Some pyrazole and pyrazolo[3,4-d]pyrimidine derivatives: synthesis and anticancer evaluation.

5-Amino-1-p-tolyl-1H-pyrazole-4-carbonitrile (1) was used for the preparation of some novel pyrazoles and pyrazolo[3,4-d]pyrimidines 2-10. Moreover, the cytotoxicity and in vitro anticancer activities of the prepared compounds were also assessed against the MCF-7 breast cancer, HepG2 liver cancer, and A549 lung carcinoma cell lines, along with investigation of the effect of the synthesized compounds on the expression of urokinase plasminogen activator (uPA). The tested compounds exhibited remarkable cytotoxic activity against MCF-7 and HepG2 cells. Among the tested compounds, 2 and 9 revealed promising anticancer activity compared to the activity of the commonly used anticancer drug, doxorubicin, by inhibiting the expression of uPA.

Synthesis and isomerization of some novel pyrazolopyrimidine and pyrazolotriazolopyrimidine derivatives.

4-Imino-1-p-tolyl-1,4-dihydropyrazolo[3,4-d]pyrimidin-5-ylamine (2) and (1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-hydrazine (3) were prepared starting from ethyl 4-cyano-1-p-tolyl-1H-pyrazol-5-ylimidoformate (1). The structure of compound 3 was confirmed through preparation of the pyrazole derivatives 4 and 5. Also, the synthesis and structural characterization of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 7 and 9 and their isomerization to pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 6 and 8, respectively, under different suitable reaction conditions were reported. Moreover, the syntheses of 2-substituted-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 10 and 11 was described.

New pyrimidinone and fused pyrimidinone derivatives as potential anticancer chemotherapeutics.

A series of novel substituted pyrimidinones and fused pyrimidinones (compounds 3-18) were synthesized starting with oxiranylmethanone 2. The in vitro cytotoxicity against a human breast adenocarcinoma (MCF-7) cell line was investigated and most of the tested compounds showed potent cytotoxic activity against the MCF-7 cell line comparable to the activity of the commonly used anticancer drug cisplatin. Treatment of MCF-7 cells with increasing doses (2, 5, 10, and 20 µg/mL) of the tested compounds revealed that the activity of superoxide dismutase and the level of hydrogen peroxide were significantly increased, while the activities of catalase and glutathione peroxidase and the levels of reduced glutathione were significantly lowered compared with control MCF-7 cells. In general, derivatives 11 and 16 revealed the highest anticancer activity among the tested compounds.

Synthesis of new quinoline derivatives as inhibitors of human tumor cells growth.

A series of new 8-[(2H-tetrazol-5-yl)methoxy]quinoline derivatives, their sugar hydrazones, and their N-glycoside derivatives were synthesized. Furthermore, the 1,2,4-triazole-3-one derivatives 3 and 4 were synthesized from the amidrazone derivative 2. Some of the newly prepared compounds demonstrated inhibitory effects on the growth of MCF-7 human breast cancer cells as compared with the activity of the commonly used anticancer drug, cisplatin. The results of antitumor evaluation revealed that compounds 2-5, 8b, and 12 inhibited the growth of cancer cells through their effect as free-radical regulators by increasing the activity of superoxide dismutase and depletion of intracellular levels of reduced glutathione, catalase and glutathione peroxidase activities, accompanied with a high production of hydrogen peroxide, nitric oxide, and other free radicals causing the killing of tumor cells. The results suggested that the prepared compounds possess significant anticancer activity comparable to cisplatin and the antitumor activity of these prepared compounds was accompanied with a reduction in the levels of protein and nucleic acids.

Synthesis and antiviral evaluation of some new pyrazole and fused pyrazolopyrimidine derivatives.

Some novel substituted pyrazole and pyrazolo[3,4-d]pyrimidine derivatives 2, 4, 8, and 9 were synthesized. Also, some acyclic S-nucleosides of pyrazolo[3,4-d]pyrimidine derivatives 10-13 were prepared via reaction of pyrazolo[3,4-d]pyrimidine-4(3H)-thione derivative 9 with some acyclic sugars. Moreover, the N-nucleoside derivative 14 was prepared via reaction of compound 8 with glucosamine hydrochloride. The antiviral evaluation of some selected new products showed that they have promising antiviral activity against hepatitis-A virus (HAV) and herpes simplex virus type-1 (HSV-1).

Synthesis and antimicrobial activity of some cyclic and acyclic nucleosides of thieno[2,3-d]pyrimidines.

The reaction of compounds 1, 2, 3, 4, or 13 with 2-chloroethyl methyl ether or 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide, afforded some acyclic and cyclic nucleosides of thieno[2,3-d]pyrimidine derivatives. Furthermore, cyclic C-nucleosides 24 and 25 were prepared from the reaction of 20, 21 or from 26, 27 with D-glucose. The antimicrobial evaluation of some prepared products showed promising antimicrobial activity.

