Hanan M. Refaat

Synthesis and anticancer activity of some novel 2-substituted benzimidazole derivatives

In an effort to establish new candidates with improved anticancer activity, we report here the synthesis of various series of 2-substituted benzimidazoles: 2-[(4-oxothiazolidin-2-ylidene) methyl and (4-amino-2-thioxothiazol-5-yl) benzimidazoles (2 and 3, respectively); 2-[(4-fluorobenzylidene and cycloalkylidene) cyanomethyl] benzimidazoles (4 and 5, respectively), together with the synthesis of certain of 2-[(4- or 5-oxothiazolidin-2-ylidene, 4-substituted thiazolyl-2-ylidene and [1,3]thiazin-2-ylidene)cyanomethyl]benzimidazoles (6, 8, 7 and 9, respectively). Several of the synthesized products were subjected to in vitro anticancer screening that revealed that all the tested compounds exhibited antitumor activity against human hepatocellular carcinoma (HEPG2), human breast adenocarcinoma (MCF7) and human colon carcinoma (HCT 116) cell lines, with IC50s<10 microg/ml.

Synthesis and antimicrobial activity of certain novel quinoxalines

In this study, certain 3-methyl-2-[4-(substituted amino carbonyl)anilino] quinoxalines, (2a-d) and (3a-d), were synthesized from the new key compound 2-[4-(ethoxycarbonyl)anilino]-3-methyl quinoxaline (1). In addition, a series of 2-[4-(arylidene hydrazinocarbonyl)anilino]-3-methyl quinoxalines (5a-e), as well as their cyclized oxadiazolinyl derivatives (6a-e), and a series of 2-[4-N-acylhydrazinocarbonyl anilino]-3-methyl quinoxalines (7a-d), as well as their cyclized oxadiazoiyl derivatives (8a-d) were also prepared. Some of these derivatives were evaluated for antimicrobial activityin vitro. It was found that all the selected compounds exhibit antimicrobial activity and that compound5b had a broad spectrum of activity.

Synthesis and anti-inflammatory activity of certain piperazinylthienylpyridazine derivatives.

In this study, a novel series of 2-(4-substituted piperazin-l-ylmethyl)-6-(thien-2-yl)-2H-pyridazin-3-ones(3a- f), 2-(4-substituted piperazin-l-yl carbonylmethyl)-6-(thien-2-yl)-2H-pyridazin-3-ones(4a- c) and 2-[2-(4-substituted piperazin-l-ylcarbonylethyl)]-6-(thien-2-yl)-2H-pyridazin-3-ones(5a,b) were prepared from 6-(thien-2-yl)-2H- pyridazin-3-one(1). In addition, 3-(4-substituted piperazin-l-ylcarbonyl methyl thio)-6-(thien-2-yl) pyridazines(6a- c) and 3-[2-(4-substitutedpiperazin-l-ylcarbonyl ethylthio]-6-(thien-2-yl) pyridazines(7a,b) were synthesized. Furthermore, 5-(4-substituted piperazin-l-ylmethyl)-6-(thien-2-yl)-2H-pyridazin-3-ones(12a,b) were prepared. The structures of the new compounds were confirmed by elemental analysis as well as by1H-NMR,IR andMS data. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity against carrageenan-induced paw edema at a dose of 10 mg/kg using indomethacin as the reference standard.

Anticancer and radiosensitizing evaluation of some new pyranothiazole-Schiff bases bearing the biologically active sulfonamide moiety.

The present work reports the synthesis of some new Schiff bases, 5-(substituted benzylideneamino)-6-cyano-7H-7-(4-methoxyphenyl)-2-(4-sulphamoylphenylamino) pyrano[2,3-d]thiazole (5-15). The design of the structures of these compounds complies with the general pharmacophoric requirements for CA inhibiting anticancer drugs. The newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Most of the screened compounds showed interesting cytotoxic activities compared to doxorubicin as a reference drug. Compounds 4, 6-8 and 11 (IC(50): 27.51, 10.25, 9.55, 9.39 and 9.70 μM, respectively) exhibited higher cytotoxic activities than the reference drug doxorubicin (IC(50): 32.00 μM). Additionally, the previously mentioned compounds were evaluated again for their ability to enhance the cell killing effect of γ-radiation.

