In vivo and in silico pharmacological studies on some new 4-(1,3,4-thiadiazol-2-yl)benzene-1,3-diol analogues.

4-(1,3,4-Thiadiazol-2-yl)benzene-1,3-diols 5-substituted in the heterocyclic ring were obtained by the reaction of the commercially available hydrazides or thiosemicarbazides with sulfinylbis[(2,4-dihydroxyphenyl)methanethione]. The synthesized compounds were screened for their influence on CNS in the vivo model. Computer aided prediction tools were used for the evaluation of toxicological properties. Additionally, based on the Lipinski filters, the drug-likeness of compounds was assessed. They revealed that the compounds possess properties which can suggest favorable pharmacokinetics in the body after oral admission.

2-Amino-1,3,4-thiadiazole derivative (FABT) inhibits the extracellular signal-regulated kinase pathway and induces cell cycle arrest in human non-small lung carcinoma cells.

The anticancer potential of 2-amino-1,3,4-thiadiazole compounds has been documented by in vitro and in vivo studies. In our previous research, we described the synthesis as well as the antiproliferative and neuroprotective activities of 2-(4-fluorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (FABT). The aim of the present study was to investigate the molecular mechanisms involved in FABT-induced growth inhibition in A549 lung carcinoma cells. Western blotting analysis revealed that FABT inhibited the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, and Real-time PCR analysis showed no changes in the expression of P44ERK1 and CREB1 genes. Furthermore, FABT induced cell cycle arrest in the GO/G1 phase and enhanced p27/Kip1 expression. Our results suggest that FABT acts by inhibiting ERK1/2 pathway and cell cycle progression through G1 into S phase in A549 cells. Further studies are needed to completely explain the molecular mechanisms of anticancer action of this 2-aminothiadiazole derivative.

Synthesis and mycological activity of the compounds obtained in the reaction of N(3)-substituted amidrazones with sulphinyl-bis-2,4-dihydroxybenzenethioyl.

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).

Dependence of fungistatic activity of 2, 4-dihydroxythiobenzanilideson the structure and lipophilic nature of the compounds.

The quantitative dependencies of in vitro fungistatic action on the physico-chemical parameters connected with the structure of 2, 4-dihydroxythiobenzanilides were investigated. It was stated that the action of these compounds depends on lipophilicity determined by substitution of the N-aryl moiety and on electron properties of molecules. The lipophilicity expressed by R(Mw) values was determined in the reversed-phase system (HPTLC). The changes in the nature of the thioamide bond were interpreted on the basis of UV and EI-MS spectra.

In vitro inhibition properties of a new group of thiobenzanilides in relation to yeasts.

The antifungal potency of a series of 2,4-dihydroxythiobenzanilides was tested. MIC assessments were used for the estimation of potential activity in vitro against Candida, Cryptococcus, Geotrichum and Trichosporon species. The strongest fungistatic activity was observed for dichloro derivatives (MIC 7.82-31.21 microg/ml). The action of these compounds depends on lipophilicity, determined by the substitution of N-aryl moiety and the electron properties of molecules. The lipophilicity, expressed by R(Mw) values, was determined in the reversed-phase system. The changes in the nature of the thioamide bond were interpreted on the basis of UV and 1H NMR spectra.

In vitro evaluation of 2,4-dihydroxythiobenzanilides against various moulds.

The antimycotic potency of 2,4-dihydroxythiobenzanilide derivatives was tested. The MIC assessments by an agar dilution method were used for the estimation of potential activity in vitro against the four mould strains: Scopulariopsis brevicalis, Aspergillus niger, Aspergillus fumigatus and Penicillium sp. The strongest fungistatic activity was observed for 3'-fluoro-derivative (MIC 7.82 microg/ml). It was stated that the inhibition action of these compounds depends mainly on lipophilicity of molecules. Parabolic relationships between the antimycotic activity and lipophilicity were found.

N-heterocyclic derivatives of 2,4-dihydroxybenzcarbothioamide as antimycotic agents.

