Design and synthesis of some substituted 1H-pyrazolyl-oxazolidines or 1H-pyrazolyl-thiazolidines as anti-inflammatory-antimicrobial agents

Four series of 1 H-pyrazole derivatives have been synthesized. The first series was synthesized starting with the reaction of 3-(5-bromo-2-thienyl)-1-phenyl-1 H-pyrazole-4-carboxaldehyde 1 with L-serine, L-cysteine, or L-penicillamine, followed by N-protection using (Boc)(2)O to provide compounds 2. The latter compounds could be N-deprotected by 4N HCl/dioxane to afford the second series 3 or reacted with NH(4)OH in the presence of DCC/HOBt to give the corresponding amides 4 followed by N-deprotection giving rise to compounds 5. The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compound 5b (2RS, 4R)-2-[3-(5-bromo-2-thienyl)-1-phenyl-1H-pyrazol-4-yl]-5-methylthiazolidine-4-carboxamide, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.     

Synthesis of 5-(2-,3- and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory activity

New S-alkylated 5-(2-,3- and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiols (5a-c, 6a-c) and 5-(2-,3- and 4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols (7a-c, 8a-c, 9a-c) were synthesized by the alkylation of 3-(2-,3- and 4-methoxyphenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones (3a-c) or 3-(2-,3- and 4-methoxyphenyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thiones (4a-c) with 1-iodobutane or 1-(1,3-benzodioxol-5-yl)-2-bromo-1-ethanone, 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-ethanone and 2-bromo-1-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-ethanone. Compounds 3a-c and 4a-c were synthesized by the acylation of thiosemicarbazide or 4-phenyl-3-thiosemicarbazide with 2-, 3- and 4-methoxybenzoyl chlorides and further cyclization of the obtained acylderivatives 1a-c and 2a-c. The synthesized compounds 4a-c, 5a, 6a-c, 7a-c, 8a-c, 9b,c exhibit anti-inflammatory activity.     

Novel pyrazole derivatives as potential promising anti-inflammatory antimicrobial agents

Four series of 1H-pyrazole derivatives have been synthesized. The first series was synthesized starting by condensing the hydrazine derivatives 1a-d with 4-(1-ethoxycarbonyl-2-oxopropyl)azobenzoic acid 2a in ethanol or glacial acetic acid to generate the corresponding pyrazoline derivatives 3a-d. Likewise, heating 1a-d with 4-(1-acetyl-2-oxopropyl)azobenzoic acid 2b gave rise to the pyrazole derivatives 4a-d. Similarly, reaction of 1a-d with ethyl 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylazo)-3-oxobutanoate 2c or 3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl azo)pentane-2,4-dione 2d in ethanol or glacial acetic acid led to the corresponding pyrazoline derivatives 5a-d or pyrazole derivatives 6a-d. The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compound 6c, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.     

Synthesis and biological evaluation of new thiazolopyrimidines

In this study, a series of 4-amino-5-cyano-3-substituted-2,3-dihydrothiazol-2-thiones (1a-c), as well as their triazolo and triazinopyrimidine derivatives such as 8-substituted-3-benzyl-5-methylthiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-2-thiones (4-6, 10) and 3-benzyl-5-methyl thiazolo[5,4-e]pyrimidino[3,4-b][1,2,4]triazin-2-thiones (7a-b) were prepared as potential antimicrobial and antitumor agents. Some of the tested compounds showed promising antimicrobial activity and non of them showed any appreciable antitumor activity.     

Synthesis of novel 2-substituted quinoline derivatives: antimicrobial, inotropic, and chronotropic activities

Three novel series of quinoline derivatives have been prepared by cyclization of the intermediate 3-(1,3-dioxolan-2-yl)-2-substituted thiocarbamoyl-hydrazinoquinolines with different alpha-halocarbonyl compounds. These series are: 3-(1,3-dioxolan-2-yl)-2-(3-substituted-4-phenylthiazolin-2-y lidene) hydrazinoquinolines; 3-(1,3-dioxolan-2-yl)-2-(3-substituted-5-ethoxycarbonyl- 4-methylthiazoline-2-ylidene)hydrazinoquinolines and 3-(1,3-dioxolan-2-yl)-2- (3-substituted-4-thiazolidinon-2-yl)hydrazinoquinolines. The active methylene group of the latter series was used for the preparation of their arylidene derivatives. The antimicrobial as well as inotropic and chronotropic activities of the prepared compounds were studied.     

