Synthesis of some thiazolyl and thiadiazolyl derivatives of 4(3H)-quinazolinone as anti-inflammatory-antimicrobial agents.

This paper describes the synthesis of four series of 4(3H)-quinazolinone derivatives. The first series was prepared by cyclization of the intermediate 3-aryl-2-substituted thiocarbamoylhydrazonomethyl-4(3H)-quinazolinones 2a,b with ethyl bromoacetate to afford the corresponding thiazolidinonyl derivatives 3a,b. The second series were prepared by the cyclization of the intermediate 2a,b with phenacyl bromide or 4-substituted phenacyl bromide giving rise to thiazolinyl derivatives 4a-f. Furthermore, the thiazolidinonyl derivatives 5a,b were obtained by reaction of the intermediate 2a,b with thioglycolic acid. On the other hand, heating the intermediate 2a,b with acetic anhydride afforded the corresponding thiadiazolinyl derivatives 6a,b. Some of the synthesized compounds showed promising anti-inflammatory-antimicrobial activities.

Synthesis of novel pyrimidine-2,4-diones and 2-thioxo-pyrimidine-4-ones as potential anticancer and antimicrobial agents.

Two novel series of pyrimidine derivatives have been prepared, namely; 3,6-disubstituted perhydropyrimidine-2,4-diones 8a-l as well as 3,6-disubstituted 2-thioxo-perhydropyrimidine-4-ones 9a-k. The anticancer as well antimicrobial activities of these compounds and their open-chain counterparts have been determined.

Pyrimidines. Part II: Synthesis of novel pyrimidines, 1,2,4-triazolo[4,3-a]pyrimidin-7-ones and pyrimidino[2,1-c][1,2,4]triazin-8-ones for their antimicrobial and anticancer activities.

Five main classes of novel pyrimidine derivatives have been synthesized; namely 6-substituted phenyl-5-cyano-3-methyl-2-phenacylhydrazino-3,4-dihydropyrimidin-4-ones 4a-e; 6-substituted phenyl-2-arylidene hydra-zino-5-cyano-3-methyl-3,4-dihydropyrimidin-4-ones 5a-i; 6-substituted phenyl-2-acylhydrazino-5-cyano-3-methyl-3,4-dihydropyrimidin-4-ones 7a-d, 8a-e and 9a-c; three novel series of 1,2,4-triazolo[4,3-a] pyrimidones 10a,b, 11a-d and 12a-d and 6-substituted phenyl-7-cyano-9-methyl-3-phenyl or 4-chlorophenyl-4,9-dihydropyrimido[2,1-c][1,2,4] triazin-8-ones 13a-c. Besides, the azide compound 2-azido-5-cyano-3-methyl-6-phenyl-3,4-dihydropyrimidin-4-one 6 was also synthesized. The prepared compounds were tested for antimicrobial and anticancer activity. Compounds 4b and 4d showed promising activity against Escherichia coli. Compounds 3c, 5c, 5e, 5g and 7b were active in the three cell line antitumor one dose primary assay and were evaluated in the 60 human tumor full panel cell line invitro screening. Compound 5c showed promising activity against all types of leukemia especially leukemia K-562 and leukemia SR with GI50 = 1.61 and 2.63 mmol/l respectively.

Synthesis and antimicrobial evaluation of chalcone and syndrome derivatives of 4(3H)-quinazolinone.

The increasing clinical importance of drug-resistant bacterial pathogens has encouraged additional microbiological and antibacterial research. New chalcone and sydnone derivatives of 4(3H)-quinazolinone were synthesized and evaluated for their antibacterial and antifungal activity. The microorganisms used were Escherichia coli ATCC 25922 as Gram-negative bacteria, Staphylococcus aureus ATCC 19433 as Gram-Positive bacteria and Candida albicans as yeast like fungi. The most potent compound was the nitroso derivative 6b, which exhibits interesting antibacterial and antifungal activities.

Synthesis and antimicrobial activity of novel pyrazole, pyrazoline, pyrazolinone and pyrazolidinedione derivatives of benzimidazole.

Four novel series of pyrazolylbenzimidazole derivatives have been prepared, namely 2-[(1-substituted phenyl-3,5-dimethyl-4-pyrazolyl)methyl]benzimidazole 5a-d 2-[(1-substituted phenyl-3-methyl-5-oxo-4,5-dihydro-4-pyrazolyl-4-yl)methyl]benzimidazoles 6a-d; 2-[(1-substituted phenyl-3,5-dioxopyrazolidin-4-yl)methyl]benzimidazoles 7a-d and 2-[(4-(1-phenyl-5-aryl-4,5-dihydro-3-pyrazolyl)phenylaminoacetyl]thio- methyl)-benzimidazoles 12a-e. The antimicrobial testing of the prepared compounds was performed using Escherichia Coli (NCTC 5933) as Gram-negative bacteria, Staphylococcus aureus (NCTC 4163) as gram-positive bacteria and Candida albicans (NCTC 5310) as yeast like fungi. The most potent compound was the pyrazolone 6a which exhibits interesting antibacterial activity against the gram-negative bacteria E. coli.

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.

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.

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.