New anti-inflammatory agents.

The pyrrole derivatives la, b and 2a, b were used as precursors for the preparation of N-substituted pyrrole derivatives 3a, b-9a, b and pyrrolo[2,3-d]pyrimidines 13-16. Also, all the newly prepared products were tested for anti-inflammatory activity as analogues to fenamates, and some of them revealed moderate anti-inflammatory activity compared to the standard drug indomethacin.

Synthesis and biological evaluation of some pyrimidine, pyrimido[2,1-b][1,3]thiazine and thiazolo[3,2-a]pyrimidine derivatives.

4,6-Diamino-1H-pyrimidine-2-thione (1) was used for the preparation of pyrimidine derivatives 2-5. Compound 5 was cyclized to produce pyrimido[2,1-b][1,3]thiazine derivative 6 which was condensed with p-chlorobenzaldehyde to give compound 7. The latter compound was reacted with hydroxylamine to give isoxazolo[4,5-d]thiazino[2,3-a]pyrimidine 8. Compound 8b was treated with 2-chloroethyl methyl ether to afford compound 9. Similarly, compound 3 reacted with chloroacetic acid to give thiazolo[3,2-a]pyrimidine 10, which was condensed with p-chlorobenzaldehyde to give compound 11. Compound 11 was condensed with hydroxylamine to give isoxazolo[4,5-d]thiazolo[2,3-a]pyrimidine 12. Compound 12b was treated with 2-chloroethyl methyl ether to afford compound 13. Biological evaluation of some prepared products showed that many of them revealed promising antimicrobial activity.

Pyrazolopyranopyrimidines as a class of anti-inflammatory agents.

Pyrazolopyranopyrimidines 6a-c and 8a-c were prepared from the reaction of compounds 4a-c or 7a-c with methylamine or ammonium hydroxide solutions. Treatment of compounds 6a-c or 8a-c with 2-chloroethyl methyl ether afforded their corresponding acyclonucleosides 9a-c or 10a-c, respectively, as a new class of acyclonucleosides. All prepared compounds were tested as anti-inflammatory agents and some of them revealed moderate to potent anti-inflammatory activity.

Synthesis and antimicrobial screening of some fused heterocyclic pyrroles.

Pyrrole derivatives 1a,b were used as precursors for the preparation of pyrrolo[2,3-d]pyrimidine derivatives 2a,b-7a,b. Also, the formation and structure of different pyrrolotriazolopyrimidine derivatives 8a,b-11a,b were discussed. Some of the prepared products showed potent antimicrobial activity.

Anticancer evaluation of some newly synthesized N-nicotinonitrile derivative.

Some novel N-nicotinonitrile derivatives 3-14 have been synthesized starting with compound 1. The key step of this work is the coupling between compound 1 and activated sugars to afford the corresponding cyclic nucleosides 3-6. Moreover, the cytotoxicity and in vitro anticancer evaluation of the prepared compounds have also been assessed against breast MCF-7 cancer, liver HepG2 cancer and lung A549 carcinoma cell lines with investigation the effect of the synthesized compounds on the expression of urokinase plasminogen activator (uPA). The results revealed that, although all the compounds showed no anticancer activity against A549 cells without showing any effect on the expression of uPA, the tested compounds exhibited remarkable cytotoxicity activity against MCF-7 and HepG2 cell lines. Among the tested compounds, compounds 11 and 12 revealed promising anticancer activity compared to the activity of the commonly used anticancer drug, doxorubicin with inhibiting the expression of uPA.

Synthesis and anticancer effects of some novel pyrazolo[3,4-d]pyrimidine derivatives by generating reactive oxygen species in human breast adenocarcinoma cells.

A series of novel substituted pyrazolo[3,4-d]pyrimidines (compounds 2-12) were synthesized starting with pyrimidinone derivative 1. Their in vitro cytotoxicity against human breast adenocarcinoma (MCF-7) cell lines has been investigated and most of the tested compounds exploited potent cytotoxic activity against MCF-7 cell lines comparable to the activity of the commonly used anticancer drug cisplatin. Treatment of MCF-7 cells with increased doses (2, 5, 10, 20 µg/ml) of the tested compounds revealed that the activity of superoxide dismutase and the level of hydrogen peroxide were significantly increased, while the activities of catalase and glutathione peroxidase and the levels of reduced glutathione were significantly lowered compared with control MCF-7 cells. In general, acyclic nucleoside derivative 4 revealed the highest anticancer activity among the other tested compounds.

Studies on the reactivity of (9-Methyl-5,6-dihydronaphtho[1â,2â:4,5]-thieno[2,3-d]pyrimidin-11-yl)hydrazine towards some reagents for biological evaluation.

