S-Acyl derivatives of thiosalicylamides with antifungal activity. III]

Some S-acylderivatives of N-monosubstituted amides of thiosalicylic acid in which the N substituents were unsaturated alkyl groups, cyclic or branched saturated alkyl groups, aromatic or aralkyl groups, were prepared and tested for antifungal activity. The substances which were all new were prepared by condensation of 2-mercapto-N-alkylbenzamides with suitable acylating agents. The fungistatic activity of the products was tested in vitro against the following: Candida albicans and Trichophyton mentagrophytes. The results reported in Table I underline the importance of the S-acylderivatives of N-monosubstituted amides of thiosalicylic acid as antifungal agents. Study of the results in Table I has also given some insight on the structure-activity relationships. The S-acyl-N-aralkylthiosalicylamides proved the most active of the compounds tested.     

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.     

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.     

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.     

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.     

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).     

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.     

Phytotoxic activity of triazene derivatives. VI. 1-aryl-3-arylalkyl-3-alkyltriazene derivatives]

A series of of 1-aryl-3-arylalkyl-3-alkyltriazenes (B) was prepared and studied for phytotoxic activity. The previously unknown substances [Table I: substances (I leads to XVI)] were prepared by condensation of the appropriate diazonium salt with the required secondary amine in an alkaline medium and were tested against five representative plant species in both pre- and post-emergence tests at a dose of 6 kg/ha. All the substances studied were inactive in pre-emergence tests. However most of the compounds showed phytotoxic activity by absorption through the foliage. This activity was not very pronounced and always lower than triazene analogs previously studied (type A compounds) which have no aralkyl residue on nitrogen 3.     

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).     

Potential acetylcholinesterase reactivators: pyridine and alpha-oxooxime derivatives

The synthesis and pharmacological screening in vitro and in vivo of pyridine-2-carbaldoxime derivatives I and alpha-oxooximes II are described. Four compounds elicited reactivating effect on phosphorylated acetylcholinesterase comparable with that of pralidoxime used as reference substance. Among the compounds tested, interesting structures are those of oximes bearing a thioether substituent [RA 49 (Table 1) and RA 59 (Table 2)] chloro derivative of MINA [RA 55 (Table 2)] and dipyridyl glyoxime methiodide RA 56 (Table 1).     

Synthesis and quantitative structure-activity relationship analysis of 2-(aryl or heteroaryl)quinolin-4-amines, a new class of anti-HIV-1 agents

Thirty-eight 2-(aryl or heteroaryl)quinolin-4-amines, N,N-disubstituted, N-monosubstituted, and without a substituent at the amino group have been synthesized with use of novel chemistries developed by us recently. Some of these derivatives show anti-HIV-1 activity at a concentration level of 1 microM and low cell toxicity in vitro. The most active and least toxic compounds are derivatives of 2-(3-pyridyl)quinoline. The results of the quantitative structure-activity relationship analyses, including several classical, linear regression correlations and a Free-Wilson approach of de novo model, provide guidelines for the design of new active compounds of this class.     

Derivatives of 4-(p.ter. butylbenzoyl)phenol with phytoiatric antifungal activity

Some derivatives of 4-(p.ter.butylbenzoyl)phenol were prepared and tested for phytoiatric antimycotic activity. The substances, all new to the literature, were subjected to in vitro and in vivo tests (in preventive phase). The compounds studied proved to have interesting in vitro activity.     

Synthesis and antibacterial activity of 1H-pyrazolo[3,4-b]pyrazine and -pyridine derivatives

The investigations of new pyrazine and pyridine derivatives showing an antibacterial activity have been made. Upon treatment of 3-chloro-2-cyanopyrazine [1] and 2-chloro-3-cyanopyridine with 1,1-dimethyl-hydrazine, 1-aminopiperidine and 1-amino-4-methylpiperazine, either the pyrazolo-pyrazine (1), and -pyridine (2) derivatives, or ammonium salts (3-8) were obtained, according to the reaction conditions. Compound 1 was obtained in the reaction of the initial nitrile with methylhydrazine as well. The reactions of 1 gave the following derivatives: acylation-(9), that with p-chlorobenzoic aldehyde-(10), and with phenyl-isothiocyanate-(11). 3-Chloro-2-cyanopyrazine treated with hydrazine hydrate gave amidrazone (12), which upon condensation with p-chlorobenzoic aldehyde produced (13). The compounds obtained were tested in vitro for their tuberculostatic activity. The minimal inhibitory concentration (MIC) values were within 22-100 microg/cm3. Compounds 1, 5 and 6 were also tested in vitro for their activity towards 25 strains of anaerobic, and 25 strains of aerobic bacteria. They appeared to be of elevated activity towards the anaerobes and of low one towards the aerobes (Table 2).     

Amides of beta-(4-chlorophenoxy)-alpha-phenyl-ethylamines are inhibitors of cholesterol biosynthesis in vitro

Amides of beta-(4-chlorophenoxy)-alpha-phenyl-ethylamines were prepared and tested for their inhibitory activity on cholesterol biosynthesis in vitro. Among the substances prepared, (II e), (II g), (II k) and (II m) had much greater inhibitory activity than clofibrate.     

