazone moiety has a Z configuration with respect to the double C=N bond. Coordination to the metal center promotes Z/E isomerization of the hydrazone group of the ligand. Compound 3 is a dinuclear four-coordinated Cu(II) complex with the amidrazone ligand behaving as a tetradentate double deprotonated chelating one. Several biological activities of 2 and 3 were examined in vitro; they were: antimicrobial properties against selected bacterial and fungal strains, suppression of phytohemagglutinin A (PHA)-induced proliferation of human peripheral blood mononuclear cells (PBMC) and their effects on tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) production. The cytotoxic activity of Cu(II) complex was determined with respect to the four carcinoma cell lines (SW 984, CX-1, L-1210, A-431). The studied complex exhibited significant cytotoxic effects (particularly against CX-1 colon carcinoma), comparable to those reported for cisplatin. Both compounds have shown a relatively low antibacterial activity and were devoid of antifungal properties.

Two new 1,2,4-triazole-containing alkenoic acid derivatives were obtained from the reaction of N -phenyl-(pyridin-2-yl)carbohydrazonamide with itaconic anhydride, depending on the reaction conditions. The structures of 2-((4-phenyl-5-(pyridin-2-yl)-4 H -1,2,4-triazol-3-yl)methyl)acrylic acid or ( E )-2-methyl-3(4-phenyl-5-(pyridine-2-yl)-4 H -1,2,4-triazol-3-yl)acrylic acid were confirmed by means of 1D and 2D NMR spectroscopic data as well as by single-crystal X-ray diffraction analysis. The experiential 1 H and 13 C chemical shifts were compared with those calculated with B3LYP, EDF1, and EDF2 density functional theories. The theoretical study of the observed terminal-to-internal alkene isomerization was performed with density functional (DFT) B3LYP/6-31+G ∗ method using SM8 water and DMF solvation models. Antimicrobial activities of the newly prepared alkenoic acid derivatives were verified experimentally by a broth microdilution method.

A series of novel compounds were synthesized in reactions of N(3) -substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride: linear, isoindole, and triazole derivatives. All new structures were confirmed by H(1) NMR and IR spectrometry as well as elemental analysis. Potential biological effects of new compounds were predicted with the Prediction of Activity Spectra for Substances (PASS) program. Antiviral, antibacterial, analgesic, and anti-inflammatory activities were experimentally verified.

A new 1,2,4-triazole derivative, 2-(4-phenyl-5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)cyclohexanecarboxylic acid, C20H20N4O2 (I), and its dimethyl sulfoxide solvate 1:1 (II) have been synthesized and their crystal structure was established. Compound (I) was screened for its antiproliferative and antiinflammatory activity. Structural analysis indicated the substantial difference between two symmetry independent molecules in (I) and this in (II), it manifests in the relative orientation of pyridine/phenyl and triazole rings, as well as in the orientation of carboxyl group with respect to cyclohexane ring. The molecules A and B in the crystal (I) form two hydrogen-bonded chains through O–Hcarboxyl and Ntriazole atoms, giving separate catemers of symmetry independent molecules. The catemer of (IA) running along the 21 axis is homochiral, while the catemer (IB) is racemic—formed about the c glide plane. In the crystalline solvate (II) complexation of (I) with DMSO induced enantiomeric self-resolution. Obtained crystals are racemic twins, in which each part is built of one enantiomer of (I) having the relative configuration 11S,12R or 11R,12S. A pair of host–guest molecules is linked by the O–Hcarboxyl⋯ODMSO hydrogen bond.

An analysis of the products of the reaction of N 3 -phenylbenzamidrazone with cis -1,2-cyclohexanedicarboxylic anhydride at various temperatures is presented. The identification of the reaction products is carried on with the support of computational techniques. The most stable conformers of the isoindole and triazole derivatives are found within the DFT approach. The theoretical calculations reveal the possible structure of a triazole derivative not available experimentally because of the presence of two diastereoisomers of equal energy.

The activity of fungicide agents containing a quinazolinone ring was described using the quantitative structure-activity relationship (QSAR) model by applying it to data taken from literature. The title compounds exhibit two important types of activity against certain fungal pathogens, i.e. activity against yeast and activity against filamentous fungi. A correlation between both antifungal activities (e.g. FA(yst) and FA(ff)) and physicochemical parameters such as the logarithm of the n-octanol/water partition coefficient (log P), the polarizability (P), the global minimum energy (TE), the energy difference between the frontier molecular orbital (DELH) and the molar refractivity (MR), was established using multiple linear regression. The molecular descriptors of the antifungal agents were obtained by quantum chemical calculations combined with molecular modeling calculations. Statistical analysis shows that the antifungal activity depends mainly on the calculated partition coefficients, log P, of the compounds. Bi-parametric models reveal that antifungal activity relates linearly to log P and P.

