Full Paper Synthesis and Biological Evaluation of Some 1,2- Disubstituted Benzimidazole Derivatives as New Potential Anticancer Agents Leyla Yurttas ¸ 1 ,S ¸ eref Demirayak 2 , Gu ¨ ls ¸ en A. C ¸ iftc ¸i 3 ,S ¸ afak Ulusoylar Yıldırım 4 , and Zafer A. Kaplancıklı 1,5 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskis ¸ehir, Turkey 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medipol University, I ˙ stanbul, Turkey 3 Department of Biochemistry, Faculty of Pharmacy, Anadolu University, Eskis ¸ehir, Turkey 4 Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eskis ¸ehir, Turkey 5 Department of Pharmaceutical Chemistry, Graduate School of Health Sciences, Anadolu University, Eskisehir, Turkey The synthesis of some new 1-(2-aryl-2-oxoethyl)-2-[(morpholine-4-yl)thioxomethyl]benzimidazole derivatives and investigation of their anticancer activities were the aims of this work. 2-(Chloromethyl)benzimidazole compound was reacted with sulfur and morpholine via Willgerodt–Kindler reaction to give 2-[(morpholine-4-yl)thioxomethyl]benzimidazole. Then, the obtained compound was reacted with appropriate a-bromoacetophenone derivatives in the presence of potassium carbonate to give the final products. Structure elucidation of the final compounds was achieved by FT-IR, 1 H NMR spectroscopy and MS spectrometry. The anticancer activities of the final compounds were evaluated by MTT assay, BrdU method, and flow cytometric analysis on C6, MCF-7, and A549 tumor cells. Most of the synthesized compounds exhibited considerable selectivity against the MCF-7 and C6 cell lines. Keywords: Anticancer activity / Benzimidazole / BrdU / Flow cytometric analysis / Thioamide Received: November 30, 2012; Revised: January 21, 2013; Accepted: February 4, 2013 DOI 10.1002/ardp.201200452 Introduction Cancer treatment often encompasses more than one approach, and the strategy adopted depends largely on the nature of the cancer and how far it has progressed. At the present time, the main treatment strategies are still surgery, radiotherapy, and chemotherapy [1]. In cancer chemotherapy, besides drugs in use, there is much interest in the design of new anticancer agents especially small molecules that bind to DNA with sequence selectivity and noncovalent interactions [2]. Benzimidazoles are the privileged components of many bioactive compounds. Because of their synthetic utility and broad range of pharmacological activities such as antifungal, anti-helmintic, anti-HIV, antihistaminic, antiulcer, cardio- tonic, and antihypertensive; they have become a key building block for a variety of compounds that play crucial roles in the function of a number of biologically important molecules [3, 4]. In addition, it has been extensively utilized as a drug scaffold in medicinal chemistry and is an important phar- macophore due to being a structural isostere of naturally occurring nucleotides [5–8]. In recent years, benzimidazole derivatives have attracted particular interest due to their anticancer activity or as potential in vitro anticancer agents [9, 10]. In particular, they have been explored as topoisomer- ase I, PARP-1, kinase Chk2, Pgp and tyrosine kinases, metallo and serine protease inhibitors [11, 12]. Benzimidazole as ‘‘lead’’ molecule binds with other heterocyclic compounds. It acts by intercalation or blocks cell growth by inhibiting the enzymes directly responsible for the formation of nucleic acids. This inhibition is believed to prevent DNA transcrip- tion, which ultimately leads to cell death, which explains the use of these drugs to treat cancer [13, 14]. Nocodazole [15], Correspondence: Dr. Leyla Yurttas ¸, Department of Pharmaceutical Chemistry, Facultyof Pharmacy, Anadolu University, 26470 Eskis ¸ehir, Turkey. E-mail: lyurttas@anadolu.edu.tr Fax: þ902223350750 Arch. Pharm. Chem. Life Sci. 2013, 346, 403–414 403 ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim