Andrzej Niewiadomy

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.

Synthesis of some 1-(2,4-dihydroxythiobenzoyl)imidazoles, -imidazolines and -tetrazoles and their potent activity against Candida species.

Various 1-(2,4-dihydroxythiobenzoyl)imidazoles, -imidazolines and -tetrazoles were synthesized and evaluated for their in vitro antifungal activity. Compounds were prepared by the reaction of sulfinyl-bis-(2,4-dihydroxythiobenzoyl) with properly substituted azoles. The MIC values against the Candida albicans ATCC 10231 strain, the azole-resistant clinical isolates of C. albicans and non-Candida species were determined. Tetrazole derivatives were the most active against C. albicans, imidazoline derivatives against non-Candida species. All compounds showed higher activity than that of comparable drugs.

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.

Structure and retention of 2,4-dihydroxythiobenzanilides in a reversed-phase system

The effect of substitution of the N-amide system of 2,4-dihydroxythiobenzanilides on retention in a reversed-phase HPTLC system using methanol as an organic modifier was investigated. The linear relationship between RM and the volume fraction of organic solvent for all 60 tested compounds was obtained. These relationships allowed determination of the hydrophobicity indices, RMw, of these compounds using the extrapolation method. On the basis of analytical data obtained from analysis of UV–Vis and 1H NMR spectra the effect of substitution on the charge distribution in the amide system and the effect of this distribution on phase separation in relation to theoretical values is discussed.

Synthesis and antimycotic activity of N-azolyl-2,4-dihydroxythiobenzamides.

N-pyrazole and N-1,2,4-triazole derivatives of 2,4-dihydroxythiobenzamide prepared from sulfinyl-bis-(2,4-dihydroxythiobenzoyl) and commercially available azole amines were tested for their antimycotic activity. The chemical structure of compounds was confirmed by IR, 1H NMR, MS and elemental analysis. The MIC values against the reference strain Candida albicans ATCC 10231, azole-resistant clinical isolates of Candida albicans and non-Candida albicans species were determined for their potential activity in vitro. The compounds exhibited comparable or higher activity than itraconazole and fluconazole tested under the same experimental conditions. Pyrazoline derivatives showed higher activity than other analogues. The strongest fungistatic activity for N-(2,3-dimethyl-1-phenyl-1,2-dihydro-5-oxo-5H-pyrazol-4-yl)-2,4-dihydroxythiobenzamide was found with MIC values significantly lower than those for the studied drugs.

Influence of modifier and molecular structure of some dihydroxythiobenzanilides on retention in reversed-phase high-performance thin-layer chromatography

Abstract The retention behaviour of ten dihydroxythiobenzanilides in a reversed-phase high-performance thin-layer chromatographic system has been examined. Using water–organic modifier (acetone, acetonitrile or methanol) as the mobile phase, a linear relationship between the volume fraction of the organic solvent and the R M values over a limited range was established for each solute. The physico-chemical properties of these compounds were characterized by their hydrophobicity parameters ( R M w ), determined by extrapolation of the linear relationships for retention data in binary solvent systems to pure water. The effect of individual substituents on retention was quantified by using the group contribution parameter Δ R M .

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.

In vitro anti-Candida albicans activity of new thiatriazole derivative agents

__________________________________________________________________________________________ Purpose: We tested the antifungal activity of N,Nphenyl-1,2,3,4-thiatriazole-5-yl-2,4-b-resorcylcarbothioamide (PTR) ; n-3-(1,2,4-dithiazole-5thione)--resorcylcarbothioamide (DTRTA) ; N,Nphenyl-1,2,3,4-thiatriazol-5-yl-2,4-b-resorcylcarbothioamide (PHARA) against Candida albicans strains in vitro. Materials and methods: We synthesized PTR, DTRTA and PHARA at the Department of Chemistry, University of Agriculture in Lublin. We tested the selected three samples with the lowest value of MIC PTR, DTRTA and PHARA. A reference strain of C. albicans ATCC 10231 and 250 strains of C. albicans isolated from patients were used. Enzymatic activity of the yeast-like fungi was performed by API ZYM test (bioMériux). Results: The mean MIC C. albicans ATCC 10231 on Sabouraud’s Medium was 12.5 mg/L, and YNB Medium and RPMI medium 6.25 mg/L. The mean MIC C. albicans on Sabouraud’s Medium exposure to PTR 19.77 mg/L; exposure to DTRTA 21.06 mg/L, exposure to PHARA 21.54 mg/L; on YNB Medium exposure to PTR 17.79 mg/L, exposure to DTRTA 16.23 mg/l, exposure to PHARA 18.92 mg/L; and RPMI Medium exposure to PTR 12.73 mg/L, exposure to DTRTA -10.93 mg/l, exposure to PHARA 10.65 mg/L. The reference C. albicans strain ATCC 10231 had 5 enzymes inhibited – exposure to PTR inhibited the enzymatic activity of 13 enzymes, exposure to DTRTA inhibited the enzymatic activity of 10 enzymes, and exposure to PHARA inhibited the enzymatic activity of 13 enzymes. The C. albicans isolates had 3 enzymes inhibited after exposure to PTR 5 enzymes were inhibited, exposure to DTRTA 9 enzymes were inhibited, and exposure to PHARA 4 enzymes were inhibited. Conclusion: The synthesized compounds PTR, DTRA and PHARA exert a moderate antifungal activity against C. albicans strains in vitro.