Selective inactivation by chlorofluoroacetamides of the major phenobarbital-inducible form(s) of rat liver cytochrome P-450

Five N-monosubstituted chlorofluoroacetamides have been tested as potential specific irreversible inhibitors of the major phenobarbital-inducible form of rat liver cytochrome P-450 (P450IIB1). In vitro, N-(2-phenethyl)chlorofluoroacetamide was ineffective in causing a time-dependent loss of P450IIB1-mediated androstenedione 16 beta-hydroxylase activity in liver microsomes from phenobarbital-treated rats. However, addition of a nitro or bromo substitutent at the para position of the phenyl group or addition of a second phenyl group at the 1- or 2-position on the phenethyl side chain yielded compounds that caused a selective time-dependent decrease in androstenedione 16 beta-hydroxylase activity relative to four other P-450 form-specific androstenedione or progesterone hydroxylase activities monitored. The two compounds that were the most effective in inactivating P450IIB1 in vitro, N-(2-p-bromophenethyl) and N-(2-p-nitrophenethyl)chlorofluoroacetamide were also administered ip to phenobarbital-treated rats, and inhibition of cytochromes P-450 was assessed by in vitro assays of steroid and R- and S-warfarin hydroxylation in subsequently prepared hepatic microsomes. Both compounds selectively inhibited P450IIB1, and at a dose (200 mg/kg) of N-(2-p-nitrophenethyl)chlorofluoroacetamide that reduced androstenedione 16 beta-hydroxylase activity to approximately one-third of the control level, only two other activities, both attributable to P450IIB1, were decreased. In contrast, steroid and warfarin hydroxylase activities indicative of at least five other cytochromes P-450 were unaffected by the compound. These results indicate the feasibility of an empirical approach to the design of specific cytochrome P-450 inactivators.     

Reactivity of 3-aryl-4-amino-5-mercapto-4H-1,2,4-triazoles: synthesis and biological evaluation of 3,6-diaryl derivatives of 7H-1,2,4-thiazole[3,4-b][1,3,4]thiadiazines, of 3-aryl-4-amino-5-carboxymethylthio-4H-1,2,4-triazoles

Starting from 3-aryl-4-amino-5-mercapto-4H-1,2,4-triazoles (II), two series of 3,6-disubstituted 7H-1,2,4-triazol [3,4-b] [1,3,4] thiadiazines (III) and their 5-carboxymethylthio derivatives (IV) were prepared. From the mercapto-amino-triazoles (II) because of their reactivity in some oxidising media, were obtained the triazole derivatives (V), (VI) and (VII). The synthesis of the alpha-thioketones (VIII) of 3-aryl-5-mercapto-1,3,4-oxadiazoles (I), used in alternative synthesis of triazole-thiadiazines (III), is also reported. All the substances described were subjected to biological screening. In the tests, the carboxymethylthiotriazole (IV) showed weak antiinflammatory activity (carrageenin edema) and more consistent scavanger activity, in vitro, on superoxide anions. The triazole-thiadiazines (III) and triazoles (II), (V) and (VI) showed moderate antimycotic activity.     

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.     

Quinolozidinylalkylamines with antihypertensive activity]

Since lupinylamine [(I); R = H] exhibits hypotensive activity, mainly due to ganglionic blocking properties, and it is known that a high degree of steric hindrance around the basic function of other ganglioplegic amines is of paramount importance for optimal activity, several guinolizidine derivatives were prepared. They differ in the length of the alkyl chain connected to the ring and in the position of the amino group along the chain. Some N-substituted derivatives of 2-quinolizidin-1'alpha-yl-ethylamine (II) together with O-lupinylhydroxylamine and 2-quinolizidin-1'beta-yl-ethylamine, respectively isosteric and epimeric to it, were also prepared. When administered orally to spontaneously hypertensive rats, the amines (II), (III) and (XI) produced high and long-lasting antihypertensive activity, while the remaining compounds so far tested were inactive or had only modest effect on blood pressure. Compared with alpha-methyl-DOPA, amine (II) appears to be approximately two to three times as potent. The antihypertensive activity of (II) appears to be linked to glanglionic blocking properties, since this amine proved 1,2 times as potent as mecamylamine in the inhibition of cat nictitating membrane response to stimulation of the preganglionic sympathetic nerve.     

Vasoconstrictive drugs increase carbonic anhydrase I in vascular smooth muscle while vasodilating drugs reduce the activity of this isozyme by a direct mechanism of action

Carbonic anhydrase (CA) is a zinc enzyme that catalyses the reversible hydration reaction of CO2 and plays a major role in the acid-base balance. We have previously shown that certain vasoconstrictive therapeutic agents increase CA I activity whereas vasodilating drugs reduce the activity of this isozyme by a direct mechanism of action. In this paper we studied the effect of other vasoconstrictive and vasodilating agents on CA I activity in order to elucidate the involvement of vascular smooth muscle CA I in vasoconstrictive and vasodilating processes. We studied the in vitro effects of noradrenaline, prostaglandin F2 alpha, thromboxane A2, leukotriene B4, angiotensin II, vasopressin, indomethacin, prazosin, hydralazine, clonidine, reserpine, prostaglandin I2, indapamide, furosemide, amlodipine, verapamil and irbesartan on purified human red blood cell CA I and vascular smooth muscle CA I isolated from rabbits. In vivo, we selected six groups of five rabbits each, which were administered the following substances in acute experiments: orciprenaline (group 1), desmopressin (group 2), verapamil (group 3), irbesartan (group 4), acetazolamide (group 5) and placebo (control group). Vascular smooth muscle CA I activity and systolic blood pressure were determined and compared with those of the control group. In vitro results showed that all the vasoconstrictive agents studied increased purified and human erythrocyte CA I activity as well as vascular smooth muscle CA I, while vasodilating substances reduced the activity of isozyme by a direct mechanism of action. The same results obtained in vivo showed that activation of vascular smooth muscle CA I increased blood pressure while its inhibition reduced blood pressure. The results of this study suggest that pHi changes, induced by activating or inhibiting CA I in vascular smooth muscle, might be responsible for changes in vascular tonus.