The phytoiatric antifungal activity of various derivatives of 2-iodobenzanilides

Some 2'-thioalkyl-2-iodobenzanilides and N-substituted 2-iodobenzanilides were prepared, in order to test their antimycotic activity against representative plant parasites. The substances (I----XI) were subjected to in vitro tests for antimycotic activity. The N-phenyl-2-iodobenzanilide (XI) proved to have very interesting activity.     

A new group of antibiotics, hydroxamic acid antimycotic antibiotics. II. The structure of neoenactins NL1 and NL2 and structure-activity relationship

The structures of neoenactins (NEs) NL1 and NL2, novel antimycotic antibiotics produced by Streptoverticillium olivoreticuli in a precursor-oriented fashion, were elucidated by 1H and 13C NMR and mass spectroscopic studies. The structures of both antibiotics are closely related to that of NE-A, the major component of NE congeners, being classified in the group of hydroxamic acid antimycotic antibiotics in which L-serine and a diketo amine form a hydroxamic acid structure. To study the role of the carbonyl groups in the biological activities of the hydroxamic acid antimycotic antibiotics, NE-A was modified by reaction with various carbonyl reagents. In terms of antimycotic activity, the derivatives are classified into two distinct groups; the first ones are fairly comparable to but not exceeding and the second ones are less active than NE-A depending on their tendency to revert to NE-A by hydrolysis. In general, the biological activities of the derivatives are inversely proportional to their stabilities to hydrolysis.     

Effect of cyclodextrins on the solubility and antimycotic activity of sertaconazole: experimental and computational studies

This study investigated the effects of the complexation of sertaconazole nitrate with different cyclodextrin (CD) derivatives (alpha-CD, beta-CD, gamma-CD, hydroxypropyl-beta-CD, and hydroxypropyl-gamma-CD) on the aqueous solubility and antimycotic activity of the drug. Phase solubility studies indicated that the solubility of sertaconazole in enzyme-free simulated gastric- and enzyme-free simulated enteric fluids was significantly increased in the presence of cyclodextrins. The observed order of solubility increasing effect was: gamma-CD > HPgamma-CD > HPbeta-CD > beta-CD > alpha-CD. Solid-state sertaconazole-cyclodextrin complexes were prepared by freeze drying, and characterized by X-ray powder difractometry, differential scanning calorimetry (DSC), and infrared spectroscopy (FTIR). Freeze-dried complexes showed markedly higher solubility than both physical mixtures and sertaconazole alone. The antimycotic activities of sertaconazole-cyclodextrin complexes in solution were evaluated by inhibition zone assays with Candida albicans. The activity ranking agrees with the solubility ranking observed for these complexes, with the gamma-CD-sertaconazole complex showing the strongest antimycotic activity. Finally, molecular modeling studies were carried out using the MM2 force field method, for complexes in vacuum and in water. This enable indentification of the preferred orientation of sertaconazole in the gamma-CD cavity and of the main structural features responsible for the enhancement of its solubility and antimycotic activity.     

Synthesis and antifungal activity of some amidrazone derivatives

The synthesis and in vitro antifungal activity of some pyridincarboxyamidrazone derivatives are described. 2-pyridincarboxyamidrazone derivative (IIa) in comparison with miconazole showed an interesting even if low antimycotic activity.     

New heterocyclic derivatives with germicidal activity. VI. Synthesis and activity of new 2-benzoxazoyl-2'-furanes and -thiophenes variously substituted in 5 and 5' positions

Seventeen derivatives of 2'-furyl-2-benzoxazole and three derivatives of 2'-thienyl-2-benzoxazole, having different substituents in the benzene moiety (position 5) and in the furanic or thiophenic ring (position 5'), are described, with the aim of studying antibacterial and antimycotic structure-activity relationships. None of the compounds show an important antibacterial and/or antimycotic activity, when tested against nine bacteria and Candida albicans cultures; in any case it was much lower than that previously reported for the corresponding benzimidazoles. It seems that the = NH group of the imidazole ring, which is absent in the benzoxazole derivatives, might be important for the biological activity of this class of compounds.     

Actions of new iminium compounds on bacteria and fungi. 27. Synthesis of 1-n-decyl-2-phenyl-3-(n-alkylthiomethyl)- and 1-n-decyl-2-phenyl-3-(n-alkoxymethyl)imidazolium chlorides]

The imidazolium compounds 1-3 were prepared by quaternization of 1-decyl-2-phenylimidazole with the pertinent chloromethyl-n-alkyl ethers. 1-3 were tested for their antibacterial and antimycotic efficacies.     

The bromination of 6-methyl-4-methoxy-2H-thiopyran-2-one.

The bromination of 6-methyl-4-methoxy-2H-thiopyran-2-one was studied under ionic and radical conditions. The 6-bromomethyl, respectively 6-dibromomethyl derivatives were hydrolyzed to the corresponding 6-hydroxymethyl and 6-formyl derivatives. The antibacterial and antimycotic activities of the new compounds were tested.     

