Synthesis of 2-[1,2-dihydropyrazol-4-yl]-1,3,4-thiadiazole derivatives as potential antimicrobial agents

The synthesis of some 2-[1,2-dihydropyrazol-4-yl]-1,3,4-thiadiazole derivatives is performed by reacting 4-dithiocarboxylic acid hydrazides of 3-amino-1,2-dihydro-5H-pyrazol-5-one and 3-amino-1,2-dihydro-1-methyl-5H-pyrazol-5-one with carboxylic acid derivatives. The unusual behaviour of 3-amino-1,2-dihydro-1-methyl-5H-pyrazol-5-one towards acetylating agents is described. The antimicrobial activity of some 2-[1,2-dihydropyrazol-4-yl]-1,3,4-thiadiazole derivatives is tested in a preliminary screening.     

Synthesis and biological activity of 7-(2-nitroimidazoles and 7-(2-aminoimidazole) methyleneamino cephalosporin and their derivatives

The synthesis of 7-[[(1-methyl-2-nitro-1H-imidazol-5-yl)methylene]amino] and 7-[[(2-amino-1-methyl-1H-imidazol-5-yl)methyle-ne]amino]cephalosporanic acids and of some derivatives is described. Their physico-chemical characteristics are reported. The compounds show no appreciable antibacterial activity in vitro. They show no synergy with cephaloridine against Enterobacter cloacae 214 (producer of class I beta-lactamase) and therefore have no anti-beta-lactamase activity.     

Synthesis of some glycoside analogs and related compounds from 9-amino-6-(methylthio)-9H-purine.

Additional information on the anticancer activity of 9-amino-9H-purine-6(1H)-thione and its derivatives was sought by the synthesis of some 9-(substituted amino)-6-(methylthio)-9H-purines in which the 9-substituent contained functional groups capable of either reversible or irreversible binding with an enzymatic site. Condensation of 9-amino-6-(methylthio)-9H-purine (1) with some carbonyl compounds followed by hydride reduction of the azomethine linkage in the intermediates leads to the 2-pyrrolylmethyl (8), 2,3,4-trihydroxybutyl (10), and the 1,5-dihydroxy-2- and 3-pentyl (11 and 12) compounds. A 4-hydroxybutyl derivative (13) was obtained by alkylation of 18, the 9-acetyl derivative of 1, with 4-chlorobutyl acetate followed by saponification. The cyclization of 13 and 11 with a sulfonyl chloride gave the 9-pyrrolidin-1-yl (27) and the 9-[2-(tosyloxymethyl)pyrrolidin-1-yl] (28), respectively. Acylation of 1 with ethyl L-2-pyrrolidine-5-carboxylate and ethyl 1-methyl-5-pyrrolidone-3-carboxylate, respectively, in Me2SO containing NaH gave the corresponding amides 15 and 17. Alkylation of 18 with 1-bromo-2-chloroethane and epichlorohydrin gave the N-(2-chloroethyl) and N-(1,2-epoxy-3-propyl) derivatives 19 and 20. The chloro group of the chlorobutyl derivative of 18 was displaced with KSCN and NaN3, respectively, to give the thiocyanate and azido derivatives 23 and 24. Hydrogenation of the latter gave the amine (25), which was acylated with ethyl chloroformate to give the (ethoxycarbonyl)amino compound 26. None of these compounds showed activity against L1210 leukemia cells implanted ip in mice on a single-dose schedule, suggesting that the activity observed in the simpler 9-aminopurines resulted from cleavage of the hydrazino linkage to give pH-purine-6(1H)-thione.     

Synthesis and antimicrobial evaluation of some new thiazolo[4,5-d] pyrimidines.

In this study, by starting from ethyl 4-amino-2,3-dihydro-3-methyl-2-thioxothiazole-5-carboxylate (1), the compounds having 2,3-dihydro-3-methyl-5-mercapto-6-methyl/ethyl-2- thioxothiazolo[4,5-d]pyrimidin-7(6H)-one (2a, 2b) structure and their 5-(4'-nonsubstituted/-substituted benzoylmethyl)thio derivatives (3a-h) were synthesized. The chemical structures of the compounds were proved by IR, 1H-NMR and elemental analysis data. In vitro antimicrobial activities of the synthesized compounds were investigated against some bacteria and yeasts using the microdilution method. In view of the antimicrobial activity results, a significant inhibitory effect was observed only for compound 2a against Gram-positive bacteria and yeasts, whereas the other compounds had no remarkable activity against the tested microorganisms.     