Novel 3,3a,4,5,6,7-hexahydroindazole and arylthiazolylpyrazoline derivatives as anti-inflammatory agents

A novel series of 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole substituted at the 2-position were synthesized. The reaction of 2, 6-bis-benzylidenecyclohexanone (1) with thiosemicarbazide in the presence of NaOH afforded a mixture of the 3-H, 3a-H trans 2 and cis 2a diastereoisomers which have been separated by fractional recrystallization. Interaction of the first intermediate 2 with substituted phenacyl bromides, aromatic aldehydes and chloroacetic acid in presence of a mixture of acetic acid and acetic anhydride, and 2, 3-dichloroquinoxaline yielded the corresponding 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole derivatives substituted at the 2-position with 4-aryl-2-thiazolyl 3a, b, 5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl 4a, b and thiazolo[4, 5-b]quinoxalin-2-yl 5, respectively. Moreover, the other intermediates 3, 5-diaryl-1-thiocarbamoyl-2-pyrazolines 7a-d were reacted with the previously-mentioned reagents and gave the corresponding 3, 5-diaryl-1-(4-aryl-2-thiazolyl)-2-pyrazolines 8a-h, 3, 5-diaryl-1-(5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl)-2-pyrazolines 9a-d and 3, 5-diaryl-1-(thiazolo[4, 5-b]quinoxalin-2-yl)-2-pyrazoline derivatives 10a, b, respectively. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity. The structures of the new compounds were confirmed by elemental analyses as well as (1)H-NMR, IR, and MS data.     

Fluorine-containing heterocycles: synthesis and some reactions of new 3-amino-2-functionalized-6-(2'-thienyl)-4-trifluoromethylthieno [2,3-b]pyridines

3-Cyano-6-(2'-thienyl)-4-trifluoromethylpyridine-2(1H)-thione (2) was prepared and reacted with chloroacetone or phenacyl bromide to yield the 2-acetyl or benzoyl-3-amino-6-(2'-thienyl)-4-trifluoromethylthieno[2,3-b]pyridines (3a, b). In contrast, the reaction of 2 with chloroacetamide or its N-aryl derivatives gave the corresponding 2-carbamoylmethyl thiopyridines 4a-c. Upon treatment of these educts with K2CO3 or C2H5ONa in ethanol, they underwent intramolecular Thorpe-Ziegler cyclization to afford 3-amino-2-carbamoyl-6-(2'-thienyl)-4-trifluoromethyl-thieno[2,3-b]pyridine (5a) and its N-aryl analogs 5b, c. Compounds 5a-c underwent some reactions to yield new pyrido[3',2':4,5]thieno[3,2-d]pyrimidines and pyrido[3',2':4,5]thieno[3,2-d][1,2,3] triazines.     

1-phenyl-1H-pyrazole derivatives with antiinflammatory, analgesic and antipiretic activities

Reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates 2 with phenylhydrazine gave the corresponding esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids 3 in high yields. Esters 3 were hydrolyzed to the relative carboxylic acids 4, which were converted by heating to 5-substituted 1-phenyl-1H-pyrazoles 5 in excellent yields. Reaction of methyl 5,5-dimethyl-3-dimethylaminomethylene-2,4-dioxohexanoate with phenylhydrazine afforded methyl 1-phenyl-4-pivaloyl-1H-pyrazole-5-carboxylate 8 b, which was converted as above to the corresponding carboxylic acid 10 b and this to 1-phenyl-4-pivaloyl-1H-pyrazole 11 b. Starting from 5-methoxymethyl-1-phenyl-1H-pyrazole, 1-phenyl-1H-pyrazole-5-acetic acid 18 and its alpha-methyl derivative 19 were also synthesized. Compounds 18, 19, 10 b and 11 b showed a strong antiinflammatory activity in rats; the same compounds in general as well as 8 b, showed appreciable analgesic and antipyretic activities in mice and rats, respectively.     