N-heterocyclic derivatives of 2,4-dihydroxybenzcarbothioamide were synthesized from sulfinylbis(2,4-dihydroxybenzenethioyl) and commercially available heterocyclic amines. The composition and chemical structures were confirmed by IR, (1)H NMR, EI-MS, and elemental analysis. For the estimation of potential activity in vitro the MIC values against 15 strains of dermatophytes, yeasts, and molds were determined. The strongest fungistatic potency was found for N-5'-(3'-oxobenzfurylidyne)-2,4-dihydroxybenzcarbothioamide in relation to all tested dermatophyte strains with MIC = 0.48-0.98 microg/mL. On the basis of the spectroscopic data the influence of N-heterocyclic substitution on antimycotic activity is discussed.

Reversed-phase thin-layer chromatography with different stationary phases in studies of quantitative structure-biological activity relationship of new antimycotic compounds.

Reversed-phase thin-layer chromatography with RP-8, RP-18, and RP-18W stationary phases was used in quantitative structure-activity relationship (QSAR) studies of new antimycotic compounds. The retention behavior of 10 dihydroxythiobenzanilides was examined for acquisition of log k' data. With water-acetone mixtures as the mobile phases, the concentration range for which the correlation between log k' and acetone concentration is linear was established for each stationary phase and used to determine hydrophobicity parameters log k'w by linear extrapolation. The effect of substituents on retention constants was quantitated by using the group contribution parameters tau W. On the basis of QSAR equations obtained from these studies, log k'w data can be used to predict antifungal activities of dihydroxythiobenzanilides with satisfactory accuracy.

Use of reversed-phase high-performance liquid chromatography in QSAR analysis of 2,4-dihydroxythiobenzanilide analogues.

Thiobenzanilides are found to show strong biological activity as antimicrobial, antimycotic, and tuberculostatic agents. In addition, they are relatively weakly toxic to higher organisms. A large set of new (N-phenyl-)-2,4-dihydroxybenzenecarbothioamide derivatives was obtained. Preliminary studies showed high microbiological action of some of them. In the process of chromatographic analysis, several different chromatographic parameters were obtained. In case of RP-HPLC, these parameters correspond to hydrophobicity of the solute. Obtained chromatographic parameters exhibited moderate correlation with calculated log P parameter. Linear dependence of bacteriostatic or fungostatic activity on lipophilicity was observed. The degree of correlation of different parameters was compared. The lipophilicity of analysed tioamides was the most important factor responsible for fungostatic and bacteriostatic activity. In comparison to methanol eluent system, chromatographic parameters obtained in acetonitrile system were better correlated with bioactivity. Conversely with the calculated log P values, the experimentally derived parameters exhibited significant higher correlation to fungostatic activity determined on dermatophytes. While in case of other tested microorganisms log P was comparably or sometimes slightly better correlated.

Evaluation of the toxicity of substituted benzthioanilides by using in vitro tests.

The cytotoxicity of 12 benzthioanilides substituted in the N-aromatic ring, and of two commercial preparations (imaverol and thiuram) for comparison, was studied with clone 81 cat cells, by determining the highest tolerated dose, and by using the neutral red uptake assay and the kenacid blue assay for total protein. The concentrations that induced 20%, 50% and 80% (IC20, IC50 and IC80) inhibition relative to controls were calculated from dose-response curves. For some compounds, rat LD50 values were also determined. All the benzthioanilide preparations showed in vitro toxicities lower than those of the fungicides imaverol and thiuram. It was confirmed that the cytotoxicities of the compounds depend on the type of substituent. The least toxic compound contained a CONHCH(2)CO(2)H substituent in the para position of the N-aromatic ring, and the most toxic compounds contained chloro and fluoro, or three chloro substituents in the anilide moiety. All the benzthioanilides tested showed fungistatic activity for dermatophytes; two of the compounds (compound 5 and compound 12) also inhibited the development of yeasts at concentrations lower than those which caused toxicity in vitro. The LD50 values and the cytotoxic concentrations in vitro were linearly related.

