S-acyl derivatives of thiosalicylamides and their anti-fungal activity. IV]

Some S-acyl derivatives of N-alkylthiosalicylamides [Table I, II: substances (I leads to XXXIII)] in which the acyl group on S in a carbamic or thiocarbamic N-monosubstituted group were prepared and tested in vitro for antifungal activity. All the substances which are not previously recorded were prepared by condensation of 2-mercapto-N-alkylbenzamides with suitable isocyanates or isothiocyanates. The fungistatic activity of the products prepared was tested in vitro against the two strains: Candida albicans and Trichophyton mentagrophytes. The results (Table I and II) show that the N-monosubstituted S-carbamoyl and S-thiocarbamoyl derivatives of N-monosubstituted amides of thiosalicyclic acid have marked in vitro antimycotic activity. Many derivatives have activity of the same order of magnitude as that of clotrimazole and of these the most active compound is 2-(N-phenylcarbamoylmercapto)-N,n-heptylbenzamide (XXVI).     

S-acylderivatives of thiosalicylamides with antifungal activity. I.]

A series of S-acylderivatives of N-ethylthiosalicylamide (substances I leads to XXIII) was prepared and tested for in vitro antifungal activity. The substances, not previously reported, were prepared by the reaction of 2-mercapto-N-ethylbenzamide with suitable acylating agents. The fungistatic activity of the prepared products was tested in vitro against Candida albicans and Trichophyton mentagrophytes. The results given in Table I show that the S-acylderivatives of N-ethylthiosalicylamides have interesting antifungal activity. From examination of the results (Tables I and II) some information on the structure-activity relationship was obtained. 2-Acetylmercapto-N-ethylbenzamide (I) and 2-propionylmercapto-N-ethylbenzamide (III) proved the most active of the compounds tested.     

Aryl esters of N-benzyldithiocarbamic acid with antimycotic activity

Some aryl esters of N-benzyldithiocarbamic acid [substances (I leads to XVI)], in which S aryl substituents were hydrophylic or potentially hydrophylic groups, were tested for in vitro antifungal activity against the following strains: Candida albicans, Saccharomyces cerevisiae and Trichophyton mentagrophytes. The substances were prepared by condensation of benzylisothiocyanate with suitable benzenethiols. The results, given in Table I, show the marked activity as antifungal agents of the N-benzyldithiocarbamic acid aryl esters studied; the antifungal activity, connected with the N-benzyldithiocarbamic group, is only slightly influenced by the nature of the substituents.     

Antimycotic 2-alkyldithio, 2-aralkyldithio, 2-aryldithiobenzamides

Some 2-alkyldithio, 2-aralkyldithio, 2-aryldithio benzoic acids, their methyl esters and N-monosubstituted amides were prepared and tested in vitro against Candida albicans and Trichophyton mentagrophytes. Some N-monosubstituted amides displayed activities similar to those of clotrimazole and pyrrolnitrin. Against Candida albicans, N-monosubstituted amides exhibited a generally higher activity than the corresponding N-monosubstituted amides of 2,2'-dicarboxydiphenyldisulfide.     

S-Acyl derivatives of thiosalicylamides having antifungal activity. II]

Some S-acyl derivatives of N-alkylthiosalicylamides [Table I: substances (I leads to XXXI)] were prepared and tested for antifungal activity. The substances, most of which had not been previously reported, were prepared by condensation of 2-mercapto-N-alkylbenzamides with suitable acylating agents. The antifungal activity of the compounds was tested in vitro against Candida albicans and Trichophyton mentagrophytes. For some compounds the was tested activity against the above strains fungicidal, Candida tropicalis and Saccharomyces cerevisiae. Many of the compounds proved to have high antifungal activity comparable with that of Clotrimazol. The results extended knowledge on the structure-antifungal activity relationships of this class of compounds. The compounds with the highest antifungal activity were: 2-acetylmercapto-N,n-heptylbenzamide (XXVIII); 2-acetylmercapto-5-Cl-N,n-propylbenzamide (XIV); 2-acetylmercapto-N,n-octylbenzamide (XXXI); 2-acetylmercapto-N,n-pentylbenzamide (XXV); 2-acetylmercapto-N,n-hexylbenzamide (XXVII).     

