Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 68 No. 4 pp. 519ñ534, 2011 ISSN 0001-6837 Polish Pharmaceutical Society Benzimidazole derivatives are very useful intermediates/subunits for the development of mole- cules of pharmaceutical or biological interest. Substituted benzimidazole derivatives have found applications in diverse therapeutical areas including antimicrobial (1ñ3), antioxidant (4), antiviral (5, 6), antihypertensive (7), antiprotozoal (8), anti-inflam- matory (9) and molluscicidal (10) agents. Furtheremore, benzimidazoles showed anticancer activity against DNA topoisomerase I (11, 12) and colon cancer cell lines (13). The need for anticancer agents that selectively kill or inhibit the growth of neoplastic cells without affecting non-cancerous host tissues is high and persistent. Thus, the aim of the current study was the synthesis of novel benzim- idazole derivatives that incorporated different hete- rocycles of anticancer activity, such as different compounds with the backbone of chalcones and acethydrazides, which have been found to exhibit potent cytotoxic activity against the growth of sus- pended leukemia (14) and lymphomas (15). They were also active in a number of solid tumor screens, e.g., HELA uterine carcinoma, PC12, SOS bone osteosarcoma, lung MB9812, lung A549 and Mcf-7 breast growth (16ñ18) Also, it was of interest to prepare benzimida- zole N-glycoside Schiffís bases skeleton as bioisos- teric of naturally occurring molecules, hopping to produce anticancer agents (19) of high potency and selectivity. In this study some newly synthesized benzimidazole compounds 2c, 2e, 4b, 5a, 9, 12, 14, 15a, 15b, 21a, 21b, 21d, 21f, 21g, 21h and 22h were evaluated as anticancer agents in HEPG2 (human liver carcinoma cell line) and PC12 (pheochromocy- toma of the rat adrenal medulla) cells. EXPERIMENTAL All melting points are uncorrected and were taken in open capillary tubes using silicone oil on Gallenkamp apparatus. Elemental microanalyses were performed at Cairo University, Egypt. The IR spectra were recorded on FT/IR-330E, Fourier trans- form, Infrared spectrometer at cm -1 scale using KBr NOVEL BENZIMIDAZOLE DERIVATIVES AS EXPECTED ANTICANCER AGENTS ZIENAB M. NOFAL 1 *, ELSYED A. SOLIMAN 2 , SOMAIA S. ABD EL-KARIM 1 , MAGDY I. EL- ZAHAR 1 , ALADDIN M. SROUR 1 , SHALINI SETHUMADHAVAN 3 and TIMOTHY J. MAHER 3 1 Therapeutical Chemistry Department, National Research Centre, Dokki, Cairo, Egypt 2 Chemistry Department, Faculty of Science, Ain Shams University, El Abbassia, Cairo, Egypt 3 Massachusetts College of Pharmacy and Health Sciences, Boston, USA Abstract: A series of 1-(1H-benzimidazol-2-yl)-3-(substituted)-2-propen-1-one and its 1-methyl analogues 2c- h were synthesized and cyclized with different reagents such as ethyl cyanoacetate, thiourea, hydroxylamine hydrochloride, guanidinium sulfate, methylhydrazine, phenylhydrazine and/or hydrogen peroxide in different reactions to produce pyridones 3a,b, pyrimidinethione 4a,b, isoxazole 5a,b, aminopyrimidine 6a,b, pyrazoline 7i-k and epoxy derivative 8, respectively. Acetohydrazide 10 reacted with formic acid, acetic anhydride, car- bon disulfide and/or thiosemicarbazide to yield compounds 11ñ19. Also compound 21a,b was condensed with different monosaccharides to yield the corresponding N-glycoside Schiffís bases derivatives 22a-h, which upon treatment with acetic anhydride afforded 23a-h derivatives. The anticancer activity of some of the newly syn- thesized compounds was evaluated against HEPG2 (human liver carcinoma cell line) and PC12 (pheochromo- cytoma of the rat adrenal medulla) cells. Benzimidazole-2-isoxazole 5a derivative exhibited high potency against HEPG2 and PC12 cells. Benzimidazole chalcones 2c,e, benzimidazole mercaptoacetohydrazide 14 and benzimidazole thiosemicarbazide 15a,b derivatives gave high potency against PC12 cells. Keywords: 2-acetylbenzimidazole, chalcones, acetohydrazide, glycosides, anticancer activity, HEPG2, PC12 519 * Corresponding author: e-mail: dr.zmnofal@yahoo.com