Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors.

EGFR and VEGFR-2 represent promising targets for cancer treatment as they are very important in tumor development as well as in angiogenesis and metastasis. In this work, 6-amino-4-(2-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 1 and (E)-4-(2-Bromobenzylidene)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 11 were selected as starting materials to synthesize different fused pyrazole derivatives; dihydropyrano[2,3-c]pyrazole 1, 2, 7-9, and 15, pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine 3-6, pyrazolo[3,4-d]pyrimidine 12 and 13, and pyrazolo[3,4-c]pyrazole 14 derivatives were synthesized to evaluate their anticancer activity against HEPG2 human cancer cell lines compared to erlotinib and sorafenib as reference drugs. Seven compounds 1, 2, 4, 8, 11, 12, and 15 showed nearly 10 fold higher activity than erlotinib (10.6 µM) with IC50 ranging from 0.31 to 0.71 µM. In vitro EGFR and VEGFR-2 inhibitory activity were performed for the synthesized compounds, and the results identified compound 3 as the most potent EGFR inhibitor (IC50 = 0.06 µM) and compound 9 as the most potent VEGFR-2 inhibitor (IC50 = 0.22 µM). Moreover, compounds 9 and 12 revealed potent dual EGFR and VEGFR-2 inhibition, and these results were supported by docking studies of these two compounds within the active sites of both enzymes.

Efficient one-pot preparation of novel fused chromeno[2,3-d]pyrimidine and pyrano[2,3-d]pyrimidine derivatives.

Some novel chromeno[2,3-d]pyrimidinone, pyrano[2,3-d]pyrimidine, dihydropyrimidine, pyridopyranopyrimidine and pyrimidopyranopyrimidine have been synthesized. The structures of target compounds were confirmed by elemental analyses and spectral data. The antimicrobial activity of all the target synthesized compounds were tested against various microorganismst such as Pseudomonas aeruginosa; Staphylococcus aureus (Bacteria), Aspergillus flavus (Fungus) and Candida albicans (Yeast fungus) by the disc diffusion method. In general, the novel synthesized compounds showed a good antimicrobial activity against the previously mentioned microorganisms.

Design and synthesis of some new thiophene, thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents.

4-acetamide Pyrazolone 2 was synthesized by acetylation of 4-amino antipyrine 1 in excellent yield. 4-acetamide pyrazolone 2 was exploited as a starting material for the syntheses of hitherto unknown different types of new heterocyclic compounds incorporating the antipyrine moiety which expect highly biological activity against various microorganisms. Thus, Claisen condensation of 4-acetamide pyrazolone 2 with diethyl oxalate have been utility to afford new 4-oxaloacetyl antipyrine 3, which upon hydrazinolysis of the ester function to obtain the acetohydrazide derivative 18 which used as starting material to synthesize 1,2,4-triazol 19 and hydrazone 20 derivatives. 4-aminothiophene carboxylate derivatives 6, 7 were synthesized by utility of Gewald reaction. On the other hand, Michael type addition of the enolate ion of acetyl functions in acetamide pyrazolone 2 to the activated double bond in arylidenemalonoester to furnish pyrane derivative 9 was done. Finally, 4-acetamide pyrazolone 2 was treated with aromatic substituted aldehyde to exhibit thiophenacrylamide derivative 10. Compound 6 gave characteristic reaction for enaminonitriles, thus, the behavior of o-aminoester of 4-aminothiophene carboxylate derivative 6 toward electrophilic reagent, one carbon donars, amide and acid was also investigated to afford the correspondence thiophene derivatives 11,12,13,15 and 16. In addition, treatment of carboxamide derivative 16 with thionyl chloride afforded the thienothiadiazine derivative 17. The characterization of all synthesized compounds was done by elemental analysis and spectral studies. Moreover, all the synthesized compounds were tested against antimicrobial activities by the disc diffusion method, which exhibited higher promising biological activities.

Novel antitumor acetamide, pyrrole, pyrrolopyrimidine, thiocyanate, hydrazone, pyrazole, isothiocyanate and thiophene derivatives containing a biologically active pyrazole moiety.

4-Amino-N-(1-phenyl-1H-pyrazol-5-yl)-benzenesulfonamide (sulfaphenazole) 1 was selected as strategic starting material for the synthesis of some novel acetamide 2, pyrrole 4, pyrrolo[2,3-d]pyrimidine 5, thiocyanate 6, hydrazone 7a,b pyrazole 8, isothiocyanate 9 and thiophene 12 derivatives to evaluate theantitumor activity. Compound 4 was more effective than the reference drug, doxorubicin (CAS 23214-92-8) as positive control.