Interaction between saquinavir and antimycotic drugs on C. albicans and C. neoformans strains

Candidiasis and cryptococcosis are the most common fungal diseases among patients suffering from HIV infection. In the present work we assess whether the combined therapies, proteinase inhibitors and antimycotic drugs, could modify the therapeutic effect of antimycotics. An in vitro study to evaluate the antifungal effect of saquinavir and antimycotic drugs combination on yeast growth was performed. Strains of C. albicans and C. neoformans from HIV-seropositive patients were used. Susceptibility tests of yeasts to amphotericin B, 5-fluorocytosine, miconazole and fluconazole, singly and in combination with saquinavir, were performed in two different media. In the combinations the antimycotic agents and saquinavir were tested at sub-inhibitory concentrations: 0.1-10 microg ml(-1) and 12.50 microg ml(-1), respectively. The fractionary inhibitory concentration (FIC) index was also calculated. The results show that the interaction between saquinavir and all the antimycotic drugs never resulted in antagonism. Fluconazole acts in more synergistic way, no matter which medium is used. The combined therapy miconazole/saquinavir results in synergism, especially in Sabouraud. The total absence of antagonism and the presence of synergism suggest that a combined therapy could be proposed in the treatment of HIV-seropositive patients to reduce side effects, thanks to the use of lower doses of antimycotic drugs.     

Formation and antimycotic effect of cyclodextrin inclusion complexes of econazole and miconazole

The stability constants between β-cyclodextrin (β-CD) and the two antimycotic imidazole derivatives, miconazole and econazole were measured. Increased ionization of the imidazole derivatives decreased the size of the stability constants. The same phenomenon was observed for miconazole and hydroxypropyl-β-cyclodextrin. In addition, the type of solubility diagram obtained was dependent on the degree of ionization of the imidazole derivatives. A type Bs solubility diagram was obtained for econazole and β-CD in buffer solution, pH 7.1. An econazole β-CD complex with a molar ratio of 1:1 was isolated. In a fluid medium the antimycotic effect of the econazole β-CD complex against a strain of Candida albicans was superior to the effect of a physical mixture of the two compounds. A small inhibitory effect of β-CD on the growth of the test organism was observed.     

An econazole β-cyclodextrin inclusion complex: an unusual dissolution rate,supersaturation, and biological efficacy example

Genuine cyclodextrin inclusion complexes of the antimycotic econazole and β-cyclodextrin had higher antimycotic activity than a physical mixture of econazole and β-cyclodextrin. Surprisingly, the econazole dissolution rate from the physical mixture was higher than the dissolution rate from the inclusion complex. The improved antimycotic activity of the inclusion complex might be due to the superior ability of the complex to cause econazole supersaturation. A new procedure was applied to disclose the drug supersaturation. The genuine inclusion complex molar ratio econazole:β-cyclodextrin 2:3 gave rise to more hemolysis than the corresponding physical mixture. Toxicity testing on a human buccal epithelium in vitro model — based on TR146 cells — showed that the physical mixture was more toxic than the inclusion complex when TR146 cell mortality was evaluated. Neither measurement of the transepithelial electrical resistance of TR146 cell layers exposed to either the physical mixture or the inclusion complex nor analysis of the protein liberation from the TR146 cells during exposure revealed any differences between the two compositions.     

Antimycotic drugs, IX: Fluorinated 2-benzylthiopyrimidines (author's transl)]

Antimycotic Drugs, IX: Fluorinated 2-Benzylthiopyrimidines By condensation of benzylisothiourea (1) with the fluorinated β-diketones 2a-g , the fluorinated 2-benzylthiopyrimidines 3a-g were obtained. Compound 3b exhibits antimycotic activity.     

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.     

Studies for the elucidation of the mode of action of the antimycotic hydroxypyridone compound, rilopirox.

Rilopirox is a synthetic, fungicidal antimycotic agent with hydrophobic characteristics. Its chemical name is 6-[4-(4-chlorophenoxy)-phenoxy-methyl]-1-hydroxy-4-methyl-2-pyridone and it has a molecular weight of 357.79. Rilopirox is very soluble in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) but poorly soluble in water. The amount of antimycotic agent remaining in the solution is dependent on the final concentration of the solvent and the amount of rilopirox used. Complexometric studies show that rilopirox has a high affinity for iron ions [unpubl. data]. Catalase, an iron-containing enzyme, is inhibited by the chelating agent rilopirox. Studies on yeast mitochondria and submitochondrial particles show that rilopirox inhibits the respiratory chain. Complex I (NADH-ubiquinone oxidoreductase) contains iron-sulfur proteins and is the main system which is inhibited.     

