Rania B. Bakr

Synthesis and anticancer activity of some new pyrazolo[3,4-d]pyrimidin-4-one derivatives.

3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-d][1,3]oxazin-4-one (3) was prepared by hydrolysis of ethyl 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (1) to afford the corresponding carboxylic acid 2, which was reacted with acetic anhydride to give 3. The pyrazolo[3,4-d][1,3]oxazin-4-one 3 was reacted with hydroxylamine hydrochloride, urea, thiourea, thiosemicarbazide, phenylhydrazine and aromatic amines to afford the corresponding pyrazolo[3,4-d]pyrimidin-4-ones 4, 5a,b, 6, 7, 8a–e, respectively. Condensation of pyrazoloxazine derivative 3 with 99% hydrazine hydrate afforded the 5-aminopyrazolo[3,4-d]pyrimidine derivative 9. Coupling of 9 with aromatic aldehydes yielded a series of 3,6-dimethyl-5-(4-substitutedbenzylideneamino)-1-phenyl-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-ones 10a–e. The new compounds were tested for their antitumor activity on the MCF-7 human breast adenocarcinoma cell line. Almost all the tested compounds revealed antitumor activity, especially 3,6-dimethyl-5-(4-nitrobenzylideneamino)-1-phenyl-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (10e) which displayed the most potent inhibitory activity with a half maximal inhibitory concentration (IC50) of 11 µM.

Design, synthesis and antitumor activity of novel pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors.

A novel series of 2-(3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(4-substitutedbenzylidene)acetohydrazide (12a-g) was prepared and their structures were confirmed by spectral and elemental analyses. The cytotoxic activity of the newly synthesized compounds was evaluated against breast carcinoma (MCF-7), non-small cell lung cancer (A549) and human colorectal adenocarcinoma (HT-29) cell lines using MTT and colony formation assays. The tested compounds showed a marked anticancer activity against all the tested cell lines, especially compound 12g, which was the most potent anticancer agent with half maximal inhibitory concentrations (IC50) between 5.36 and 9.09μM. Docking studies into ATP binding site of EGFR protein tyrosine kinase were performed to predict their scores and mode of binding to amino acids, In addition, the inhibitory activity of the target compounds against epidermal growth factor receptor tyrosine kinase (EGFR-TK) was evaluated. Results indicated the ability of the target compounds to inhibit EGFR-TK with half maximal inhibitory concentrations (IC50) in the range of 4.18-35.88μM. Furthermore, The most active compounds 12g, 12c and 12d were assayed against Fibroblast Growth Factor Receptor (FGFR), Insulin Receptor (IR) and Vascular Endothelial Growth Factor Receptor (VEGFR). The activity of the reported compounds warrants further optimization as novel members in cancer treatment protocols.

Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of new 1-phenylpyrazolo[3,4-d]pyrimidine derivatives

Abstract A new group of 1-phenylpyrazolo[3,4-d]pyrimidine derivatives 14a–d–21 were synthesized from 2-(6-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)acetohydrazide (12). All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity and ulcerogenic liability. All the target compounds were more potential in inhibiting COX-2 than COX-1. Compounds having pyrazolyl moiety in a hybrid structure with pyrazolo[3,4-d]pyrimidine scaffold (14a–d, 16 and 17) showed higher edema inhibition percentage activities (34–68%) and the 5-aminopyrazole derivative (14c, ED50 = 87.9 μmol/kg) was the most potent one > celecoxib (ED50 = 91.9 μmol/kg). While, the in vivo potent compounds (14a–d, 16, 17 and 21) caused variable ulceration effect (ulcer index = 0.33–4.0) comparable to that of celecoxib (ulcer index = 0.33), the pyrazol-3-one derivative (16) and the acetohydrazide (21) were the least ulcerogenic derivatives showing the same ulcerogenic potential of celecoxib.

Nitric oxide-NASIDS donor prodrugs as hybrid safe anti-inflammatory agents.

Selective inhibition of cyclooxygenase-2 (COX-2) isozyme afforded a useful drug design concept that resulted in the development of effective anti-inflammatory drugs that are devoid of adverse side effects, in particular gastrointestinal irritation, ulcerogenicity and renal toxicity attributed to inhibition of the cytoprotective cyclooxygenase-1 (COX-1) isozyme. Unfortunately, some selective COX-2 inhibitory drugs such as rofecoxib and valdecoxib are believed to be responsible for cardiovascular complications. Nitric oxide (NO) is an effective vasodilator that also inhibits platelet aggregation. Therefore hybrid NSAIDs containing NO-donor moieties have been developed to obtain effective treatment of inflammation with reduced GI and cardiovascular side effects. Here we review some of the most promising recent advances in NO-NAISDs donor drug development and summarizes medicinal chemistry efforts in search for new NO-NSAIDs prodrugs in an attempt to pave the way for further development in this promising area of research.