Preparation and antifungal activity of carbamic and thiocarbamic esters of thiophenols

A series of N-substituted carbamic and thiocarbamic esters of thiophenols [substances (I leads to XLII)] was prepared and tested for in vitro antifungal activity. The substances were obtained by condensation of thiophenols with suitable isocyanates and isothiocyanates. The antifungal activity of the products was tested in vitro against the following strains: Candida albicans, Candida tropicalis, Saccharomyces cerevisiae and Trichophyton mentagrophytes. The results obtained, given in the Table I, show that the carbamic and thiocarbamic esters of the thiophenols examined have marked antifungal activity. The results give some information on structure-activity relationships and also show that in general the derivatives of dithiocarbamic acid are more active than the bioisosteric derivatives of thiocarbamic acid. Of the compounds examined the most active were esters of N-benzyl and N-allyldithiocarbamic acid.     

Antimycotic agents: evaluation of some derivatives of 2-thiocyanobenzoic acid

The AA. have tested some amides, esters and thioesters of 2-thiocyanobenzoic acid for their antimycotic activity in vitro against fungal strains representative of human diseases. The results pointed out the remarkable antimycotic activities of 2-thiocyanobenzamides N-monosubstituted.     

Studies on the in vitro hepatic microsomal formation of amides during the metabolism of certain secondary and tertiary benzylic amines.

Part of our interest during the last few years has been to investigate the possible intermediate(s) and mechanism(s) involved in the formation of amides from N-benzylic amines. A number of benzylic amines with different aryl and alkyl moieties introduced onto the constituent nitrogen were prepared, thus creating a wide variety of secondary, tertiary and heterocyclic benzylic amines with different logP and pKa characteristics (Tables I & II). In some experiments, the possible intermediates of this reaction, i.e. nitrones (Table III), imines (Table IV) and amides themselves (Table V), were used as substrates in our metabolic studies. Their in vitro hepatic microsomal metabolism was studied in order to obtain a structure/metabolic activity relationship for the formation of amides from benzylic amines. This communication reviews these studies and reports our conclusions as to the mechanism of formation of amides from N-benzylic amines.     

Derivatives of lithocholic acid with antibacterial and antifungal activity. IV

A series of N-substituted amides of litocholic acid and some N-substituted derivatives of 3 alpha-hydroxy-24-amino-5 beta- cholane were prepared and their in vitro antibacterial and antifungal activity determined against a variety of gram-positive and gram-negative strains and two kinds of mycetes . Some of the tested compounds showed an interesting activity against gram-positive strains and mycetes .     

Synthesis and antimicrobial activity of some new 1-alkyl-2-alkylthio-1,2,4-triazolobenzimidazole derivatives

Some new derivatives of 1,2,4-triazolo[2,3-a]benzimidazoles were synthesized through the reaction of 1,2-diaminobenzimidazole with carbon disulfide. The resulting 1,2,4-triazolo-[2,3-a]benzimidazole-2-thione intermediate was reacted with one equivalent of alkyl halides to give the corresponding 2-alkylthio derivatives, which were further alkylated through the reaction with another one equivalent of different alkyl halides to afford the target compounds; 1-alkyl-2-alkylthio-1,2,4-traizolo[2,3-a]benzimidazoles. On the other hand, the 1,2-disubstituted derivatives with two identical alkyl substituents were prepared by the reaction of 1,2,4-triazolo[2,3-a]benzimidazole-2-thione with two equivalents of the alkyl halides. The structures of the new compounds were assigned by spectral and elemental methods of analyses. The synthesized compounds were tested for their antibacterial and antifungal activities. Most of the tested compounds proved comparable results with those of ampicillin and fluconazole reference drugs. The study indicated that, the antibacterial as well as the antifungal activities of the test compounds were improved with increase in the bulkiness of the introduced alkyl groups. Also, some active antibacterial compounds were tested for their antimycobacterial activity. All the test compounds showed equipotent antitubercular activity as that of INH as a reference drug.     

Sensory effects of capsaicin congeners I. Relationship between chemical structure and pain-producing potency of pungent agents.