Synthesis and evaluation of antileukemic activity of 5-thienyl- or 5-(2-furyl)-2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine bis(alkylcarbamates) and derivatives

Treatment of N-(2-furoyl)proline or N-thenoylprolines and N-(2-thenoyl)thiazolidine-4-carboxylic acid with acetic anhydride and dimethyl acetylenedicarboxylate gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate and derivatives of dimethyl 5-(2-thienyl)pyrrolo[1,2-c]thiazole. Reduction of 2 with lithium aluminum hydride gave the diols 3a, 3b, 3c and 3d. These diols yielded the corresponding diacetates 4 by treatment with acetic anhydride. The bis(methylcarbamates) 5a, 5b, 5c, and 5d and bis(isopropylcarbamates) 6b and 6c are obtained with the appropriate isocyanates. The 1-substituted pyrrolizines were synthesized, the 1-acetoxy compounds 7b and 7c further transformed into 1-hydroxy and 1-oxo analogues. The action of hydrochloric acid on 1-acetoxy derivatives gave 3H-pyrrolizines. Evaluation of antileukemic activity was investigated on the leukemia L1210 in vivo, on several bis(alkylcarbamates). The compounds 5c and 5d show good antileukemic activity comparable with the mitomycin.     

Antilipidemic agents, Part. IV: Synthesis and antilipidemic testing of some heterocyclic derivatives of hexadecyl and cyclohexyl hemisuccinate esters

Two main classes of novel esters containing a hexadecyl or cyclohexyl group and various heterocyclic rings, like quinazolines, triazoles, thiadiazoles and pyrazoles have been synthesized. The first class involves the synthesis of the hexadecyl ester derivatives; namely 3-substituted-2-(hexadecyloxycarbonylpropionylthio)-4(3H)-quinazol inones 4a-c; 4-substituted-3-(4-pyridyl)-5-(hexadecyloxycarbonylpropionylthio)- 4H- 1,2,4-triazoles 6a-c; 5-substituted-2-(hexadecyloxycarbonylpropionylamino)-1,3,4-thiadia zoles 8a-c, 4-[4-(hexadecyloxycarbonyl)phenyl]azo-5-hydroxy-3-methyl-1-phen ylpyrazole 16; and 1-[4-(hexadecyloxycarbonyl) phenyl]-3-methyl-2-pyrazolin-5-one 19. The second class comprises the synthesis of the cyclohexyl ester derivatives; namely 3-substituted-2-(cyclohexyloxycarbonylpropionylthio)-4(3H)-quinazo linones 11a, b, 4-substituted-3-(4-pyridyl)-5-(cyclohexyloxycarbonylpropionylthio) -4 H-1,2,4-triazoles 12a, b and 5-isopropylthio-2-(cyclohexyloxycarbonylpropionylamino)-1,3, 4-thiadiazole 13. The antihypercholesterolemic as well as antihyperlipidemic activities of representative compounds have been studied. All the compounds tested resulted in a decrease in the lipid indices (cholesterol, LDL-cholesterol, HDL-cholesterol and serum triglycerides levels) studied in mice. Compounds 4b, 11a and 12a showed the highest antihyperlipidemic activity; their activities were almost equal to that of beta-sitosterol which was used as a standard.     

Synthesis and anxiolytic activity of 1-phenyl-2-(4-aryl-1,3,4,5-tetrahydropyrido[2,3-b][1 ,4]diazepin-2-ylidene)-ethanone

A two-step, general synthesis of 1-phenyl-2-(4-aryl-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepin-2-ylidene)-ethanones 3-9 is presented. This synthesis employs a condensation of 2,3-diaminopyridine with benzoylacetone followed by a basic-activated cyclization reaction with substituted benzaldehydes for final closure of the seven-membered ring. Molecular diversity is fixed by appropriate aldehydes: 2-chloro-, 4-chloro-, 2-bromo-, 4-bromo-, 4-fluoro-, 4-trifluoro- and 3-bromo-4,5-dimethoxybenzaldehyde. Compounds 4, 6, 8, 9 and 10 were examined for their anxiolytic activity. The most active was the compound with the chlorophenyl substituent i.e. 1-phenyl-2-{4-(4-chlorophenyl)-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepin-2-ylidene}-ethanone (4).     

