Exploring the Antiproliferative Potency of Pyrido[2,3-d]Pyrimidine Derivatives: Studies on Design, Synthesis, Anticancer Evaluation, SAR, Docking, and DFT Calculations.

Herein, an efficient method for the synthesis of a new series of pyrido[2,3-d]pyrimidine derivatives has been adopted through the reaction of hydrazinyl pyrido[2,3-d] pyrimidine derivative (1) with different electrophilic species, such as ethyl cyanoacetate and different 1,3 diketone derivatives, gave the corresponding derivatives (2-5). Meanwhile, pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines (6-11) were synthesized via reaction of hydrazine derivative 1 with phenylisothiocyanate, potassium thiocyanate, and carbon disulfide. Compound 1 was also submitted to react with different carbonyl compounds to afford pyrido-pyrimidine derivatives (12-15).

Synthesis and Antimicrobial, Anticancer and Anti-Oxidant Activities of Novel 2,3-Dihydropyrido[2,3-d]pyrimidine-4-one and Pyrrolo[2,1-b][1,3]benzothiazole Derivatives via Microwave-Assisted Synthesis.

In our attempt towards the synthesis and development of effective antimicrobial, anticancer and antioxidant agents, a novel series of 2,3-dihydropyrido[2,3-d]pyrimidin-4-one - and pyrrolo[2,1-b][1,3]benzothiazoles - were synthesized. The synthesis of 2-(1,3-benzo thiazol-2-yl)-3-(aryl)prop-2-enenitrile (-) as the key intermediate was accomplished by a microwave efficient method. Via a new variety oriented synthetic microwave pathway, these highly functionalized building blocks allowed access to numerous fused heteroaromatic such as 7-amino-6-(1,3-benzo thiazol-2-yl)-5-(aryl)-2-thioxo-2,3dihydropyrido [2,3-d]pyrimidin-4(1H)-one - and 1-amino-2-(aryl)pyrrolo[2,1-b][1,3]benzothiazole-3-carbonitrile derivatives - in order to study their antimicrobial and anticancer activity.

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.

Synthesis and evaluation of antitumor activity of new 4-substituted thieno[3,2-d]pyrimidine and thienotriazolopyrimidine derivatives.

3-Methyl-6-phenyl-2-thioxo-2,3-dihydrothieno[3,2-d]pyrimidin- 4(1H)-one (2), on treatment with phosphorous oxychoride, affored 4-chloro-3-methyl-6-phenyl -thieno[3,2-d]pyrimidine- 2(3H)-thione (3). A series of novel 6-phenyl-thieno[3,2-d]pyrimidine derivatives 4-9 bearing different functional groups were synthesized via treatment of compound 3 with different reagents. On the other hand, compound 2 was used to synthesize ethyl-[(3-methyl-6-phenyl-2-thioxo-2,3-dihydrothieno[ 3,2-d]pyrimidin-4-yl)-oxy]acetate (10), 2-hydrazinyl- -3-methyl-6-phenyl-thieno[3,2-d]pyrimidin-4(3H)-one (11), 3-methyl-2-(methyl-sulfanyl)-6-phenyl-thieno[3,2-d]pyrimidin- 4(3H)-one (12) and N-(phenyl)/4-chlorophenyl or methoxy- phenyl)-2-[(3-methyl-4-oxo-6-phenyl-3,4-dihydrothieno[ 3,2-d]pyrimidin-2-yl)-sulfanyl]-acetamide (13a-c).

Synthesis of thiophene and N-substituted thieno[3,2-d] pyrimidine derivatives as potent antitumor and antibacterial agents.

A novel series of carbamothioylamino-benzene-sulfonamide-thiophene-carboxylates 4a-c and thieno[3,2-d]pyrimidin-2-yl-amino-benzene-sulfonamides 5a-c were synthesized in a series of synthetic steps and were used as key intermediates for the synthesis of thienotriazolopyrimidine-benzene-sulfonamide derivatives 6a-c and 7a-c. Thieno[3,2-d]pyrimidinones (8 and 9) were also prepared. Compound 9 was used as an intermediate for the synthesis of imidazole/1,2,4-triazole and tetrazine functionalized thieno[3,2-d]pyrimidine derivatives (10-12).

Synthesis and Biological Evaluation of N- Pyrazolyl Derivatives and Pyrazolopyrimidine Bearing a Biologically Active Sulfonamide Moiety as Potential Antimicrobial Agent.