Synthesis, anticancer activity and effects on cell cycle profile and apoptosis of novel thieno[2,3-d]pyrimidine and thieno[3,2-e] triazolo[4,3-c]pyrimidine derivatives

Motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines a series of 24 new 2-substitutedhexahydrocycloocta[4,5] thieno[2,3-d]pyrimidines with different substituents at C-4 position and hexahydrocycloocta[4,5]thieno[3,2-e]-1,2,4-triazolo[4,3-c]pyrimidines were synthesized. The anticancer activity of 17 compounds were evaluated by National Cancer Institute (USA) using a two stage process utilizing 59 different human tumor cell lines representing leukemia, melanoma, cancers of lung, colon, central nervous system (CNS), ovary, kidney, prostate as well as breast. Compound 9c showed broad spectrum potent anticancer activity in nano molar to micro molar range against 56 human tumor cell lines with GI50 less than 10 μM ranging from 0.495 to 5.57 μM, also it is worth mentioning that compound 9c had the marked highest selectivity against the two cell lines T-47D and MDA-MB-468 belonging to breast cancer with GI50 = 0.495 and 0.568 μM respectively, and its effect was further studied on cell cycle progression and induction of apoptosis in the MDA-MB-468 cell line. Results showed that compound 9c induced cell cycle arrest at G2/M phase and also, showed accumulation of cells in pre-G1 phase which may result from, degradation or fragmentation of the genetic materials indicating a possible role of apoptosis in compound 9c-induced cancer cell death and cytotoxicity and verifying this compound as promising selective anticancer lead. Compound 6c was selective against K-562, SR and MOLT-4 cell lines belonging to leukemia showing growth inhibition percentages 86.38, 65.76 and 60.40 at a single dose test, at the same time it showed lethal activity against HOP-92 representing non-small cell lung cancer. Interestingly, leukemia SR, CNS cancer SNB-75 and renal cancer UO-31 cell lines proved to be sensitive to compound 6d with growth inhibition percentages 52.86, 50.94 and 53.99 respectively. Additionally, compound 6d demonstrated lethal activity to HOP-92 belonging non-small cell lung cancer.

Synthesis of potent anticancer thieno[2,3- d ]pyrimidine derivatives

As part of our program to identify novel cytotoxic agents, various series of hexahydrocycloocta[4,5]thieno[2,3-d] pyrimidines and pyrimidin-4-ones substituted by aryl at the C-2 position together with phenylethylamino, substituted amino, hydrazinyl or arylidenhydrazinyl substituents at the C-4 position were synthesised. These compounds were prepared as bioisosteres of gefitinib, an antitumour drug used for the treatment of gastrointestinal stromal tumours. All compounds exhibited antitumour activity against (HCT 116) cell line in vitro. Eight compounds (IC50: 3.89, 4.65, 6.63, 6.94, 7.89, 9.53, 12.00 and 12.30 μg mL−1 respectively) exhibited 4.3 to 1.3 fold more potent antitumour activity than imatinib (IC50: 16.93 μg mL−1). Also, a docking study of the newly synthesised compounds with the active site of CDK2 was described.

Synthesis of novel pyridazinyl benzimidazole, benzothiazole and benzoxazole of expected anti-inflammatory activity

In this study, a novel series of 6-oxopyridazinyl benzazoles and 3, 6-dioxopyridazinyl benzazoles were prepared from the starting compounds, 2-hydrazinobenzimidazole, 2-hydrazinobenzothiazole and 2-hydrazinobenzoxazole by reaction with butyric acid derivatives and cyclic anhydrides respectively. The structures of the new compounds were confirmed by elemental analysis as well as 1H NMR, IR and MS data. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity using carrageenan induced paw edema at dose 100 mg kg−1 using indomethacin as a reference standard and were found to be bioactive.

Application of resin-bound reagents for the synthesis of benzimidazole derivatives

In an efficient exploitation of solid-phase chemistry, this work describes the preparation of the new resin-bound 4-(N-arylamino)-3-aminobenzoates and their successful cyclocondensations with the sodium bisulfite adducts of different aldehydes and triethyl orthoformate or triethyl orthoacetate, followed by resin cleavage to produce the target 1,2-diaryl- and 1-aryl-2-(un)substituted benzimidazole-5-carboxylic acid derivatives, respectively. In another variation, the cyclocondensation of the resin-bound 4-(N-arylamino)-3-aminobenzoates with carbon disulfide afforded the corresponding resin-bound thioxobenzimidazoles, which upon cleavage gave the corresponding 2-thioxobenzimidazoles. S-Alkylation of the resin-bound thioxobenzimidazoles with benzyl chloride and 4-bromophenacyl bromide furnished 2-benzylsulfanyl benzimidazoles and 4-bromophenyl-2-oxoethylsulfanyl-benzimidazoles, respectively. Reacting the resin-bound 4-(N-arylamino)-3-aminobenzoates with phenyl isothiocyanate gave the open-form 4-(arylamino)-3-(3-phenylthioureido) benzoic acids. Moreover, the reaction of the resin-bound 4-(N-arylamino)-3-aminobenzoates with N,N-carbonyldiimidazole yielded the corresponding 2-bezimidazolones.