A new class of isoxazole derivatives: the M 1-9 series of compounds with immunotropic activity

The isoxazole derivatives are interesting objects for synthesis in the search for various sorts of biological activity. Looking for more active immunomodulators we synthesized a series of 5-amino-3-methyl-4-isoxazolecarboxylic acid semicarbazides and thiosemicarbazides in the reaction of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide with isocyanates and isothiocyanates. The biological effect of these compounds on the proliferative response of human mononuclear peripheral blood cells to phytohemagglutinin A (PHA) was described.     

Synthese und Umsetzungen von 3,6-, 5,6- und 3,5-Diaminosalicylsäureestern

Synthesis and Reactions of 3,6-, 5,6- and 3,5-Diaminosalicylates Methyl esters of 3-amino- and 5-amino-4-methyl-6-morpholino salicylic acids ( 1c, 1e ) are accessible from the esters of the 3- and 5-nitroso- or -nitro acids 1a, 1b, 1d by means of catalytic hydrogenation with Pt(IV) oxide. The reduction of the methyl ester of 4-methyl-6-morpholino-3,5-dinitrosalicylic acid ( 1f ) with Pt(IV) oxide as a catalyst affords the methyl 3-amino-4-methyl-6-morpholino-5-nitrosalicylate ( 1g ). With Pd on active charcoal as the catalyst reductive elimination of the morpholino substituent takes place and methyl 3,5-diamino-4-methylsalicylate ( 2 ) is formed. — The methyl esters of 3- and 5-amino-4-methyl-6-morpholinosalicylic acids ( 1c, 1e ) react with methyl acetoacetate ( 4 ) to yield the enamines 3 and 5 .     

Novel potent AMPA/kainate receptor antagonists: synthesis and anticonvulsant activity of a series of 2-[(4-alkylsemicarbazono)-(4-amino-phenyl)methyl]-4,5-methylenedioxyphenylacetic acid alkyl esters

In this paper we describe the synthesis of a series of novel 2-[(4-alkylsemicarbazono)-(4-aminophenyl)-methyl]-4,5-methylenedioxyphenylacetic acid alkyl esters (10-19) carrying an alkylsemicarbazono moiety at a benzylic site. The influence of this group on the biological activity was evaluated by testing the corresponding derivatives 20-22 in which the 4-alkylsemicarbazono moiety was removed (compound 20) or its alkylureido portion shifted at position 1 (compounds 21-22). Furthermore, the involvement of the 4-aminobenzyl moiety in the anticonvulsant activity was evaluated by testing derivative 23. The anticonvulsant activity of all compounds was assayed against audiogenic seizures induced in DBA/2 mice. Within this series of derivatives, 2-[(4-aminophenyl)-(4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl ester (10) proved to be the most active compound. It displayed a potency 5-fold higher than that shown by 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonist. Compound 10 was also effective in suppressing seizures induced in Swiss mice by maximal electroshock (MES) or pentylenetetrazole (PTZ). Furthermore, it antagonized in vivo seizures induced by icv administration of AMPA or kainate (KA). Using the patch-clamp technique in primary cultures of granule neurons we tested compounds 10 and 21 for their ability to modulate currents evoked by KA and 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid (ATPA). These two derivatives reduced KA and ATPA currents to a larger extent than that shown by reference compound 1. Compounds 10 and 21 were also able to reduce neuronal cell death induced by the application of KA (100 microM).     

Synthesis and antimicrobial evaluation of some cephem derivatives.