The lipophilicity of the novel 12 products of the reaction of N3-substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride (4 linear, 4 triazole-like and 4 isoindole ones) with potential pharmacologic activity was evaluated by thin layer and liquid chromatography. Using organic-aqueous eluent systems (with methanol or acetonitrile) on RP18 plates and C18 column, a linear relationship between the volume fraction of modifiers and the retention indices was obtained. The retention values, log k or R M were extrapolated to zero organic modifier content to obtain the log k w or R MW values. 12 compounds with known literature lipophilicity were used as a calibration dataset. The results were compared in a multivariate way with in silico methods (ALOGPs, AC_logP, AB/LogP, COSMOFrag, miLogP, ALOGP, MLOGP, KOWWIN, XLOGP3).

(Z)-3-(3,4-diaryl-1,2,4-triazole-5-yl)prop-2-enoic acid derivatives were obtained in the course of the reaction of N 3-substituted amidrazones with maleic anhydride, and isomerized into the (E) isomers by heating under reflux in acetic acid solution. The molecular structure of the compounds obtained was confirmed by IR and 1H NMR spectroscopy, and by X-ray crystallography for (2E)-3-(4,5-diphenyl-4H-1,2,4-triazol-3-yl)prop-2-enoic acid. The antiviral and immunomodulating activity of several of the compounds was examined.

Process of thermal decomposition and stability of the methyl esters of 3-(2-pyridyl)-4-phenyl-1,2,4-triazol-5-carboxylic acid (I), 3-(2-pyridyl)-4-(4-methyl-phenyl)-1,2,4-triazol-5-carboxylic acid (II), 3-(2-pyridyl)-4-(4-methyl-phenyl)-5-oxo-1,2,4-triazine-6-acetic acid (III) and 3-(2-pyridyl)-4-phenyl-5-oxo-1,2,4-triazine-6-acetic acid (IV) were studied. The compounds are stable up to fusion point. Next they decompose in several overlapping stages. Among the decomposition products CO2, H2O, NH3 and CH3OH molecules are presented. When kept in air under atmospheric pressure at temperature over the range of 20-80°C and relative humidity over the range of 50-90% the esters do not change their structure and composition.

2-Phenyl-5-(2,4-dihydroxybenzene)-1,3,4-thiadiazole (4), 2-(2-pyridyl)-2,4-dihydroxybenzene-1,3,4-thiadiazole (5), N(1)-2,4-dihydroxybenzenecarbothio-N(3)-phenyl-benzamidrazone (6) and N(1)-2,4-dihydroxybenzenecarbothio-N(3)-phenyl-2-picoline-amidrazone (7) were prepared and tested for their antimycotic activity. The chemical structures were confirmed by IR, 1H-NMR, EI-MS and elemental analysis. The minimal inhibitory concentration (MIC) values against dermatophytes, yeasts and moulds were determined for the estimation of potential activity in vitro. The strongest fungistatic activity for compound 5 in relation to dermatophytes was found with MIC 0.48-0.99 microg mL(-1).

The title compound, C13H10N4, is a disubstituted 1,2,4-triazole derivative. The pyridyl and phenyl rings form dihedral angles of 46.7 (3) and 55.9 (4)°, respectively, with the central triazole ring. The mol­ecules in the crystal structure form two types of centrosymmetrically related dimers through hydro­phobic C—H⋯N and π–π intermolecular interactions.

The title compound, C14H12N4, is a disubstituted 1,2,4-triazole derivative. The triazole ring is planar and its dihedral angles with the attached pyridyl and methyl­phenyl rings are 25.2 (3) and 66.9 (3)°, respectively. The crystal structure is stabilized by a number of C—H⋯N hydrogen bonds and C—H⋯π intermolecular interactions.

In this research, conditions of cyclization of dimethyl 2-[(1-arylamino-1-arylme-thylidene)hydrazono]succinate 1 – 5 leading to the formation of 3,4-diaryl-5-carboxymethyl-1,2,4-triazole 6 – 10 and methyl 2-(5-oxo-3,4-diaryl-1,4,5,6-tetrahydro-1,2,4-triazine-6-ylidene)acetates 11 – 15 and the biological activity of some of them have been examined. Their chemical structures were confirmed by IR, 1 H-NMR, EI-MS and elemental analysis. Substances 8 and 13 exhibited moderate virucidal activity and partially inhibited absorption of the viruses to the susceptible cells. The acute toxicity of compounds 6–10 was established. For compounds 8 and 13 , the influence on the central nervous system of mice and rats in behavioral tests was examined.