Synthesis and antimicrobial testing of 4H-1,2,4-triazole, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives of 1H-benzimidazole.

Three novel series of benzimidazole derivatives namely 6-substituted 3-[1-(2-alkyl-1 H-benzimidazolyl)methyl]-1,2,4-triazolo[3,4-b][1,3,4] thiadiazoles 5a-h, 6-substituted 3-[1-(2-alkyl-1H-benzimidazolyl)methyl]-7H-1,2,4 -triazolo[3,4-b]-[1,3,4]thiadiazines 6a-j and 6-thioxo-3-[1-(2-alkyl-1H-benzimidazolyl)methyl]-5,6-dihydro-1,2,4 -triazolo[3,4-b][1,3,4]-thiadiazoles 7a, b have been prepared by cyclization of the key intermediate 1-[(4-amino-5-mercapto-4 H-1,2,4-triazol-3-yl)methyl]-2-alkyl-1 H-benzimidazoles 3a, b. Furthermore, 1-[(4-arylideneamino-5-mercapto- 4H-1,2,4-triazol-3-yl)-methyl]-2-alkyl- 1 H-benzimidazoles 4a-h have been prepared and some of them were cyclized to 6-substituted 3-[1-(2-alkyl-1H-benzimidazolyl)methyl]-1,2,4-triazolo [3,4-b][1,3,4]thiadiazoles 5d, h using thionyl chloride. The prepared compounds were tested for antimicrobial activity in vitro; they showed moderate activity.

Synthesis and antimicrobial testing of novel oxadiazolylbenzimidazole derivatives.

Three novel series of oxadiazolylbenzimidazole derivatives have been prepared, namely 1-[(2-alkylthio or aralkylthio-1,3,4-oxadiazol-5-yl)methyl]-2-alkyl-1 H-benzimidazoles 3a-f; 1-[(3-substituted aminomethyl-2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)methyl ]-2-alkyl-1 H-benzimidazoles 4a-f and 1-[(2-substituted amino-1,3,4-oxidiazol-5-yl)methyl]-2-alkyl-1 H-benzimidazoles 6a-j. The antimicrobial testing of the prepared compounds was performed, some of them showed week activity.

Synthesis and antimicrobial testing of thiazolinyl-, thiazolidinonyl-quinoxalines and 1,2,4-triazolo[4,3-a]quinoxalines.

Three novel series of quinoxaline derivatives namely 1-substituted amino-4-phenyl-1,2,4-triazolo[4,3-a]quinoxalines 3a-c, 2-[3,4,5-trisubstituted-2,3-dihydrothiazol-2-ylidene) hydrazono]-3-phenylquinoxalines 4a-j, 5a-e, and 2-[(3-substituted-4-oxothiazolidin-2-ylidene) hydrazone]-3-phenylquinoxalines 6a-e have been synthesized by cyclization of the key intermediates 2-substituted thiocarbamoylhydrazino-3-phenylquinoxalines 2a-e. The prepared compounds were tested in vitro for their antimicrobial activity.

Synthesis and biological investigations of some novel thiazolylbenzimidazoles, and benzimidazolyl-thiazolo[4,5-d]pyrimidines.

Several thiazolyl-benzimidazoles 2, 4a-c were synthesized through the reaction of 2-cyanomethyl-1 H-benzimidazole with isothiocyanates followed by cyclization of the produced intermediates 1a-b with either ethyl bormocetate or phenacyl bromides. When the cyclization was performed in alkaline medium, thiophenyl-benzimidazoles 5, 6a, b were produced. Another series of thiazolyl-benzimidazoles 8 a-d was obtained from 2,3-dihydrothiazole-2-(3 H)-thiones 7a-d and 2-cyanomethyl-1 H-benzimidazole, then cyclized to the corresponding thiazolo[4,5-d]pyrimidine 10a-d. Most of the prepared compounds were evaluated for their in-vitro antibacterial, antifungal, anti-HIV and anti-cancer activities. They showed promising antifungal activity.

Synthesis of novel thiazolo[4,5-d]pyrimidine derivatives for antimicrobial, anti-HIV and anticancer investigation.

Some novel thiazolo[4,5-d]pyrimidines containing 6-arylideneamino (3a-e). 2-dicyanomethylidene (5a), 2-(cyanoethoxy carbonyl) methylidene (5b) or 2-hydrazono (7a, b) moieties were synthesized. The prepared compounds were tested in vitro for their antibacterial, antifungal, anti-HIV and anticancer activities. Most of them showed promising antifungal activity, but only a few compounds exhibited anticancer activity.

Synthesis and biological investigations of some new thiazolylbenzimidazoles and benzimidazolylthiazolo[3,2-a]pyridines.

2-[(4-Oxo-4,5-dihydrothiazol-2-yl)methyl]-1H-benzimidazole (2) was prepared through the reaction of 2-cyanomethyl-1H-benzimidazole (1) with thioglycolic acid. The syntheses of its arylidene 3 and diazo-coupled compounds 5 and the cyclization of the aforementioned thiazolylbenzimidazole to benzimidazolylthiazolo[3,2-a]pyridines 8 were also performed. The prepared compounds were screened for their in-vitro antibacterial, antifungal, anti-HIV, and anticancer activities: they show promising antifungal activity.

