Identification of new potent phthalazine derivatives with VEGFR-2 and EGFR kinase inhibitory activity.

Efforts to develop new antitumor agents are now directed towards multitarget therapies that are believed to have high potency and low tendency to resistance compared to conventional drugs. Herein, we highlighted the synthesis and antitumor activity of five series of phthalazine-based compounds featuring a variety of bioactive chemical fragments at position 1 of the phthalazine nucleus. The antitumor activity of the target compounds was performed against fourteen cancer cell lines where all compounds were active in the nanomolar level. In addition, the mechanism of action of the target compounds was investigated through an enzymatic inhibitory assay against VEGFR-2 and EGFR kinases, revealing potent and preferential activity toward VEGFR-2. Binding mode of the most active compounds was studied using docking experiment.

Synthesis and molecular modeling studies of anti-inflammatory active 1H-pyrrolizine-5-carboxamides.

A variety of N-aryl-7-cyano-2,3-dihydro-1H-pyrrolizine-5-carboxamides 5, 6, 8, and 9 were synthesized via reaction of the 2-amino derivatives 4 with acid chlorides and aromatic aldehydes. Meanwhile, 4a,b were obtained through the reaction of 2-pyrrolidinylidenepropanedinitrile 1 with chloroacetanilides 2a,b. In addition, the tricyclic pyrimido[5,4-a]pyrrolizines were formed through conducting the reaction of 4a,b with 90% formic acid. Anti-inflammatory activity screening of some synthesized compounds utilizing in vivo acute carrageenan-induced paw edema standard method in rats exhibited that the prepared heterocycles possess considerable pharmacological properties especially, 4a, 4b, 10a, and 10b which reveal remarkable activities relative to diclofenac sodium (reference standard). Ulcerogenic liability of the highly promising synthesized anti-inflammatory active agents were evaluated and 4a and 4b showed ulcerogenic liability lower than that of the standard used drug. Molecular modeling studies were initiated herein in order to validate the attained pharmacological data and provide understandable evidence for the observed anti-inflammatory behavior.

Synthesis and vasodilation activity of some novel bis(3-pyridinecarbonitrile) derivatives.

A variety of bis(2-alkoxy-6-aryl-3-pyridinecarbonitriles) 4a-m were prepared via reaction of bis(2-propen-1-ones) 3a-g with malononitrile in the appropriate alcohol in the presence of KOH. The reaction was assumed to take place via Michael addition followed by cyclization due to the alkoxide nucleophilic attack at one of the nitrile groups. This assumption was substantiated by the reaction of ylidenemalononitrile 5 with the corresponding acetophenone 2 in the appropriate alcohol in the presence of KOH. The starting bis(2-propen-1-ones) 3e and f were prepared stereoselectively as E,E'-geometric isomer via condensation of bisbenzaldehyde 1 with substituted acetophenones 2e and f in ethanolic KOH solution. Vasodilating activity screening of the synthesized compounds 4a-g and 4i-m utilizing isolated rat's thoracic aorta pre-contracted by norepinephrine hydrochloride exhibited that many of the tested compounds reveal considerable vasodilating properties, especially 4e and f which reveal remarkable activities.

Regioselective synthetic approaches towards 1,2,8,9-tetraazadispiro[4.1.4.2]trideca-2,9-dien-6-ones of potential antimicrobial properties.

Reaction of 2,5-bis(arylmethylidene)cyclopentanones 1a-d with nitrilimines (generated in situ via triethylamine dehydrohalogenation of the corresponding hydrazonoyl chlorides 2a,b) in 1:2 molar ratio proceeds in a high regioselective manner affording monocycloadducts 3 and dicycloadducts in the form of two isomers 4, 5. Single crystal X-ray diffraction studies of the isolated crystalline form of 3c support the established structure and indicate that the formed product is 7E, 4S, 5R. Antimicrobial activity screening of the synthesized compounds 3-5, utilizing a variety of gram-positive (Staphylococcus aureus, Enterococcus fecalis and Streptococcus agalactiae), gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae and Proteus vulgaris) and yeast (Candida albicans), exhibited that all the prepared analogues acquire promising activities against both gram-positive and gram-negative bacteria especially compounds 3b, 4a (antimicrobial active agents against gram-positive bacteria) and 3c (antimicrobial active agent against gram-negative bacteria).