A quantitative method for measuring the efficiency of pungent agents of capsaicin-type by the pain reaction elicited on the eye of rats is described. About 50 derivatives -- most of them amides or esters of homovanillic acid -- were tested by this method and the share of different chemical groups of the molecule in the pungent action was analyzed. It turned out that the presence of an acylamide linkage or alkyl chain is not essential for pungency, since acylamide linkage can be replaced by an esteric group and the alkyl chain by cycloalkyl rings. The importance of OH group on the aromatic ring is confirmed. On the basis of the findings a hypothetical pharmacological receptor for capsaicin on pain sensory nerve endings is presented.     

Synthesis and antifungal activity of a series of novel 1,2-disubstituted propenones

To find an antifungal agent other than those of the imidazole and triazole series, a new class of 1,2-disubstituted propenones I and II was prepared and tested for antifungal activity. Comparison of the structure-activity relationships showed that the conjugated structure of carbonyl and exomethylene groups in I and II plays an important role in potent antifungal activity. However, it is noteworthy that compounds 53, 54, and 56, which have a hydroxymethyl or methoxymethyl group instead of an exo-methylene group in I, also showed potent activity. Although many compounds exhibited strong antifungal activity in vitro, none showed activity in vivo of oral efficacy against subacute systemic candidiasis in mice.     

2, 3-Bis(5-alkyl-2-thiono-1, 3, 5-thiadiazin-3-yl) propionic acid: one-pot domino synthesis and antimicrobial activity

In a search for promising antibacterial and antifungal compounds, two new series of 2, 3-bis(5-alkyl-2-thiono-1, 3, 5-thiadiazin-3-yl)propionic acid 1 and their corresponding N, N-dimethylpropionamide 6 have been synthesized. The reaction of 2, 3-diaminopropionate 3, carbon disulfide, formaldehyde, and the appropriate alkyl amines furnished the title compound 1. N, N-dimethylpropionamides 6 were obtained by the reaction of 1 with dimethyl amine in the presence of POCl(3). The newly prepared compounds were screened in vitro against certain strains of Gram-positive and Gram-negative bacteria and compared with nalidixic acid and ciprofloxacin. Moreover, the title compounds were tested for their antifungal activity in vitro against Candida albicans, phytopathogenic, Penicillum expansum and Trichoderma hazianum, and aflatoxin-producing Aspergillus flavus. These compounds exhibit varied activity against the tested pathogenic bacteria and remarkable inhibitory effects on growth or sporulation of some of the tested fungal species.     

Activation of TRPA1 by farnesyl thiosalicylic acid

The nonselective cation channel TRPA1 (ANKTM1, p120) is a potential mediator of pain, and selective pharmacological modulation of this channel may be analgesic. Although several TRPA1 activators exist, these tend to be either reactive or of low potency and/or selectivity. The aim of the present study, therefore, was to identify novel TRPA1 agonists. Using a combination of calcium fluorescent assays and whole-cell electrophysiology, we discovered several compounds that possess potent, selective TRPA1-activating activity, including several lipid compounds (farnesyl thiosalicylic acid, farnesyl thioacetic acid, 15-deoxy-Delta(12,14)-prostaglandin J(2), and 5,8,11,14-eicosatetraynoic acid), and two marketed drugs: disulfiram (Antabuse; a compound used in the treatment of alcohol abuse) and the antifungal agent chlordantoin. Farnesyl thiosalicylic acid activates the channel in excised patches and in the absence of calcium. Furthermore, using a quadruple TRPA1 mutant, we show that the mechanism of action of farnesyl thiosalicylic acid differs from that of the reactive electrophilic reagent allylisothiocyanate. As a TRPA1 agonist with a potentially novel mechanism of action, farnesyl thiosalicylic acid may be useful in the study of TRPA1 channels.     

Methionine derivatives with liver protecting activity

Some methionine derivatives with the amine group acylated with an aliphatic group bearing a free, esterified or etherified thiol group in the omega position were prepared and tested for protection against CCl4, paracetamol, ethyl alcohol and ethionine intoxication. Acid (XIV) (MG 28013) (Table I) and some of its alkyl derivatives (XVIII) (MG 28228) and (XIX) (MG 28226) proved to have significant activity in these tests. A more in-depth study on MG 28226 however indicated a slight intolerance when subacute toxicity was examined (90 gg).     