Two novel cephem derivative series were synthesized: 7-(D-alpha-aminophenyl-acetamido-)-3-methyl-3-cephem-4-carboxylic acid monohydrate (Cephalexin) derivatives and those of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)-thio methyl-3-cephem-4-carboxylic acid (7-AMTCA). The antimicrobial activity of the prepared compounds was studied and compared to that of known cephalosporin antibiotics of the first generation against 12 standard strains and 189 clinical isolates of Gram-positive and Gram-negative microorganisms. The Cephalexin derivatives 4a-f show a narrow activity spectrum and are inactive while 5c and 5d are more active than the Cephalexin and Cephazolin antibiotics against clinically isolated S. aureus and S. epidermidis strains.     

Design and synthesis of novel thiophenecarbohydrazide, thienopyrazole and thienopyrimidine derivatives as antioxidant and antitumor agents

2-Amino-5-acetyl-4-methyl-thiophene-3-carboxylic acid ethyl ester (1) and 5-acetyl-2-amino-4-methylthiophene-3-carbohydrazide (2) were synthesized and used as starting materials for the synthesis of new series of 1-(5-amino-4-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3a), 1-(5-amino-4-(4-chloro-3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3b), 1-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl)pyrazolidine-3,5-dione (4), (Z)-N'-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl) formohydrazonic acid (5a), (Z)-ethyl-N'-4-methyl-2-amino-5-acetylthiophene-3-carbonylformo hydrazonate (5b), 6-acetyl-3-amino-2,5-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (8), 5-methyl-3-amino-2-mercapto-6-acetylthieno [2,3-d]pyrimidin-4(3H)-one (10) and 5-methyl-6-acetyl-2-thioxo-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one (12) as potential antioxidant and antitumor agents. Pharmacological tests showed that compounds 6a, 6b, 8, 10 and 12 exhibited significant antitumor and antioxidant activity.     

Synthesis and pharmacological activities of 1,8-naphthyridine derivatives

In the present study, a series of 2-substituted-4-methyl-7-amino/4,7-dimethyl-1,8-naphthyridines were synthesized and characterized by IR, 1H-NMR and elemental analysis. The compounds were investigated for anticonvulsant (125, 250 mg/kg), cardiac and antimicrobial activities. The compounds were screened for antibacterial activity against gram (+) bacteria (Staphylococcus epidermidis, Bacillus subtilis, Enterococcusfaecalis and Micrococcus luteus) and gram (-) bacteria (Proteus vulgaris, Pseudomonas aeruginosa, Escherichia coli and Salmonella typhi). All the compounds except 2-(3'-phenylaminopropyloxy)-4-methyl-7-amino-1,8-naphthyridine exhibited significant anticonvulsant activity. The anticonvulsant activity of 2-(3-morpholino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine, 2-(3'-diphenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine and 2-(3'-diethanolamino-propyloxy)-4,7-dimethy-1,8-naphthyridine at the dose of 250 mg/kg were found to be equivalent to diazepam (5 mg/kg). Sympathetic blocking activity was observed with 2-(3'-phenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine, 2-(3'-diethanolamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine and 2-(3'-diphenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine only. All the compounds were devoid of antibacterial activity against the tested bacteria.     

Antimitotic agents. Chiral isomers of ethyl [5-amino-1,2-dihydro-3-(4-hydroxyphenyl)-2-methylpyrido[3,4-b]pyrazin-7 -yl]carbamate.

Metabolism studies with ethyl [5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - yl]carbamate (1) in mice were reported previously to give a hydroxylated metabolite, which was methylated to give a methoxy derivative. The metabolite and its derivatives were considered to be 4-(substituted)phenyl compounds, which have been confirmed by the synthesis of the [1,2-dihydro-3-(4-hydroxyphenyl)- and [1,2-dihydro-3-(4-methoxyphenyl)pyrido[3,4-b]-pyrazin-7-yl]carbama tes (17 and 16). Both the S- and R-isomers of 17 are active in several biological systems, but the S-isomer is more potent then the R-isomer. The difference in activity between the S- and R-isomers of 17 is similar with that observed for S- and R-isomers of 1. As model reactions, several O-substituted derivatives were prepared by alkylation of (RS)-17 with benzyl chloride and condensation of (RS)-17 with butyl isocyanate and (S)-17 with 2-chloroethyl isocyanate.     

