Ismail A. Abdelhamid

ENAMINES AS PRECURSORS TO POLYFUNCTIONAL HETEROAROMATIC COMPOUNDS; A DECADE OF DEVELOPMENT

Recent synthesis and utilization of enamines as precursors for heterocyclic and carbocyclic compounds are reviewed. Two general synthetic routes for preparation of enamines based on condensation and addition reactions. Enamines and azaenamines can be used as building blocks for carbocyclic, five-and six-membered heterocyclic as well as fused heterocyclic compounds.

Chapter 1 Recent Developments in Pyridazine and Condensed Pyridazine Synthesis

Publisher Summary This chapter discusses recent developments in pyridazine and condensed pyridazine synthesis. Today, the pyridazine nucleus and its 3-oxo derivatives have been recognized as versatile pharmacophores. This key subunit is constituted in many biologically active substances with a broad range of biological and pharmaceutical activities including inhibitors of PED III, IV, a 1 - and a 2 - adrenoceptors, antibacterial and antifungal activities, 5-lipoxygenase inhibitors and inhibitors of interleukin, b-production. This chapter surveys recent reported synthetic approaches to pyridazines and highlights new methodologies. It discusses synthesis of pyridazine by two bond formation (via 3+3 atom and 4+2 atom), by combining alkylpyridazinylcarbonitrile with a,b-unsaturated nitriles, and by coupling aromatic diazonium salts with carbon nucleophilic 4 atom fragments. It also discusses the synthesis of condensed pyridazine via one bond formation (5+1 combination) and by utilizing functionally substituted arylhydrazones precursors via one bond formation.

Cytotoxic and Antimicrobial Evaluations of Novel Apoptotic and Anti‐Angiogenic Spiro Cyclic 2‐Oxindole Derivatives of 2‐Amino‐tetrahydroquinolin‐5‐one

A novel series of cyclic 2‐oxindole derivatives incorporating 2‐amino‐tetrahydroquinolin‐5‐one were prepared. The structures of the prepared compounds were elucidated using different spectral tools. The regio‐orientation of the reaction products was elucidated through NOE difference experiments and through using substituents on the ortho position to affect further cyclization. Antitumor and antimicrobial evaluations were performed on the prepared compounds. Most of these compounds exhibited high to moderate antimicrobial activity. With respect to the antitumor activity, the compounds showed more potent cytotoxic effect only toward the human breast cancer cell line MCF‐7. Also, we found that derivatives containing an ester group (8c, 11b, 14b, and 15b) are more active than those containing a cyanide group (8a, 11a, 14a, and 15a). Moreover, compounds 15b and 8b are the most active derivatives in this group. These two compounds showed apoptotic inhibition of the proliferation of human breast adenocarcinoma MCF‐7 cells through DNA fragmentation, induction of the tumor suppressor protein p53, induction of caspase‐9, and finally the inhibition of angiogenesis by decreasing vascular endothelial growth factor expression and secretion.

Chalcones incorporated pyrazole ring inhibit proliferation, cell cycle progression, angiogenesis and induce apoptosis of MCF7 cell line.

A Series of chalcone derivatives containing pyrazole ring was prepared and their cytotoxicity against different human cell lines, including breast (MCF-7), colon (HCT-116) liver (HEPG2) cell lines, as well as normal melanocyte HFB4 was evaluated. Two of these chalcone derivatives with different IC50 and chemical configuration were chosen for molecular studies in detail with MCF-7 cells. Our data indicated that the two compounds prohibit proliferation, angiogenesis, cell cycle progression and induce apoptosis of breast cancer cells. This inhibition is mediated by up regulation of tumor suppressor p53 associated with arrest in S-G2/M of cell cycle. This work provides a confirmation of antitumor activity of the novel chalcones and assists the development of new agents for cancer treatment.

An easy synthesis of 5-functionally substituted ethyl 4-amino-1-aryl- pyrazolo-3-carboxylates: interesting precursors to sildenafil analogues

3-Oxo-2-arylhydrazononitriles 1a-c react readily with chloroacetonitrile, ethyl chloroacetate, and with phenacyl chloride to give 4-aminopyrazoles 4a-e. The pyrazolo[4,3-d]pyrimidine derivatives 7 and 10 are synthesized via reaction of the aminopyrazole 4b with phenylisothiocyanate and DMFDMA/NH4OAc respectively.