A series of novel pyrazole-5-carboxylate containing N-triazole derivatives 3,4; different heterocyclic amines 7a-b and 10a-b; pyrazolo[4,3-d]pyrimidine containing sulfa drugs 14a,b; and oxypyrazolo[4,3-d]pyrimidine derivatives 17, 19, 21 has been synthesized. The structure of the newly synthesized compounds was elucidated on the basis of analytical and spectral analyses. All compounds have been screened for their in vitro antimicrobial activity against three gram-positive and gram-negative bacteria as well as three fungi.

Simple approach to thieno[3,2-d]pyrimidines as new scaffolds of antimicrobial activities.

6'-(4-Chlorophenyl)-spiro[cyclohexane-1,2'-thieno[3,2-d][1,3] oxazin]-4'(1'H)-one (1) was synthesized and used as a starting material for the synthesis of a novel series of spiro compounds having biologically active sulfonamide 2a-e and 3'-(4-acetylphenyl)-6'- (4-chlorophenyl)-1'H-spiro[cyclohexane-1,2'-thieno[3,2-d] pyrimidine-4'(3'H)-one (3). Compound 2a was used as a key intermediate for the synthesis of sulfonyl carbothioamide derivatives 4a-c. Also, compound 3 was used as an intermediate for the synthesis of 3'H-spiro[cyclohexane-1,2'-thieno[3,2-d]pyrimidin]-3'-yl] phenyl}-2-imino-4-(substituted phenyl and/or thienyl)-1,2-dihydropyridine- 3-carbonitrile derivatives 5a-e, 3'H-spiro[cyclohexane- 1,2'- thieno[3,2-d]pyrimidin]-3'-yl]phenyl}-2-oxo-4-(substituted phenyl and/or thienyl)-1,2-dihydropyridine-3-carbonitrile derivatives 6a-e, and 4-[(2Z)-3-substituted-arylprop-2-enoyl] phenyl-1'H-spiro[cyclohexane-1,2'-thieno[3,2-d]pyrimidine derivatives 7a-e.

Novel pyrazole derivatives with oxa/thiadiazolyl, pyrazolyl moieties and pyrazolo[4,3-d]-pyrimidine derivatives as potential antimicrobial and anticancer agents.

A series of [4-amino-3-(4-chlorophenyl)-1H-pyrazol-5-yl](3,5-dimethyl-1H-pyrazol-1-yl)-methanone and 6-amino-3-(4-chlorophenyl)-5-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one have been synthesized from ethyl 4-amino-3-(4-chlorophenyl)-pyrazol-5-carboxylate. The newly synthesized compounds were characterized by IR, (1)H NMR, (13)CNMR, Mass spectra and Elemental analysis. The compounds were evaluated for their in vitro antimicrobial and anticancer activity.

Facile heterocyclic synthesis and antimicrobial activity of polysubstituted and condensed pyrazolopyranopyrimidine and pyrazolopyranotriazine derivatives.

Reaction of 6-amino-3-methyl-4-(substituted phenyl)-1,4- dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) with triethylorthoformate followed by treatment with hydrazine hydrate, formic acid, acetic acid, phenylisocyanate, ammonium thiocyanate and formamide afforded the corresponding pyranopyrimidine derivatives 2-6. Cyclocondensation of 1 with cyclohexanone afforded pyrazolopyranoquinoline 7. One-pot process of diazotation and de-diazochlorination of 1 afforded pyrazolopyranotriazine derivative 8, which upon treatment with secondary amines afforded 9 and 10a- c.

Synthesis of pyranopyrazolo N-glycoside and pyrazolopyranopyrimidine C-glycoside derivatives as promising antitumor and antimicrobial agents.

As a part of systematic investigation of the synthesis and biological activities of pyrazole analogues linked to various heterocyclic systems, a new series of pyrazolo-N-glycoside derivatives, pyrazolopyranopyrimidine and C-glycoside of pyrazolopyranotriazolo-pyrimidine derivatives was synthesized through the reaction of the key intermediate 6-amino-3-methyl-4-(substituted-phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (3a,b) with different reagents. Structures of the newly synthesized compounds were elucidated by elemental microanalysis and spectroscopic methods. The compounds were subjected to in vitro antitumor evaluation using the MTT assay.

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).

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.

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.

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.

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.

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.

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.

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.