Synthesis of [1,2,4]triazolo[1,5-a]pyridines of potential PGE2 inhibitory properties.

A variety of 5-amino-6,8-dicyano-1H-[1,2,4]triazolo[1,5-a]pyridin-4-ium-2-thiolate containing compounds 3a-i, 5a-c were prepared via reaction of arylidenemalononitriles 1a-c, 4a and 4b with 2-[(substituted amino)thiocarbonyl]cyanoacetohydrazides 2a-d in refluxing ethanol in the presence of triethylamine. Anti-inflammatory activity screening of the synthesized compounds (at a dose of 50mg/kg body weight) utilizing in vivo acute carrageenan-induced paw oedema standard method in rats exhibited that the prepared heterocycles possess considerable pharmacological properties especially, 3f, 3h, 5b and 5c which reveal remarkable activities relative to indomethacin (which was used as a reference standard at a dose of 10mg/kg body weight). PGE(2) inhibitory properties of the highly promising synthesized anti-inflammatory active agents (3f, 3h, 5b and 5c) were determined by PGE(2) assay kit technique, which reveal remarkable activity coinciding greatly with the observed anti-inflammatory properties. Anti-tumor activity screening of 3b and 3e, as representative examples of the synthesized compounds, at a dose of 10 microM utilizing 59 different human tumor cell lines, representing leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate and kidney exhibited that the tested compounds reflect mild or no activity at all against most of the used human tumor cell lines. However, compound 3e reveals considerable anti-tumor properties against leukemia CCRF-CEM and HL-60(TB) cell line.

Facile synthesis of bis(4,5-dihydro-1H-pyrazole-1-carboxamides) and their thio-analogues of potential PGE(2) inhibitory properties.

A variety of bis(3-aryl-4,5-dihydro-1H-pyrazole-1-thiocarboxamides) 2a-h were prepared via reaction of bis(2-propen-1-ones) 1a-h with thiosemicarbazide in ethanolic KOH solution. Meanwhile, bis(3-aryl-4,5-dihydro-1H-pyrazole-1-carboxamides) 3a-d were obtained through reaction of 1a-d with semicarbazide hydrochloride in refluxing with acetic acid. Anti-inflammatory activity screening of the synthesized compounds 2a-f,h; 3a-d (at a dose of 50mg/kg of body weight) utilizing in vivo acute carrageenan-induced paw oedema standard method in rats exhibited that many of the tested compounds reveal considerable anti-inflammatory properties, especially 2e and f which reveal remarkable activities relative to indomethacin (which was used as a reference standard at a dose of 10mg/kg of body weight). Ulcerogenic liability for the most promising prepared anti-inflammatory active agents (2b,c,e and f) (at a dose of 50mg/kg of body weight) using indomethacin as a reference standard (at a dose of 10mg/kg of body weight) indicated that compounds 2b and c exhibit lower ulcer index values than the used reference standard itself. PGE(2) inhibitory properties of the highly promising synthesized anti-inflammatory active agents (2b,c,e and f) were determined by PGE(2) assay kit technique, which reveal remarkable activities coincide greatly with the observed anti-inflammatory properties.

Novel synthesis of nicotinamide derivatives of cytotoxic properties.

A variety of 2-substituted-4,6-diaryl-3-pyridinecarboxamides 5 were synthesized through aromatic nucleophilic substitution reaction of secondary amines with 2-bromo analogues 4. The latter were obtained via bromination of 2-cyano-3,5-diaryl-5-oxo-N-substituted pentamides 3 in glacial acetic acid. Moreover, pentamide derivatives 3 were prepared through base-catalyzed Michael addition of cyanacetanilides 2 with 1,3-diaryl-2-propen-1-ones 1. Otherwise, reaction of 2-bromo-3-pyridinecarboxamides 4 with primary aromatic amines in refluxing pyridine afforded the corresponding 2-(arylamino)-3-pyridinecarboxamides 6 besides the unexpected 2-unsubstituted amino analogues 7. Antitumor properties of the synthesized pyridinecarboxamides utilizing 59 different human tumor cell lines, representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate as well as kidney, were screened. Many of the tested compounds show considerable in vitro antitumor properties especially 5c and 7a, which reveal moderate activities against most of the used human tumor cell lines. It has also been achieved that, all the tested nicotinamide derivatives reveal promising antitumor properties against MDA-MB-231/ATCC (breast cancer).