Derivatives of phenoxyacetamide and antimycotic activity

Novel N-(3-methyl-4-R-isoxazol-5-yl)-2-R1-4-R2-phenoxyacetamides and N-(3-methyl-4-R-isoxazol-5-yl)-2-(2-R1-4-R2-phenoxyacetamido) benzamides were prepared and tested against Candida albicans and Cryptococcus neoformans. The results of the antimicrobial assay showed that the presence of two amidic groups usually enhances antimycotic activity.     

Synthesis and structure-activity relationships of benzo[b]thienylallylamine antimycotics

Benzo[b]thiophene analogues of the allylamine antimycotic terbinafine (2) bearing the side chain at various positions and optionally substituted by halogen have been prepared and their antifungal activity studied. Derivatives bearing the side chain at positions 3, 4, or 7 are bioequivalents of 2. Compounds containing the allylamine side chain at position 7, with a further substituent at position 3, showed significantly enhanced activity against Candida albicans, an effect which appears to be specifically linked only to this particular substitution pattern. 3-Chloro-7-benzo[b]thienyl derivative 7m was found to be the most potent allylamine antimycotic identified so far. In general, substituted benzo[b]thiophenes can be used not only as potential equivalents of naphthalene in bioactive compounds but also as a tool to selectively modify biological activities.     

2-(4-Toluidino)pyrimidine

Antidiabetic Agents, II: 2-(4-Toluidino)pyrimidines Condensations of 4-tolylguanidine (1) with the β-diketones 2a-g yield the 2-(4-toluidino)pyrimidines 3a-g which comprise compounds exhibiting antidiabetic and antimycotic activities.     

Inhibition of rat liver microsomal cytochrome P-450 steroid hydroxylase reactions by imidazole antimycotic agents

The imidazole antimycotic agents ketoconazole, miconazole and clotrimazole were tested for their abilities to inhibit the reactions involved in the oxidative metabolism of androst-4-ene-3,17-dione by rat liver microsomal cytochromes P-450. All three compounds were found to function as potent inhibitors of steroid hydroxylase reactions, producing 50% inhibition of 6 beta-, 16 beta-, and 16 alpha-hydroxylase activities at concentrations between 10(-7) and 10(-5) M. The antimycotic agents, when added to liver microsomes, bound to cytochrome P-450 with high affinity to produce a "type II" spectral complex. These agents showed differential inhibition of the various steroid hydroxylases and were found not to affect the activities of the liver microsomal steroid 5 alpha-reductase or the androst-4-ene-3,17-dione 17-oxidoreductase. The results presented demonstrate an interaction of these imidazole antimycotic agents with the various cytochromes P-450 of liver microsomes, resulting in selective inhibition of monooxygenase activity.     

Antimycotic influence of beta-cyclodextrin complexes--in vitro measurements using laser nephelometry in microtiter plates

To determine the in vitro susceptibility of fungal organisms to beta-cyclodextrin (CD) complexes with the antifungal agents econazole-nitrate (EC) and ciclopirox-olamine (CI), a fast, rapid and simple method using laser nephelometry in 96-microtiter plate is used. The antimycotic influence of the complexes against Candida albicans DSM 11225 and Candida krusei ATCC 6258 species was determined using this method. A rapid inhibition and even killing of both fungi was observed only above certain concentrations of complex ranged between 12.5 and 100 microg/ml for beta-CD-econazole complex (CD-EC), while for the complex with ciclopirox-olamine (CD-CI) the range was between 150 and 400 microg/ml. The stability constants of the CD complexes with the two antimycotic derivatives are given. In addition, the nephelometric method allows the determination of solubilities of active agents. Thus, the improvement of solubility of both antimycotic agents in PBS buffer solution was observed by complexation with CD.     

Design and synthesis of 14 alpha-methyl-15-aza-D-homosterols as novel antimycotics

A novel series of 14 alpha-methyl-15-aza-D-homosterols 3-7 has been synthesized. These compounds display significant antimycotic activity in vitro (MIC = 0.8-3.1 micrograms/mL) that compares quite favorably to the activity observed for fluconazole (MIC = 0.8 micrograms/mL). Azasterols 3 and 4 were active in vivo as reflected in the increased survival time of Candida albicans infected mice. The antimycotic activity of 3-7 is hypothesized to be a consequence of the inhibition of fungal 14,15-sterol reductase.     

Synthesis and potential antimycotic activity of 4-substituted-3-(thiophene-2-yl-methyl)-Delta2-1,2,4-triazoline-5-thiones

In the reaction of hydrazide of thiophene-2-acetic acid (1) with isothiocyanates, the respective thiosemicarbazides 2a-g were obtained. Further cyclization with 2% NaOH led to formation of 4-substituted-3-(thiophene- 2-yl-methyl)-Delta2-1,2,4-triazoline-5-thiones (3a-g). These compounds showed promising antimycotic activity.