The title compound, C(19)H(13)N(5)O(2), crystallizes in two monoclinic forms depending on the solvent used. From methanol or acetone, a yellow form [(Ia), m.p. 533 K] in the space group P2(1) is obtained, while with ethanol as the solvent, an orange form [(Ib), m.p. 541 K] in the space group Cc results. The conformers observed in the two polymorphs differ primarily in the relative orientation of pyridine/phenyl and triazole rings. Molecules of both polymorphs form chains through carboxyl O-H...N hydrogen bonding; however, in each crystal structure, a different group acts as acceptor, viz. a triazole and a pyridyl N atom for (Ia) and (Ib), respectively. This is the first case of polymorphism observed for crystals of a 3,4,5-trisubstituted 1,2,4-triazole derivative.

The asymmetric unit of the title compound, 2C18H16N4O2·H2O, consists of two organic molecules and one solvent molecule. The symmetry-independent organic molecules have slightly different conformations: the 1,2,4-triazole ring forms dihedral angles of 84.61 (4), 89.68 (5) and 22.38 (6)°, respectively, with the 2-propenecarbocylic, p-tolyl and 4-pyridyl groups in one independent molecule, and 71.35 (4), 82.13 (5) and 24.82 (6)°, respectively, in the second. In the crystal, molecules ralated by the 21 screw axes are assembled via O—H...N and O—H...O hydrogen bonds into infinite chains and these are linked by further O—H...N hydrogen bonds into undulating sheets parallel to the bc plane. Adjacent sheets are connected by weak C—H...O interactions, forming a three-dimensional structure.

New 3-(3,4-diaryl-1,2,4-triazole-5-yl)propenoic acid derivatives (8–14) were synthesized by condensation of N3-substituted amidrazones (1–7) with maleic anhydride. Molecular structure of obtained compounds was confirmed by an elemental analysis, IR and 1H NMR spectra, and the X-ray crystallography for compound 11. The influence of the compound 9 on the central nervous system (CNS) of mice in some behavioural test was examined. The investigated compound showed anticonvulsive activity and potent antinociceptive action.

In this research, conditions of cyclization of dimethyl 2-[(1-arylamino-1-arylme-thylidene)hydrazono]succinate 1 – 5 leading to the formation of 3,4-diaryl-5-carboxymethyl-1,2,4-triazole 6 – 10 and methyl 2-(5-oxo-3,4-diaryl-1,4,5,6-tetrahydro-1,2,4-triazine-6-ylidene)acetates 11 – 15 and the biological activity of some of them have been examined. Their chemical structures were confirmed by IR, 1 H-NMR, EI-MS and elemental analysis. Substances 8 and 13 exhibited moderate virucidal activity and partially inhibited absorption of the viruses to the susceptible cells. The acute toxicity of compounds 6–10 was established. For compounds 8 and 13 , the influence on the central nervous system of mice and rats in behavioral tests was examined.

The crystal structure of the title compound, C14H12N4, is built from two symmetry-independent mol­ecules which are nearly related by translation by the vector a/2. The two mol­ecules exhibit almost identical bond distances and angles but they show significantly different conformations. The relative orientations of the pyridyl and benzene rings about the triazole ring are different in the two mol­ecules, and they pack differently in the crystal structure. Weak inter­molecular C—H⋯N, C—H⋯π and π⋯π inter­actions stabilize the crystal structure [the distance between the triazole ring centroids is 3.687 (4) A].

Retention behavior and specific hydrophobic surface area of some new derivatives of (4,5-Diaryl-1,2,4-triazole) acrylic acid-3 in a reversed-phase thin layer chromatographic system have been determined. Using organic-aqueous eluent systems with addition of formic acid as mobile phases, a linear relationship between the volume fraction of organic modifier and the retention parameter (RM) was established for each solute over the whole examined range of methanol and acetone concentrations and the limited range of acetonitrile content in the mobile phase. For the last system used, the parabolic dependence of this relationship was additionally examined. This allowed determining chromatographic lipophilicity parameters: RMW values by extrapolation technique and φ0 by interpolation technique for each organic modifier applied in the mobile phase. The effect of different mobile–phase modifiers (methanol, acetone, acetonitrile) on chromatographic lipophilicity parameters has been studied.