New thiazolo[4,5-d]pyrimidine derivatives as potential antimicrobial agents

In this study, by starting from ethyl 4-amino-2,3-dihydro-3-phenyl-2-thioxothiazole-5-carboxylate (1), three compounds having 2,3-dihydro-3-phenyl-5-mercapto-6-alkyl/phenyl-2-thioxothiazolo[4,5- d]pyrimidin-7(6H)-one (2a-c) structure and their 5-(4'-nonsubstituted/-substituted benzoylmethyl)thio derivatives (3a-l) were synthesized. The antimicrobial activities of the synthesized compounds were investigated against some bacteria and fungi using the microdilution method. 2,3-Dihydro-3,6-diphenyl-5-(4'-bromobenzoylmethyl)thio-2-thioxothiazolo [4,5-d]pyrimidin-7(6H) one (3k) possessing remarkable activity against Gram-positive bacteria and yeast like fungi was found to be the most active compound in this series.     

Studies on the synthesis of antiulcer agents. VI. Synthesis and antiulcer activity of dihydrobenzofuranone derivatives

The derivatives (2) of 3-(2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) acrylic acid (2b) were synthesized. The compounds (3a-g) in which bromo, methoxy, nitro, amino or acetamido group was introduced on the benzene ring of the derivatives (2) and the compounds (3h-k) in which acryloyl moiety was introduced on the 6- or 7-position of the benzofuranone skeleton also synthesized. Furthermore, propionic acid derivatives (4a-c), acetic acid derivatives (4d-g), formic acid derivatives (4h-k) and oxyacetic acid derivatives (5) were prepared by converting the acryloyl moiety of the derivatives (2) into propionyl, acetyl, formyl and oxyacetyl groups. These compounds were tested for antiulcer activities. Among these compounds, 1-[3-(2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl)acryloyl]piperidine (2d) and 4-[3-(2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl)acryloyl] morpholine (2g) were found to have stronger antiulcer activities.     

Synthesis of 3-aryl-2-substituted-4(3H)-quinazolines as potential antimicrobial agents

Three new series of 4(3H)-quinazolinone derivatives were synthesized, namely: [3-Aryl-4(3H)-quinazolinon-2-yl]-methylenehydrazino-(N- substituted)-thiocarbamides, 3-Aryl-2-(3-substituted-4-phenyl-2,3-dihydrothiazol-2-ylidenehy drazonomethyl)-4 (3H)-quinazolinones and 3-Aryl-2-(3-substituted-4-oxothiazolidin-2-ylidenehydrazonometh yl)-4(3H)-quinazolinones. The antimicrobial activities of the synthesized compounds were also studied.     

Synthesis and antioxidant evaluation of some new pyrazolopyridine derivatives

4,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-3-amine (1) was used as a key intermediate for the synthesis of imidazolopyrazole derivatives 7-11 upon interaction with 3-(2-bromoacetyl)-2H-chromen-2-one (2), 2-(benzothiazol-2-yl)-4-chloro-3-oxobutanenitrile (3), 2,3-dibromonaphthalene-1,4-dione (4), naphtha[2,3-b]oxirene-2,7-dione (5), 2,5-dichloro-3,6-dihydroxyhexa-2,5-diene-1,4-dione (6), respectively. Acetylation of 11 afforded the bis-acetyl 12. Also, the imidazolopyrimidine 15 was prepared via treatment of 1 with sodium 3,4-dioxo-3,4-dihydronaphthalene-1-sulfonate (13) in DMF followed by cyclization of the bis-pyrazolopyrimidine 14 with glacial acetic acid. On the other hand, compound 1 was reacted with (E)-1-(4-methoxyphenyl)-5-(piperidin-1-yl)pent-1-en-3-one hydrochloride (16), 2-hydroxy-3-((piperidin-1-yl)-methyl)-naphthalene-1,4-dione (17), 2-styryl-2H-indene-1,3-dione (18), enaminone 22, chloroquinoline-3-carbaldehyde 27a, chloroquinoline-(6-methyl)-3-carbaldehyde 27b and 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (28) to afford pyrazolo[3,4-a]pyrimidines 19-21, 23, 29a, 29b and 30, respectively. Also, the pyrazolopyrimidinone 33 was obtained via treatment of 1 with 1-cyanoacetyl-3,5-dimethylpyrazole (31) followed by cyclization of the formed intermediate 32 with glacial acetic acid. Finally, treatment of 1 with o-terephthalaldehyde in glacial acetic acid afforded diazepine 34. The newly synthesized compounds were screened for their antioxidant properties in which some of them exhibited promising activities. Compounds 1, 14, 15, 23, 26, 29a, 30 and 32 have the ability to protect DNA from the damage induced by bleomycin.     