Design, synthesis and biological evaluation of some novel benzothiazole/benzoxazole and/or benzimidazole derivatives incorporating a pyrazole scaffold as antiproliferative agents

In an aim at developing new antiproliferative agents, new series of benzothiazole/benzoxazole and/or benzimidazole substituted pyrazole derivatives 11a-c, 12a-c and 13a-c were prepared and evaluated for their antiproliferative activity against breast carcinoma (MCF-7) and non-small cell lung cancer (A549) cell lines. The target compound, 2-acetyl-4-[(3-(1H-benzimidazol-2-yl)-phenyl]-hydrazono-5-methyl-2,4-dihydropyrazol-3-one (12a) was the most active compound against both MCF-7 and A549 cell lines with half maximal inhibitory concentrations (IC50)=6.42 and 8.46μM, respectively. Furthermore, the inhibitory activity of the all the target compounds against COX enzymes was recorded as a proposed mechanism for their antiproliferative activity. The obtained results revealed that the benzothiazolopyrazolone derivative 13c was the most potent COX-2 inhibitor (IC50=0.10μM), while the 5-acetylbenzimidazolylpyrazolone derivative 12a was the most COX-2 selective (S.I.=104.67) in comparison with celecoxib (COX-2 IC50=1.11μM, S.I.=13.33). Docking simulation on the most active compounds 12a and 13c had been performed to investigate the binding interaction of these active compounds within the binding site of COX-2 enzyme.Collectively, this work demonstrated the promising activity of the newly designed compounds as leads for further development into antiproliferative agents.

New advances in synthesis and clinical aspects of pyrazolo[3,4-d]pyrimidine scaffolds

Pyrazolo[3,4-d]pyrimidine ring system constitute an important class of heterocyclic compounds which can serve as a promising scaffold exhibiting many pharmacological activities. This ring system received much attention as it is a purine isostere by replacing imidazole ring in purine with pyrazole moiety in pyrazolo[3,4-d]pyrimidine. Here we concentrate on new advances in the synthesis of this important ring and other clinical aspects in an attempt to sheld the light to assist in discovery of new pyrazolo[3,4-d]pyrimidine derivatives.

Synthesis, EGFR Inhibition and Anti-cancer Activity of New 3,6-dimethyl-1-phenyl- 4-(substituted-methoxy)pyrazolo[3,4-d]pyrimidine Derivatives

as EGFR inhibitors, mammalian target of rapamycin (mTOR) inhibitors, Src or dual Src/Abl inhibitors, glycogen synthase kinase-3b (GSK-3b) inhibitors or cyclin dependent kinase (CDK) inhibitors. OBJECTIVE A new series of hybrid pyrazolo[3,4-d]pyrimidine scaffold with a heteroaryl moiety as pyrazole, oxadiazole, triazole or phthalimide moiety (14a-f, 16, 17, 19, 20) was synthesized and biologically evaluated for the cytotoxicity against human liver cancer cell line (HEPG-2), human breast cancer cell line (MCF-7) and human colon cancer cell line (HCT-116). Results and Method: While the pyrazolo hybrid compounds (14a-f) showed good activity against HEPG-2, MCF- 7 and HCT-116 cell lines (IC50 = 3.65 - 39.98, 1.45 - 54.19 and 2.00 - 50.6 µM respectively) in comparison with doxorubicin (IC50 = 5.66, 2.60 and 8.48 µM respectively), the triazolo derivatives (17, 19) showed considerable potency (IC50 = 22.20 - 54.61, 14.98 - 88.78, and 10.79 - 53.40 µM respectively), the oxadiazolo hybrid compound (16, IC50 = 149.91, 115.89 and 110.07 µM respectively) and phthalimido hybrid compound (20, IC50 = 96.02, 131.19 and 120.36 µM respectively) showed low potency. The pyrazolo derivative (14d, IC50 = 3.65, 1.45 and 2.00 µM) was the most potent among all compounds against HEPG-2, MCF-7 and HCT-116 cell lines respectively. Also, the hybrid pyrazolo[3,4-d]pyrimidine derivatives were evaluated for their inhibitory activity to epidermal growth factor receptor tyrosine kinase (EGFR-TK) and they showed a good inhibitory activity (IC50 = 8.27 - 19.03 µM). With the exception of the pyrazolo derivative (14c, IC50 = 18.82 µM), the inhibitory activity against EGFR-TK was consistent with the in vitro cytotoxic activity against HEPG-2, MCF-7 and HCT-116 cell lines. CONCLUSION The newly synthesized compounds showed good activity against HEPG-2, MCF-7 and HCT-116 cell lines in comparison with the reference drug doxorubicin.

Synthesis and studies molecular docking of some new thioxobenzo[g]pteridine derivatives and 1,4-dihydroquinoxaline derivatives with glycosidic moiety

ABSTRACT The present work is mainly dedicated to heterocyclic compounds as well as S-glycoside. 1,4-dihydroquinoxaline derivatives 3 were obtained from the reaction 2 with carbon disulfide in presence of potassium hydroxide. S-glycoside 4 was prepared from the reaction of compound 3 with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide. Several heterocyclic derivatives containing thioxobenzo[g]pteridine ring systems were obtained starting from ethyl 3-amino-1,4-dihydroquinoxaline-2-carboxylate 1. These newly synthesized compounds were docked within the active site of cyclooxygenase-2 (COX-2). The results of this docking study revealed that the new compounds might exhibit good anti-inflammatory activity. The structure of new compounds was demonstrated by elemental analysis, IR, 1H NMR spectra and mass spectra.