Novel bis(1-acyl-2-pyrazolines) of potential anti-inflammatory and molluscicidal properties.

A variety of bis[3-aryl-4,5-dihydro-1H-pyrazol-1-carboxaldehydes] 4a-h were obtained via reaction of bis[1-aryl-2-propen-1-ones] 3a-h with hydrazine hydrate in refluxing formic acid. In addition, the corresponding bis[1-acetyl-3-aryl-4,5-dihydro-1H-pyrazoles] 4i-m were formed through conducting the reaction of 3 with hydrazine hydrate in refluxing acetic acid. The starting bis(2-propen-1-ones) 3a-h were prepared stereoselectively as E,E'-geometric isomer via condensation of bisbenzaldehydes 1a,b with (un)substituted acetophenones 2 in ethanolic KOH solution. Anti-inflammatory as well as ulcerogenic activities of the prepared pyrazolines were evaluated in vivo and compared with that of a standard drug (indomethacin). Many of the tested compounds show remarkable anti-inflammatory properties with an ulcerogenic liability (especially 4f, g, j, and k) lower than that of the standard used drug. Compound 4f was established to be the best effectively prepared anti-inflammatory active pyrazoline derivative and safer than indomethacin with respect to its ulcerogenic liability. Molluscicidal activity of the prepared compounds against Biomphalaria alexandrina snails (the intermediate host of Schistosoma mansoni) was screened. Where, some of the prepared compounds show considerable activities.

Novel nicotinate esters of vasodilatation activity.

A variety of 2-substituted-4, 6-diaryl-3-pyridinecarboxylates 4 were obtained through aromatic nucleophilic substitution. reaction of secondary amines with 2-bromo-3-pyridinecarboxylate derivatives 3. The latters were obtained through bromination of 3-aryl-4-benzoyl-2-cyanobutyrates 2 in glacial acetic acid. However; reaction of primary aromatic amines with 2-bromopyridines 3 afforded 2-arylamino-3-pyridinecarboxylates 5 beside the unexpected 2-amino analogues 6. On the other hand, 3-hydroxy-1H-pyrazolo[3,4-b]pyridines 7 were isolated via reaction of 3 with hydrazine hydrate. Good to complete muscle relaxation of rabbit's jejunium, rat's uterus and rabbits aorta was observed during screening representative examples (3a, 4c, Sd, 5f and 6b) of the newly synthesized 3-pyridinecarboxylates indicating the vasodilatation and antihypertension activity for the tested compounds.

New 3-pyridinecarbonitrile derivatives and their antimicrobial properties.

2-Alkoxy-4,6-diaryl-3-pyridinecarbonitriles 2a-f were prepared through the reaction of 1,3-diaryl-2-propen-1-ones 1a-c with malononitrile in the appropriate alcohol in the presence of sodium. The reaction was assumed to take place through Michael addition followed by cyclization due to the alkoxide nucleophilic attack at one of the nitrile groups. This assumption was substantiated by isolation of the open-chain Michael adduct 4, followed by independent cyclization to the corresponding 2-alkoxy-3-pyridinecarbonitriles 2 upon treatment with the appropriate alcohol in the presence of sodium. Bromination of 4a,b with bromine in glacial acetic acid, afforded directly the corresponding 2-bromo-3-pyridinecarbonitriles 6a,b. The latters readily underwent nucleophilic substitution with different amines. The antimicrobial properties of the prepared compounds against Gram positive, Gram-negative, acid-fast bacteria and yeast were screened. Many of the prepared compounds show remarkable antimicrobial activity.