(9-Methyl-5,6-dihydronaphtho[1â,2â:4,5]thieno[2,3-d]pyrimidin-11-yl)hydrazine (1) was used as a precursor for preparation of some novel 1-(9-methyl-5,6-dihydronaphtho[1â,2â:4,5]thieno[2,3-d]pyrimidin-11-yl)-1H-pyrazoles 2â7, -1H-isoindole-1,3(2H)-dione 8, and -pyridazin-3(2H)-one 9. Moreover, the acyclic C-nucleosides 10 and 11 were prepared by treating compound 1 with D-glucose. The in vitro antimicrobial activity of the tested compounds was evaluated by measuring the zone diameters and some of the prepared products showed potent antimicrobial activity in compared with those of well known drugs (standard). In general, the non-acetylated sugar hydrazone derivative 10 showed the highest antibacterial and antifungal potency among the tested compounds and standard with IZ = 22, 21 and 22 mm and MIC = 62.5 and 31.25 Îg/ml, respectively.

A facile synthesis and anti-avian influenza virus (H5N1) screening of some novel pyrazolopyrimidine nucleoside derivatives.

Treatment of 5-amino-1-(9-methyl-5,6-dihydronaphtho[1',2':4,5]thieno[2,3-d]pyrimidin-11-yl)-1H-pyrazole-4-carbonitrile (1) with formic acid afforded pyrazolo[3,4-d]pyrimidin-4-one derivative 2. The sodium salt of the latter compound (generated in situ) was treated with some alkyl halides to afford the corresponding N-substituted compounds 3-7. The siloxy derivative 8 (generated also in situ from 2) was ribosylated and glycosylated to yield compounds 9 and 11, respectively. Deprotection of compounds 9 and 11 in methanolic ammonia produced the free nucleosides 10 and 12, respectively. Moreover, the prepared compounds were tested for antiviral activity against H5N1 virus [A/chicken/Egypt/1/2006] and some of them revealed moderate results compared with the other tested compounds.

Synthesis and screening of some novel fused thiophene and thienopyrimidine derivatives for anti-avian influenza virus (H5N1) activity.

Several derivatives containing dihydronaphtho, naphtho[2,1-b]thiophene and thieno[2,3-d]pyrimidine ring systems were prepared starting from 2-amino-4,5-dihydronaphtho[2,1-b]thiophene-1-carbonitrile (1). Structure characterization of the thioxo derivative 7 was also performed and its reaction with some chloro and bromoalkyl reagents was studied. Moreover, the prepared products were tested for antiviral activity against H5N1 virus [A/chicken/Egypt/1/2006 (H5N1)] by determination of both EC50 and LD50 and confirmed by plaque reduction assay on MDCK cells. Compounds 5, 7 and 8 showed the highest effect compared with the other tested compounds.

Synthesis and in vitro antitumor activity of new substituted thiopyrimidine acyclic nucleosides and their thioglycoside analogs.

Some new thiopyrimidine acyclic nucleosides and thioglycoside derivatives 3a-c, 4a-c, 6a,b, and 7a,b were synthesized. The cytotoxicity and antitumor evaluation of all prepared compounds have been tested in vitro against Ehrlich's ascites carcinoma cell line and their activity against glutathione peroxidase and catalase were reported. The role of the prepared compounds as free radical regulators and the therapeutic antitumor effect of a balanced generation of free radicals are discussed. Compounds 2, 3b, 3c, 4a, and 4c inhibited significantly in a dose dependent manner the growth of Ehrlich ascites carcinoma cells while the other compounds did not show any antitumor activity even at higher concentrations.

Synthesis and anti-HSV-1 evaluation of some pyrazoles and fused pyrazolopyrimidines.

5-Amino-1-substituted-1H-pyrazole-4-carbonitrile derivative 1 was used as a precursor for preparation of some novel substituted pyrazole and pyrazolo[3,4-d]pyrimidine derivatives 2-10. Furthermore, the preparation of sugar hydrazone derivatives 11a,b, 12a,b and their annelated C-nucleosides 13a,b was described. Some of the prepared products revealed promising antiviral activity against herpes simplex virus type-1 (HSV-1) in comparison to Acyclovir as a control.

Synthesis and biological evaluation of some pyrrolo[2,3-d]pyrimidines.

Pyrrolo[2,3-d]pyrimidine and tetrazolopyrimidine derivatives 2a, b-5a, b were prepared. Also, acyclic and cyclic C-nucleosides 7a, b-12a, b were prepared by treating compound 6 with some aldoses. All prepared products were tested for antiviral activity against hepatitis-A virus (HAV, MBB-cell culture adapted strain) and herpes simplex virus type-1 (HSV-1). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with tested compounds. Compound 2a showed the highest effect on HAV, while compound 11b showed the highest effect on the HSV-1 virus.