Magda M. F. Ismail

Synthesis and Antimicrobial Activities of Some Novel Quinoxalinone Derivatives

Department of Chemistry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, EgyptFax: 002(088)325436, E-mail: m_elgaby@hotmail.comReceived: 29 April 2000 / Accepted: 13 June 2000 / Published: 18 June 2000Abstract: Condensation of 4-benzoyl-1,2-phenylenediamine with sodium pyruvate in aceticacid furnished two products which were identified as 6-benzoyl and 7-benzoyl-3-methyl-2(1H)quinoxalinones ( 1a ,b ). Fusion of 1a with aromatic aldehydes furnished the styryl de-rivatives 2a -c. Alkylation of 1a ,b with dimethyl sulphate or ethyl chloroacetate produced theN-alkyl derivatives 3a ,b and 4a ,b . Hydrazinolysis of the ester derivative 4a with hydrazinehydrate afforded the hydrazide derivative 5 which underwent condensation with aldehydes togive the corresponding hydrazone derivatives 6a ,b . In addition, chlorination of 1a withthionyl chloride afforded the 2-chloro derivative 7 which was subjected to reaction with s o-dium azide and n-butylamine to yield the corresponding tetrazolo (8) and n-butylamino (9)derivatives, respectively. The structures of the compounds prepared were confirmed by an a-lytical and spectral data. Also, some of the synthesized compounds were screened for antim i-crobial activity.Keywords: Quinoxalinones, 4-benzoyl-1,2-phenylenediamine, antimicrobial activity.

A novel synthesis of dibenzo[c, f]chromenes, dibenzo[c, h]chromenes and benzo[7,8]chromeno[3,4-f]isoindoles as antimicrobial agents

Naphtho[2,1-b]pyranone (3) was allowed to react with arylmethylenemalononitriles to yield 4-amino-5-oxo-2-aryl-5H-dibenzo[c,f]chromene-3-carbonitriles (4a,b); with ethyl 3,4-dichlorobenzylidene cyanoacetate to furnish dibenzo[c,f]chromene (5) and with elemental sulfur in dioxane containing piperidine to give thieno[3,4-d]naphtho[2,1-b]pyranone (6). Similarly, naphtho[1,2-b]pyranone (7) was reacted with arylmethylenemalononitriles and elemental sulfur to furnish dibenzo[c,h]chromenes (8) and thieno[3,4-d]naphtho[1,2-b]pyranone (10), respectively. Compound 10 underwent cycloaddition with N-arylmaleimides to yield benzo[7,8]chromeno[3,4-f]isoindoles (11a-c). Some of these compounds were screened in vitro for their antimicrobial activities.

New quinoxaline 1, 4-di-N-oxides: Anticancer and hypoxia-selective therapeutic agents

A new series of quinoxaline 1,4-di-N-oxides was synthesized and evaluated for antitumor and hypoxic-selective cytotoxic activities. Antitumor activity against liver carcinoma (Hepg2) and brain tumor (U251) human cell lines were evaluated, among the tested compounds, 5b and 9b exhibited potential cytotoxic effect against Hepg2 with IC50 values of 0.77 and 0.50 microg/mL respectively, whereas, all the tested compounds lack antitumor activity against U251 human cell line. Moreover, compound 4 was the most potent hypoxia selective-cytotoxin on EAC cell line; IC50 2.5 microg/mL, potency 22 microg/mL, and was approximately 5.4-times more selective cytotoxin (HCR>40) than 3-amino-2-quinoxalinecarbonitrile1,4-dioxide (standard, HCR>7.4). Compounds 8b and 9b were more selective than the standard.

Biological Validation of Novel Polysubstituted Pyrazole Candidates with in Vitro Anticancer Activities

With the aim of developing novel antitumor scaffolds, a novel series of polysubstituted pyrazole derivatives linked to different nitrogenous heterocyclic ring systems at the C-4 position were synthesized through different chemical reactions and characterized by means of spectral and elemental analyses and their antiproliferative activity against 60 different human tumor cell lines was validated by the U.S. National Cancer Institute using a two stage process. The in vitro anticancer evaluation revealed that compound 9 showed increased potency toward most human tumor cell lines with GI50MG-MID = 3.59 µM, as compared to the standard drug sorafenib (GI50 MG-MID = 1.90 µM). At the same time, compounds 6a and 7 were selective against the HOP-92 cell line of non-small cell lung cancer with GI50 1.65 and 1.61 µM, respectively.

Synthesis and biological evaluation of novel imidazolone derivatives as potential COX-2 inhibitors

Three novel series of 2-(substituted phenyl)-4-(substituted arylidene)-imidazolone-5-(4H)-ones were derived from the corresponding oxazolones by condensation with different arylamines. Eleven of the synthesized compounds were selected and evaluated for their effect on carrageenan-induced rat paw edema. Compound 4b had the same efficacy as the reference standard (indomethacin), and compounds 3b, 3c, 4a, 4d and 9a showed good to excellent activities, with other compounds only weakly active. The potent compounds were evaluated for their inhibitory activities against COX-2-catalyzed PGE2 production, with 4a, 4b and 3c showing strong inhibitory activity.

Synthesis and docking studies of novel benzopyran-2-ones with anticancer activity

Novel series of 7-substituted-benzopyran-2-ones was synthesized by incorporating heterocyclic rings as oxadiazole, triazole, pyrazole or pyrazolin-5-one to benzopyran-2-one nucleus at p-7 via methylene-oxy or acetoxy linker. In-vitro anticancer activity was evaluated for these hybrids; twelve compounds were selected by National Cancer Institute for anticancer screening. Among them, compound 9a exhibited broad spectrum antitumor activity showing full panel median growth inhibition (GI(50)) = 5.46 microM. According to docking results using Molsoft ICM 3.4-8c program, the target compounds may act through inhibition of topoismerase 1, where camptothecin is used as ligand.

Novel Pirfenidone Analogs as Antifibrotic Agents: Synthesis and Antifibrotic Evaluation of 2-Pyridones and Fused Pyridones

A new series of substituted 1-(2-ethylphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles have been synthesized. Moreover, substituted bicyclic derivatives e.g. thieno[3,4-c]pyridone, pyrido[3,4-c]pyridone, benzo[c]pyridone, and tricyclic derivatives, chromeno[3,4-c]pyridones have been prepared and evaluated for their antifibrotic activity. Among the tested compounds, compounds 4d and 5a exhibited potent antifibrotic activity without harmful side effects on liver and kidney functions. Detailed synthesis, spectroscopic and biological data are reported.