Synthesis, characterization and antitumor activity of novel tetrapodal 1,4-dihydropyridines: p53 induction, cell cycle arrest and low damage effect on normal cells induced by genotoxic factor H2O2

Synthesis of novel tetrakis(2,6-dimethyl-4-phenyl-1,4-dihydropyridinyl)methanes 5a–d by acid-catalyzed condensation of the tetrakis-aldehydes 6a–d with eight equivalents of 3-aminobut-2-enenitrile 2 is reported. The structures of 5a–d are confirmed by different spectral tools. In vitro, cytotoxic screening assay for novel tetrapodal 1,4-dihydropyridines (5a–d) was performed on five different human cell lines (HCT116, A549, MCF7, PC3, and HEPG2). The compounds showed higher cytotoxic activity against (A549, HCT116, and MCF7) cell lines. The loss of the cytotoxic activity was observed in the case of PC3 and HEPG2 cell lines. Compound 5b showed the highest cytotoxic activity against the three lines (A549, HCT116, and MCF7). In an attempt to know the mechanism followed by the compounds to inhibit cell proliferation, compound 5b was chosen for molecular studies. Compound 5b induced apoptotic inhibition of the proliferation of human colon adenocarcinoma HCT116 cells through induction of the tumor suppressor protein p53, BAX, and through the inhibition of anti-apoptotic proteins by decreasing BCL2 gene expression using real-time PCR. Regarding cell cycle analysis, compound 5b induced G1 arrest against the three lines (MCF7, HCT116, and A549). Compound 5b has been found to reduce apoptosis of human normal melanocytes HFB4 and normal fibroblasts BHK that has been treated with genotoxic factor H2O2. Moreover, compound 5b has a potent protective effect against DNA damage, as indicated by the in vitro studying of different concentrations of 5b against two different types of healthy DNA (calf-thymus DNA and pBR322 DNA).

Molecular docking simulation and anticancer assessment on human breast carcinoma cell line using novel bis(1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile) and bis(1,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-b]pyridine-6-carbonitrile) derivatives.

An efficient route for the synthesis of novel bis(1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile) derivatives is reported. The synthetic pathway involves one pot, synthesis of bis-aldehydes, malononitrile, and pyrazolone in the presence of pyridine. The anticancer activity of the synthesized products against MCF7, HEPG2, and A549 cell lines was assessed. Docking studies were performed and indicated the best binding mode compared to the standard ligand sorafenib.

Regioselective synthesis and theoretical studies of novel bis(tetrahydro[1,2,4]triazolo[5,1- b ]quinazolin-8(4 H )-ones) catalyzed by ZnO nanoparticles

A novel series of bis(tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-ones) were prepared in a regioselective manner via a three component reaction of bis-aldehydes with 5-amino-1,2,4-triazole and dimedone under microwave irradiation as well as under conventional heating. The reactions were carried out in the absence as well as in the presence of ZnO nanoparticles as a heterogeneous catalyst. Best results were achieved when these reactions were carried out under MW heating. The presence of ZnO nanoparticles was found to improve the yields of the reactions but did not change the regioselectivity the products. The reaction mechanism and the unambiguous structural elucidation of the expected regioisomers were studied using DFT calculations as well as 2D-HMBC spectroscopy.Graphical abstract

1,ω-Bis(formylphenoxy)alkane: versatile precursors for novel bis-dihydropyridine derivatives

Reaction of β-aminocrotonitrile with a series of bis(aldehydes) containing ether linkages afforded the corresponding bis(2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile) derivatives in good to moderate yield. Oxidative aromatization of the latter compounds into the corresponding bis(2,6-dimethylpyridine-3,5-dicarbonitrile) derivatives was achieved using ceric ammonium nitrate (CAN).Graphical abstract

Synthesis and Antimicrobial Evaluations of Novel Spiro Cyclic 2-Oxindole Derivatives of N-(1H-Pyrazol-5-Yl)-Hexahydroquinoline Derivatives

A novel series of interesting spiro cyclic 2-oxindole derivatives of N-(1H-pyrazol-5-yl)hexahydroquinoline derivatives were prepared via the versatile readily accessible cyclic β-enaminones incorporating pyrazole. Antimicrobial evaluations were performed on the prepared compounds. Most of these compounds exhibited high to moderate antimicrobial activity.