Cardiotonic agents. Synthesis and inotropic activity of a series of isoquinolin-3-ol derivatives

A series of isoquinolin-3-ol derivatives (II) was prepared as analogues of the clinical cardiotonic agent bemarinone (ORF 16600, I). Although in many respects the structural requirements for the cardiotonic activity of II are similar to those of bemarinone, certain differences between the series were noted. Our structure-activity studies show that II is less sensitive to alkoxy-substitution effects than is I, and more significantly, 4-substitution of II by alkyl groups, halogen, or alkanecarboxylic acid derivatives enhances cardiotonic activity in II in contrast to I, wherein analogous substitution eliminated activity. A linear correlation between contractile force (CF) increase and cyclic nucleotide phosphodiesterase fraction III (PDE-III) inhibition by the title compounds was determined. The isoquinoline derivatives were characteristically short-acting cardiotonic agents with good potency and selectivity.     

Antiatherosclerotic properties of 4-(2,6-dimethylheptyl)-and 4-(2,6,10-trimethylundecyl)benzoic acids and their amides

Two amides with polyol-rich moieties and two other analogs with N-(β-aminoethyl)amide groups, all derived from 4-(2,6-dimethylheptyl)benzoic acid (I), and two polyol amides derived from 4-(2,6,10)-trimetylundecyl) benzoic acid (II) were synthesized and tested for antiatherosclerotic activity in vitro. None of the amides prevented excessive accumulation of cholesterol in the culture of smooth muscle cells (SMCs) raised from human aorta sclerotic plaque, although polyol amides from acid I inhibited protein synthesis in this cell culture. In human liver homogenates (HLHs) all amides derived from acid I accelerated the human cholesterol esterase-catalyzed hydrolysis of cholesteryl palmitate. Acid I displayed antiatherosclerotic effects in both SMC and HLH assays, while acid II and its amides were ineffective in either of these test systems. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 12, pp. 3–7, December, 2006.     

Substituted 5-aroylpyrazine-2-carboxylic acid derivatives: synthesis and biological activity

Homolytic aroylation of pyrazine nucleus with various substituted aromatic carbaldehydes afforded a series of 5-aroylpyrazine-2-carboxylic acid derivatives. The synthetic approach, analytical and spectroscopic data of all compounds synthesized, their preliminary in vitro evaluation of antituberculotic and antifungal activities, cytotoxicity data and subsequent SAR studies are presented. Among all derivatives prepared, only 5-(4-chlorobenzoyl)-pyrazine-2-carbothioamide (3d) showed promising activity (90% inhibition) against Mycobacterium tuberculosis. The highest antifungal effect (MIC<1.95 microM ml(-1)) against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 5-benzoylpyrazine-2-carbothioamide (3a). Thioamides exhibited higher in vitro antimicrobial activity than the corresponding amides.     

Antifungal phytoiatric activity of various benzophenoximes

Some derivatives of substituted benzophenone oximes were prepared and tested for phytoiatric antimycotic activity. The substances (I----XXI) (Table I) were subjected to in vitro and in vivo tests (in preventive phase). The compounds tested showed marked activity. The results proved the importance of the hydroximine function for the appearance of biological activity.     

Primary amides of bis-(2-carboxyphenyl)-disulfides with antimycotic activity]

A series of bis-amides of 2,2'-dicarboxydiphenyldisulfides with monosubstituted N-alkyl groups (substances I leads to XXVI) or N-aralkyl groups (substances XXVI leads to XLII) was prepared and examined for in vitro antifungal activity. The substances were obtained by condensing the chloride of 2,2'-dicarboxydiphenyldisulfide with suitable amines. The fungistatic activity of the products was tested in vitro against the following four strains: Candida albicans, Candida tropicalis, Saccharomyces cerevisiae, Trichophyton mentagrophytes. The results obtained summarised in Tables I and II amplify the structure-antifungal activity relationships of this class of compound. The most active compounds proved to be bis-(N-n.heptyl-2-carboxami-dophenyl)disulfide (XX) and bis-(N-beta-4Cl-phenylethyl-2-carboxamidophenyl)disulfide (XXXV).