Synthesis of pyrido[2,1-c][1,2,4]triazine,1,2,4 triazolo[4,3-a] pyridine and 2-(substituted-pyrazolyl)nicotinonitrile and their effect on Biomphalaria alexandrina snail enzymes

The reaction of 2-hydrazino-4-(4-methoxyphenyl)-6-pheny-nicotinonitrile 3 with halo compounds yielded 4a-c,5,6. Heating 3 with carbon disulphide gave 7-(4-methoxyphenyl)-5-phenyl-3-thioxo-2,3-dihydro [1,2,4-] triazolo [4,3-a] pyridine-8-carboxylic amide 7. The behaviour of 3 towards some alpha,beta-unsaturated nitriles ,ethoxymethylene and ketene dithioacetal derivatives has been investigated, affording 9a-c,11a-c,13a-c,16a,b respectively. The activity of compounds 4a,5,6 and 7 have been investigated as molluscicidal.     

Synthesis of 5-substituted 2-methylbenzimidazoles with anticancer activity

A series of compounds comprising the thiocarboximidopyrazolyl 5, the phenylpyrazolyl 6, the dimethylpyrazolyl 7, the nitrophenylpyrazolyl 8, the dimethyloxazolyl 9, the benzoxazepinyl 10, and pyrimidyl 11 a-c derivatives of 3-(2-methyl-1H-benzimidazol-5-ylazo)pentane-2, 4-dione was synthesized. Moreover, 5-amino-2-methylbenzimidazole (3) was reacted with phthalic anhydride or maleic anhydride in acetic acid or in toluene to produce 12-15. Treating 5, 6-diamino-2-methylbenzimidazole (16) with ethyl cyanoacetate or diethyl malonate or acetyl acetone leads to the formation of the benzodiazepine derivatives 17-20. The cytotoxic activity of the compounds 2, 7, 9, 10, and 11 was tested against 60 types of human cancer cell lines. Compounds 7 and 9 were found to be the most potent.     

Novel thiazolinyl, thiazolidinonyl, thiadiazolyl and oxadiazolyl-benzotriazole derivatives with potential antiinflammatory activity and minimum ulcerogenic effect

Four novel series of 1H-benzotriazole derivatives; containing thiazolin, thiazolidin, thiadiazole and oxadiazole moieties; namely 1-[(3,4-disubstituted thiazolin-2-ylidene)hydrazinocarbonyl]methyl-1H-benzotriazoles 3a-1; 1-[3-substituted 5-ethoxycarbonyl-4-methyl thiazolin-2-ylidene)hydrazinocarbonyl]methyl-1H-benzotriazoles 4a-c; 1-[(3-substituted-4-oxothiazolidin-2-ylidene)hydrazinocarbonyl]methyl-1H- benzotriazoles 5a-d; 1-[(5-substituted aminothiadiazol-2-yl)methyl]-1H-benzotriazoles 6a-c have been synthesized by cyclization of the key intermediates 1-[(substituted thiocarbamoylhydrazinocarbonyl)methyl]-1H-benzotriazoles 2a-d. Furthermore 1-[(5-substituted aminooxadiazol-2-yl)methyl]-1H-benzotriazoles 7a, b were obtained by one-pot synthesis starting from 1H-benzotriazol-1-acetic acid hydrazide. The antiinflammatory activity of representative compounds was evaluated in vivo against indomethacin as a standard using the sponge implantation model of inflammation in rats. Both non-immunological parameters such as exudate volume, total leucocyte count (TLC), and differential leucocyte count (DLC), and immunological parameters, for example neutrophil phagocytic function by reduced cytochrome C levels, and the assay of interleukin-1 beta (IL-1 beta) levels in drug-pre-treated rats, were determined. The ulcerogenic activity of compounds showing marked antiinflammatory activity was also studied. Compounds 3e, 5b and 5c showed antiinflammatory activity comparable to indomethacin, and they also demonstrated minimum ulcerogenic activity.     

