Synthesis of Novel Pyridine Bearing Biologically Active Imidiazolyl, Pyrazolyl, Oxa/thiadiazolyl and Urea Derivatives as Promising Anticancer Agents.

BACKGROUND: A novel series of pyridine containing 1,3,4-oxa/thiadiazol derivatives 4a,b, pyrazole derivatives 5-7, thiazole derivatives 9a,b and 17a-c, urea derivatives 12a-c, imidiazole derivative 16, imidazo[1,2-a]pyridine derivatives 18a, b, tetrazole 19, pyrane 20 and pyridine derivatives 21 has been synthesized. OBJECTIVE: This research aims to synthesize 6-(Trifluoromethyl)-2-{[3-(trifluoromethyl)phenyl] amino} nicotinohydrazide 2 and 6-(trifluoromethyl)-2-{[3-(trifluoromethyl)phenyl]amino} pyridin-3-carboaldhyde 15 as key intermediate for the synthesis of novel pyridine derivatives bearing different heterocyclic rings in order to study the additive effect of this ring toward tumor cell lines. METHODS: 6-(Trifluoromethyl)-2-{[3-(trifluoromethyl)phenyl]amino} nicotinohydrazide 2 was synthesized in a series of synthetic steps and was used as key intermediate for the synthesis of compounds 3-(1,3,4- oxa/thiadiazol-2-yl)-6-(trifluoromethyl)-N-(3- trifluoromethyl) phenyl) pyridin-2-amine 4a,b, (3,5-dimethyl- 1H-pyrazol-1-yl derivatives) [6-(trifluoromethyl)-2-{[3- trifluoromethyl) phenyl] amino} pyridin-3- yl]methanone 5a,b, 6-8, 9a,b and 12a-c. Also, 6-(trifluoromethyl)-2-{[3-(trifluoromethyl)phenyl]amino} pyridin-3-carboaldhyde (15) was used as a key intermediate for the synthesis of novel series of pyridine derivatives with different heterocyclic ring (16-21). RESULTS: Structures of the newly synthesized compounds were established by elemental analysis and spectral data. All the synthesized compounds were screened for their in vitro anticancer activity against liver cancer (HepG2), human colon cancer (HT-29) and human breast adenocarcinoma cell lines (MCF-7). CONCLUSION: All the synthesized compounds were investigated for their in vitro antitumor activity. Compounds 4b, 9a,b and 19 showed higher antitumor activity than the doxorubicin. Interestingly, pyridine with pfluorophenyl urea 12a demonstrated the most potent antitumor activity. The activity of these compounds is strongly dependent on the basic skeleton of the molecules and the nature of the heterocyclic ring attached to the pyridine moiety.

Synthesis, in vitro antimicrobial and in vivo antitumor evaluation of novel pyrimidoquinolines and its nucleoside derivatives.

Seven series of pyrimidoquinoline derivatives have been synthesized, tetrazolo[4',3':-1,2]pyrimido[4,5-b]quinoline (3), 2-aminopyrimido[4,5-b]quinoline (4), triazolo[4',3':1,2]-pyrimidoquinoline (5a,b, 10), imidazolo[3',2':1,2]pyrimido[4,5-b]-quinoline (8a,b), 6-chloro-2-methylthiopyrimido[4,5-b]quinoline (12), acetylated nucleosides (16, 17a,b) and deacetylated nucleosides (18, 19a,b). Some of the novel pyrimidoquinoline derivatives possess highly activity toward the bacteria and fungi species. The new quinolines derivatives were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute (NCI). Most of them had excellent growth inhibition activity, having LD(50) values in the low micromolar to nanomolar concentration range.

Synthesis of substituted thieno[2,3-d]pyrimidine-2,4-dithiones and their S-glycoside analogues as potential antiviral and antibacterial agents.