Synthesis and Structure Elucidation of 5-Aminomethinimino-3-methyl-4-isoxazolecarboxylic Acid Phenylamides and Their Immunological Activity

A series of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides 4 has been prepared by condensation of 5-amino-3-methyl-4-isoxazolecarboxylic acid phenylamides 1 with trichloroacetic aldehyde. Alcoholysis of trichloro derivatives 2 gave 5-alkoxymethine derivatives 3 which, on reaction with an appropriate amine, formed the corresponding compounds 4 . The compounds obtained were evaluated for their immunological activity. The properties of three compounds, described in this report, permitted inhibition of the immune response in all possible ways: diminishing both types of immune response ( 4d ), humoral immune response ( 4a ), or cellular immune response ( 4c ). Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs. Two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.     

Synthesis and preliminary evaluation of anticonvulsant activity of some [4-(benzyloxy) benzoyl]- and [4-(benzyloxy) benzyl] aminoalkanol derivatives

A variety of appropriate [4-(benzyloxy) benzoyl]- and [4-(benzyloxy) benzyl] aminoalkanol derivatives [I-XVII] was synthesized and evaluated for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (ScMet) tests in mice and rats. Neurotoxicity (TOX) was determined by the rotorod test. The most active compounds in the MES test in mice were the appropriate 4-(benzyloxy) benzyl derivatives of (R,S)- and S-(+)-2-amino-1-butanol [XI, XIII], 3-[4-(benzyloxy) benzyl] amino-3-methyl-1-butanol [XV], and S-(+)-2-[4-(benzyloxy) benzyl] amino-3-methyl-1-butanol [XVI]--all exhibiting 100% anti-MES protection (at 30 mg/kg, mice, i.p.) and non-toxic in the active doses. 4-[4-(Benzyloxy) benzyl] amino-1-butanol [X] exhibited activity in both MES and ScMet (100 mg/kg, mice, i.p., 100% anticonvulsant protection, 0.5 h and 4 h after administration, respectively).     

Synthesis and anti-inflammatory activity of derivatives of 5-[(2-disubstitutedamino-6-methyl-pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-oxadiazole-2-thiones

Synthesis and results of anti-inflammatory activity in vivo of 5-[(2-disubstitutedamino-6-methyl-pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-oxadiazole-2-thiones and their S-alkyl-, N(3)-acyl- and N(3)-aminomethyl derivatives are described. All the tested compounds possess anti-inflammatory activity comparable to that of acetylsalicylic acid and some derivatives of 5-[(6-methyl-2-piperidin-1-yl-pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-oxadiazole-2-thione were found to be much more active than ibuprofen.     

Synthesis and antileishmanial activity of some 1- or 2-(dihydroxyalkyl) and 3-(dihydroxyalkoxy)pyrazolo [3,4-d] pyrimidines

Several new derivatives of 4-amino-, 4,6-diamino- and 4-hydrazino-[3,4-d]pyrimidine dihydroxyalkyl substituted in the 1 or 2 positions, or dihydroxyalkoxy substituted in the 3 position have been synthesized. Some of these compounds were evaluated for their activity against Leishmania infantum in mice. The highest degree of antileishmanial activity was displayed by the 4-amino-1-(dihydroxyalkyl) derivatives which yielded parasite inhibition values nearly comparable with that of glucantime in a standard 5-day test.     

Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a potential substrate for new aldose reductase inhibitors.

The isoxazolo-[3,4-d]-pyridazin-7-(6H)-one (2) and its corresponding open derivatives 5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4) were used as simplified substrates for the synthesis of new aldose reductase inhibitors with respect to the previously reported 5, 6-dihydrobenzo[h]cinnolin-3(2H)one-2 acetic acids (1). Moreover, a few derivatives lacking the 5-acetyl group were prepared. Several compounds derived from 2 displayed inhibitory properties comparable to those of Sorbinil. In this class the presence at position 6 of a phenyl carrying an electron-withdrawing substituent proved to be beneficial, independently from its position on the ring (5g,j-l). Acetic acid derivatives were more effective than propionic and butyric analogues. On the contrary, all the monocyclic compounds (6-8) were either inactive or only weakly active. The 3-methyl-4-(p-chlorophenyl)isoxazolo-[3,4-d]-pyridazin-7-(6H )-one acetic acid (5g), which proved to be the most potent derivative, was also investigated in molecular modeling studies, to assess possible similarities in its interaction with the enzyme, with respect to the model 1.     