Evaluation of toxic activity of 2,4-dihydroxythiobenzanilides.

2,4-Dihydroxythiobenzanilides represent a new group of compounds with significant fungistatic and bacteriostatic properties. The results of investigations on their cytotoxicity are also very convincing. Therefore LD50 doses were determined for five compounds, they ranged from 239 to 840.5 mg/kg. The results of the tests for spontaneous locomotor activity and hexabarbiturane sleeping time indicate low toxicity of the compounds tested.

Relationship between Antifungal Activity against Candida albicans and Electron Parameters of Selected N-Heterocyclic Thioamides.

Due to the increasing demand for new pharmaceuticals showing biological activity against pathogenic microorganisms, there is increasing search for new compounds with predicted biological activity. Variously substituted thioamide derivatives with 1.3 and 1.2 ring of thiazole and 1,3,4-thiadiazole, as well as pyrazole were assessed for their activity against Candida albicans. Activity of majority of tested thioamides was larger as compared with that of the reference drugs. The electron parameters of obtained N-heterocyclic thioamides were determined and dependencies on their biological activity against Candida albicans were studied. The best electron compliance of produced bindings with the activity against Candida albicans was observed for the derivatives containing 1,3,4-thiadiazole ring.

In vitro antifungal activity of 2,5 disubstituted amino-oksometyloso-arylo-thiadiazole derivatives.

PURPOSE: The aim of the study was the determination of antifungal activity of new of 2,5 disubstituted amino-oksometyloso-arylo-thiadiazole (AOAT) derivatives against Candida albicans, non-Candida albicans. MATERIAL AND METHODS: The determination of antifungal activity AOATs against 20 Candida albicans, 18 non-Candida albicans was performed. Isolates were from different ontocenoses of patients were used for tests. AOATs were synthesized at Department of Chemistry University of Agriculture in Lublin. RESULTS: The mean MIC of AOATs against Candida albicans strains was 141.625 (37.5-200) mg/L on Sabouraud's medium (SB). The mean MIC of AOATs against non-Candida albicans strains was 153.3 (50-200) mg/L. CONCLUSION: It seems that AOATs exert potent antifungal activity against the yeast-like fungi strains in vitro.

In vitro antifungal activity of N-3-(1,2,4-dithiazole-5-thione)-beta-resorcylcarbothioamide.

The aim of the study was the determination of antifungal activity of N-3-(1,2,4-dithiazole-5-thione)-beta-resorcylcarbothioamide (DTRTA) against Candida albicans, non-Candida albicans, dermatophytes and molds and evaluation of the enzymatic activity C. albicans strains. We used reference strains C. albicans 10231 ATCC, 200 of C. albicans strains, 7 of non-C. albicans, 12 dermatophytes strains and 20 molds strains isolated from different ontocenoses from patients. DTRTA was synthesized at Department of Chemistry University of Agriculture in Lublin was used to tests. The mean MIC of DTRTA against C. albicans strains isolated from patients was 22.01 mg/L, for reference C. albicans 10231 ATCC-- 12.5 mg/L on Sabouraud's medium (SB). The mean MIC of isolates from patients was 17.8 mg/L, and reference strains--6.25 mg/L on YNB medium, respectively. The MICs of DTRTA against 7 non-C. albicans was 33 mg/L on SB and 18.2 mg/L on YNB. The MICs of DTRTA against dermatophytes ranged from 3 to 50mg/L. The MICs of DTRTA against molds were 25 mg/L and 100 mg/L, respectively. C. albicans strains had the enzymatic activity of 16 among 19 hydrolases, after exposure to DTRTA, 15 among 19 enzymes, respectively. Non-C. albicans isolates had the enzymatic activity of 13 among 19 hydrolases, after exposure to DTRTA, 11 among 19 enzymes, respectively. This findings indicate hat DTRTA exerts a potent antifungal activity against the yeast-like fungi strains, dermatophytes and molds in vitro and.