Previously, we synthesized and evaluated several thienopyrimidine derivatives containing heterocyclic ring substituents linked to the pyrimidine-2-thione nucleus at C-2 by a two- to four-atom spacer as potential anti-HIV-1 and antimicrobial agents. Also, from the literature, S-substituted pyrimidin-4-ones A and B exhibited interesting anti-HIV-1 activity. To further investigate the synthesis, tools and biological activities, we synthesized several new thienopyrimidine derivatives derived from thieno[2,3-d]-pyrimidine-2,4-dithione (3a,b) The compounds were designed to comprise the heterocyclic substituents directly linked to the thienopyrimidines nucleus at C-2. Moreover, various related triazolo[4,3-a]benzothieno[2,3-d]pyrimidines derived from 2-thioxothienopyrimidine were also prepared as isosteres. Among the synthesized derivatives 3-18, the compounds 3a, 8a, 10a, 13a and 14a were showing complete inhibition at 128 mg/mL or less.

Synthesis, biological and medicinal significance of S-glycosido-thieno[2,3-d]-pyrimidines as new anti-inflammatory and analgesic agents.

Several 2-thioglycosides were prepared. Glycosylation of 2-thioxo-thieno[2,3-d]-pyrimidines 5a,b with 1-bromo-2,3,5-tri-O-acetyl-alpha-d-arabinofuranosyle 7, 2,3,4,6-tetra-O-acetyl-alpha-d-glucopyranosyl and galacto-pyranosyl bromide 8a,b gave the protected beta-d-nuclosides 10a,b and 13a-d in high yields, which were transformed to deacetylated derivatives 14a,b and 15a-d. The structures of the compounds were elucidated by spectral and elemental analysis. Anti-inflammatory and Analgesic activities screening of the new compounds (at a dose of 100 mg/kg body weight) utilizing in vivo acute carrageenan-induced paw oedema standard method exhibited that the deacetylated derivatives 14a,b and 15a-d possess highly promising activities.

Synthesis of 4-substituted pyrido[2,3-d]pyrimidin-4(1H)-one as analgesic and anti-inflammatory agents.

4-Substituted-pyrido[2,3-d]pyrimidin-4(1H)-ones 4a-c were synthesized by oxidation of 4-substituted-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones 3a-c which were in turn prepared from arylidenemalononitriles 1a-c and 6-aminothiouracil 2. The reactivity of compounds 4a-c towards some reagents such as formamide, carbon disulfide, urea, thiourea, formic and acetic acids were studied. All the synthesized compounds were characterized by spectroscopic means and elemental analysis. Compound 4c exhibited 64% and 72% analgesic activity. Also, compound 4b showed 50% and 65% anti-inflammatory activity. Interestingly these compounds showed one-third of ulcer index of the reference aspirin and diclofenac.

S- and C-nucleosidoquinazoline as new nucleoside analogs with potential analgesic and anti-inflammatory activity.

Thioglycosides and C-glycosides have received considerable attention, because they are widely employed as biological inhibitors, inducers and ligands for affinity chromatography of carbohydrate-processing enzymes and proteins. Moreover, they are promising candidates in synthetic carbohydrate chemistry as convenient and versatile glycosyl donors. Among these glycosyl donors are the thioglycosyl and N-glycosyl heterocycles that are sufficiently stable under a variety of reaction conditions and have the ability to be readily converted into a variety of other functionalities. We report here, the synthesis of 2-thioxo-quinazolines 1a-c which were used as a base to the synthesis of S-nucleoside of types 10, 11 and acyclic C-nucleoside analogs of type 14 and their analgesic and anti-inflammatory activities were evaluated giving good results.

Synthesis and antitumor activity of substituted triazolo[4,3-a]pyrimidin-6-sulfonamide with an incorporated thiazolidinone moiety.

Chlorosulfonation of 3-methyl[1,2,4]triazolo[4,3-a]pyrimidine with chlorosulfonic acid in the presence of thionyl chloride was studied. When triazolo[4,3-a]pyrimidines are used as substrates, the substitution occurs at C-6. Also the reactivity of the hydrazides (7) towards aldehydes, thioglycolic acid and amines were studies. The newly prepared compounds 10a,d and 11a,d demonstrated inhibitory effects on the growth of a wide range of cancer cell lines generally at 10(-5)M level and in some cases at 10(-7)M concentrations.