Synthesis of 3-(1,3,4-thiadiazol-2-yl)pyrazolo[1,5-a] pyrimidine derivatives as potential antimicrobial agents

The synthesis of some 3-(1,3,4-thiadiazol-2-yl)pyrazolo[1,5-a]-pyrimidine derivatives is performed by reacting 2-(3-amino-1,2-dihydro-5-oxo-5H-pyrazol-4-il)-1,3,4- thiadiazoles with 2,4-pentanedione, ethyl 3-oxobutyrate and diethyl ethoxymethylenemalonate. The antimicrobial activity of the synthesized compounds is reported.     

The respective N-hydroxypyrazole analogues of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid

We have determined the pharmacological activity of N-hydroxypyrazole analogues (3a and 4a) of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA), as well as substituted derivatives of these two compounds. The pharmacological profile of 3a is closer to that of thioibotenic acid rather than ibotenic acid, while 4a is a selective N-methyl-D-aspartic acid (NMDA) receptor agonist. Ring substitution of 3a and 4a leads to NMDA receptor antagonists. Whereas efficacy of 3a derivatives at mglu2 receptor decreases from agonism via partial agonism to antagonism with increasing substituent size, substitution abolishes affinity for mglu1 and mglu4 receptors. Ligand- and receptor-based modelling approaches assist in explaining these pharmacological trends among the metabotropic receptors and suggest a mechanism of partial agonism at mglu2 receptor similar to that proposed for the GluR2 glutamate receptor.     

Synthesis and anticonvulsant activity of novel and potent 6,7-methylenedioxyphthalazin-1(2H)-ones

In this paper, we describe the synthesis of a series of novel substituted 4-aryl-6,7-methylenedioxyphthalazin-1(2H)-ones. The anticonvulsant activity of these compounds against audiogenic seizures was evaluated in DBA/2 mice after intraperitoneal (ip) injection. Most of these derivatives are more active than 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA receptor antagonist. As deduced by the rotarod test, all the compounds exhibit a toxicity lower than that of 1. Within the series of derivatives submitted to investigation, 4-(4-aminophenyl)-2-butylcarbamoyl-6,7-methylenedioxyphthalazin -1(2H)-one (21) proved to be the most active compound and is 11-fold more potent than 1 (i.e., ED50 3.25 micromol/kg for 21 versus ED50 35.8 micromol/kg for 1). When compared to 1, compound 21 as well as its analogue 4-(4-aminophenyl)-6,7-methylenedioxyphthalazin-1(2H)-one (16) show a longer lasting anticonvulsant activity. Compound 21 also effectively suppresses seizures induced in Swiss mice by maximal electroshock (MES) and pentylenetetrazole (PTZ). Furthermore, it antagonizes in vivo seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), 2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl)propionic acid (ATPA), and kainate (KA), and its anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 16 and 21 to antagonize KA-evoked currents in primary cultures of granule neurons was tested. They behaved as antagonists, but they proved to be less effective than 1 and 1-(4-aminophenyl)-3,4-dihydro-4-methyl-3-N-methylcarbamoyl-7,8-met hylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655) to reduce the KA-evoked currents.     

Quinazolinones. 5. Synthesis of 3-(chloroacylamino)-methyl-4(3H)-quinazolinone derivatives with anticonvulsant and hypnotic activities

Quinazolinones, V: Syntheses of 3-(Choroacylamino)-2-methyl-4(3H)-quinazolinone Derivatives with Anticonvulsant and Hypnotic Activities Starting from 3-amino-2-methyl-4(3H)-quinazolinones 1 , the amides 3a–h were obtained by acylation. Condensations with imidazole or 4-methylimidazole gave the imidazole derivatives 4a–h or the 2-pyrrolidones 5a,b . Most of these substances show significant anticonvulsant and hypnotic activities.