Synthesis, cytotoxicity, and antiviral activity of some acyclic analogues of the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics tubercidin, toyocamycin, and sangivamycin

A number of 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3d-d]pyrimidine derivatives that are structurally related to toyocamycin and sangivamycin and the seco nucleosides of tubercidin, toyocamycin, and sangivamycin were prepared and tested for their biological activity. Treatment of the sodium salt of 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]-pyrimidine with 1,3-bis(benzyloxy)-2-propoxymethyl chloride afforded compound 3, which without isolation was debrominated to obtain 4-amino-5-cyano-7-[[1,3-bis(benzyloxy)-2- propoxy]methyl]pyrrolo[2,3-d]pyrimidine. Although catalytic hydrogenolysis failed, the benzyl ether functionalities of 4 were successfully cleaved by boron trichloride to afford 4-amino-5-cyano-7-[(1,3-dihydroxy-2- propoxy)methyl]pyrrolo[2,3-d]pyrimidine. Conventional functional group transformation of the cyano group of 6 provided a number of novel 5-substituted derivatives. Tubercidin (8a), toyocamycin (8b), and sangivamycin (8c) were treated separately with sodium metaperiodate and then with sodium borohydride to afford the 2',3'-seco derivatives 9a-c, respectively. The acyclic nucleoside 4-chloro-2-(methylthio)-7-[[1,3-bis(benzyloxy)-2- propoxy]methyl]pyrrolo[2,3-d]pyrimidine was aminated, desulfurized with Raney Ni, and then debenzylated to provide the tubercidin analogue 11. Cytotoxicity evaluation against L1210 murine leukemic cells in vitro showed that although the parent compounds tubercidin (8a), toyocamycin (8b), and sangivamycin (8c) were very potent growth inhibitors, the acyclic derivatives 6, 7a-c, and 9a-c had only slight growth-inhibitory activity. Evaluation of compounds 6, 7a, 7b, 7c, 9a, 9b, 9c, 11 for cytoxicity and activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) revealed that only the carboxamide (7a) and the thioamide (7c) were active. Compound 7c was the more potent of the two, inhibiting HCMV but not HSV-1 at concentrations producing little cytotoxicity.     

Quinoxaline derivatives. Part II: Synthesis and antimicrobial testing of 1,2,4-triazolo[4,3-a]quinoxalines, 1,2,4-triazino[4,3-a]quinoxalines and 2-pyrazolylquinoxalines

Three main classes of quinoxaline derivatives have been synthesized. The first class comprises the synthesis of three novel series of 1,2,4-triazolo[4,3-a]quinoxalines; namely 1-substituted-1,2,4-triazolo[4,3-a]quinoxalines 3a-f, 1-substituted aminomethyl-1,2,4-triazolo[4,3-a]quinoxalines 14a-d and 1-cyano or ethoxycarbonylmethyl-1,2,4-triazolo[4,3-a]quinoxalines 6, 12. The second class involves the synthesis of 2-substituted-1 H-1,2,4-triazino[4,3-a]quinoxalines 4a-d. The third class deals with the synthesis of a variety of 2-pyrazolylquinoxalines, namely 2-(5-amino-3-arylpyrazol-1-yl)-3-phenylquinoxalines 5a-d, 2-[5-hydroxy-3-phenyl-4-(4-substituted sulfamoylphenyl)azopyrazol-1-yl]-3-phenylquinoxalines 15a, b, and 2-(5-hydroxy-4-nitroso-3-phenylpyrazol-1-yl)-3-phenylquinoxalin e (16). The prepared compounds were tested in vitro for their antimicrobial activity. Compounds 13 and 14b exhibited promising antifungal activity against C. albicans (MIC 25, 50 mu/ml respectively). Compound 13 was as active as the antibiotic nystatin.