Synthesis and evaluation of analgesic, anti-inflammatory and ulcerogenic activities of some triazolo- and 2-pyrazolyl-pyrido[2,3-d]-pyrimidines.

New series of 2-hydrazino-7,8-dihydro-6H-cyclopenta[5,6] pyrido[2,3-d]pyrimidines and its 1,7,8,9-tetrahydrocyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine, 1,7,8,9-tetrahydrocyclopenta[5,6]pyrido[2,3-d][1,2,3,4]tetrazolo[4,5-a]pyrimidine, 8,9-dihydro-7H-cyclopenta[5,6]pyrido[2,3-d]imidazolo[1,2-a]pyrimidine, 2-(pyrazol-1-yl)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine derivatives were prepared in order to obtain new compounds with potential anti-inflammatory and analgesic activity and low ulcerogenic effect. The compounds possessing potent anti-inflammatory activity were further tested for their analgesic and ulcerogenic activities. Compounds 3-amino-6-(4-aryl)-9-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(H)-one (4c), 1-amino-2-methyl-6-(4-aryl)-9-(4-aryl-methylene)-cyclopenta[5,6]pyrido[2,3-d]imidazolo[1,2-a]pyrimidin-5(H)-one (6a), 2-amino-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta[5,6]pyrido-[2,3-d]pyrimidine-4(H)-one (9), 2-(3-amino-5-hydroxypyrazol- 1-yl)-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta[5,6]-pyrido[2,3-d]pyrimidin-4(H)-one (10a) and 3-thioxo-6-(4-aryl)-9-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d]-[1,2,4]triazolo[4,3-a]pyrimidin-5(H)-one (13) showed significant analgesic effects. Compound 2-(3-amino-5-hydroxypyrazol-1-yl)-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta [5,6]pyrido[2,3-d]pyrimidin-4(H)-one (10a) was evaluated as the lead compound having higher anti-inflammatory activity (82.8%) than ibuprofen (79.5%) and lower ulcerogenic effect.

Synthesis, analgesic, anti-inflammatory, and antimicrobial activity of some novel pyrimido[4,5-b]quinolin-4-ones.

Novel series of pyrimido[4,5-b]quinolines (3a-c), triazolo[4',3':1,2]pyrimido[4,5-b]-quinolines (7a-e, 9, and 14), tetrazolo[4',3':1,2]pyrimido[4,5-b]quinolin-5-one (13), [1,3]-pyrazolo[3',2':1,2]pyrimido[4,5-b]quinolines (12a and 12b), and 2-pyrazolyl-pyrimido[4,5-b]-quinolines (15, 16a, 16b, and 19) have been synthesized. Some of the new compounds were tested against various bacteria and fungi species. In addition, the analgesic and anti-inflammatory activities are reported. Compounds 8 and 9a possess high activity toward the fungi as compared with the reference drug Nystatin. The tested compounds 5 and 8 have moderate anti-inflammatory activities. Moreover compounds 5, 8, 10, and 16a, have activities higher than the reference drug in peripheral analgesic activity testing, Compounds 5, 7a, 11a, and 16a have potencies as the reference drug in central analgesic activity testing.

Synthesis and biological evaluation of thieno[2,3-d]pyrimidine derivatives for anti-inflammatory, analgesic and ulcerogenic activity.

5-Methyl-6-phenyl-2-thioxothieno[2,3-d]pyrimidone derivative (2) reacted with hydrazonoyl chloride derivatives to afford triazolothienopyrimidones 4a-f. Also, acetone-1-(2-amino-5-isopropyl-thiophene-3-carbonitrile) (3) reacted with functional and bifunctional groups to yield the corresponding compounds 5-11. The new products showed anti-inflammatory, analgesic, and ulcerogenic activities comparable to that of indomethacin and acetylsalicylic acid, respectively.