Synthesis and antimicrobial activity of some novel thiazoline and thiazolidinone derivatives of 2,6-di-tertbutyl-1,4-benzoquino.

Three novel series of 2,6-di-tert-butyl-1,4-benzoquinone derivatives were synthesized: 4-[(3,4-disubstituted-2,3-dihydrothiazol-2-ylidene) hydrazono]-2,6-di-tert-butyl-2,5-cyclohexadien-1-ones, 4-[(3-substituted-5-carbethoxy-4-methyl-2,3-dihydrothiazol-2- ylidene)hydrazono]-2,6-di-tert-butyl-2,5-cyclohexadien-1-one s, and 4-[(3-substituted-4-oxothiazolidin-2-ylidene)hydrazono]-2,6- di-tert- butyl-2,5-cyclohexadien-1-ones. These compounds were prepared by cyclization of the new 4-(N-substituted thiocarbamoylhydrazono)-2,6-di-tert-butyl-2,5-cyclohexadien- 1-ones with phenacyl bromides, ethyl alpha-chloroacetoacetate and ethyl bromoacetate, respectively. Antimicrobial testing of the prepared compounds and of the key intermediate thiosemicarbazones was performed. Some of the compounds revealed higher activity than streptomycin.

Synthesis, antimicrobial, inotropic, and chronotropic activities of novel 1,2,4-triazolo[4,3-a]quinolines.

Starting from the 2-quinolylhydrazine 1 the title compounds were prepared according to Schemes 1 and 2. Some of them show activities described in the title of this paper.

Synthesis of some thiazole-, 1,3,4-thiadiazole-, and 4H-1,2,4-triazole derivatives of pyrazolo[3,4-b]quinoline.

Three novel series of pyrazolo[3,4-b]quinolines were prepared, namely: 1-(3-substituted-4-phenylthiazolin-2-ylidene)hydrazinocarbonylm ethyl-1H-pyrazolo[3,4-b]quinolines 3a-d; 1-(5-substituted amino-1,3,4-thiadiazol-2-yl)methyl-1H-pyrazolo[3,4-b]quinolines 4b-d, and 1-(4-substituted-4H-5- thioxo-1,2,4-triazole-3-yl)methyl-1H-pyrazolo[3,4-b]quinolines 5a-d. These compounds were prepared by cyclization of the new key intermediates 1-(substituted thiocarbamoylhydrazinocarbonyl)methyl-1H- pyrazolo[3,4-b]quinolines 2a-d. The alkylthio, aralkylthio 6a-f as well as the Mannich bases 8a-f derived from compounds 5a-d were also prepared. The structures of the new compounds were elucidated by elemental analyses, IR, 1H-NMR-, and mass spectra. The antimicrobial as well as inotropic and chronotropic activities were studied.

Synthesis of 1,3,4-thiadiazoles, imidazo[2,1-b]1,3,4-thiadiazoles and thiadiazolo[3,2-a]pyrimidines derived from benzimidazole as potential antimicrobial agents.

Several new 1,3,4-thiadiazole, imidazo[2,1-b]1,3,4-thiadiazole and thiadiazole[3,2-al]pyrimidine derivatives of benzimidazole were synthesized. The compounds were obtained from 1-ethyl or benzyl 2-(2-amino-1,3,4-thiadiazol-5-yl)thiomethylbenzimidazole. The antimicrobial activity of the prepared compounds was studied.

Synthesis of novel naphtho[2,1-b]-1,4,5-oxa- or thiadiazepines as potential antimicrobial and anticancer agents.

Two novel series of quinone derivatives have been synthesized. Thus, condensation of 2-ethoxycarbonylmethylthio-; 3-ethoxycarbonylmethylthio-2-methyl- and 3-ethoxycarbonylmethoxy-2-methyl derivatives of 1,4-naphthoquinone with substituted phenylhydrazines afforded the corresponding hydrazones, while cyclization of the same quinones with the same substituted hydrazines in glacial acetic acid gave the corresponding naphtho[2,1-b]-1,4,5-oxa- or thiadiazepine derivatives. The antimicrobial and anticancer activities of the synthesized compounds were studied.

Antilipidemic agents, III: Synthesis of some heterocyclic derivatives of beta-sitosterol.

Four novel series of heterocyclic derivatives of beta-sitosterol were prepared by the reaction of 3-beta-sitosterol hemisuccinate with SOCl2 then with thiols, amines or phenols. These series are: 3 beta-[(3-substituted-4(3H)-quinazolinon-2- yl)thiocarbonylproprionyloxy]stigmast-5-ene; 3 beta- ([4-substituted-5-(4-pyridyl)-4H-1,2,4-triazol-3-yl] thiocarbonylpropionyloxy)stigmast-5-ene; 3 beta- [(5-substituted-1,3,4-thiadiazol-2-yl)carbamoylpropionyloxy] stigmast-5-ene and 3 beta-(substituted carbamoyl or oxycarbonylpropionyloxy)stigmast-5-ene. The antilipidemic activity of representative compounds was studied.