Letters in Drug Design & Discovery, 2009, 6, ???-??? 1 1570-1808/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Synthesis, Antimicrobial and Antioxidant Activities of Some Benzimida- zole Derivatives Canan Ku* ,a , Gülgün Ayhan-Kılcıgil a , Meral Tunçbilek a , Nurten Altanlar b , Tülay Çoban c , Benay Can-Eke c and Mümtaz can c a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara-Turkey b Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Ankara University, Ankara-Turkey c Department of Toxicology, Faculty of Pharmacy, Ankara University, Ankara-Turkey Received January 06, 2009: Revised March 22, 2009: Accepted March 24, 2009 Abstract: A number of benzimidazole compounds namely, N-(4-(1H-benzimidazol-2-yl)phenyl)-4-(1H-benzimidazol-2- yl)-benzamide derivatives (8-10) and N-(3- or 4-(1H-benzimidazol-2-yl)phenyl)-2-phenyl-1H-benzimidazole-5- carboxamide derivatives (18-21) were synthesized and antibacterial and antioxidant activities were evaluated. Antibacte- rial activities of 9, 10, 18, and 20 against MRSA-isolate are equal to ampicillin. Compounds 18, 19, and 21 displayed better antifungal activities against Candida albicans. Antioxidant properties were evaluated by several methods, such as inhibition of lipid peroxidation, superoxide anion production, and DPPH stable free radical, and also their effects on hepatic cytochrome P450 (CYP) dependent ethoxyresorufin O-deethylase (EROD) enzyme were determined in rats in vitro. Compounds 18 and 20 had strong scavenger effect on superoxide anion (90%, and 99%, respectively) at 10 -3 M con- centration. Compound 19 showed significant inhibition on EROD activity with 98%, which is better than that of caffeine being a specific inhibitor of EROD activity (85%). Keywords: Benzimidazole, Synthesis, Antimicrobial, Antioxidant. INTRODUCTION Free radical formation is associated with the normal natu- ral metabolism occurring in aerobic cells. Owing to the oxy- gen consumption inherent in cell growth a series of oxygen free radicals such as hydroxyl (OH . ), superoxide anion (O 2 .- ), nitric oxide (NO . ) and peroxyl (RO 2 . ) spontaneously occur and these reactive oxygen species (ROS) are involved in different physiological process [1, 2]. ROS are also produced by different mechanisms includ- ing cytochrome P 450s (CYPs). CYPs are a superfamily of enzymes involved in the oxidation of numerous xenobiotics. For example, CYP1A1/2 is able to metabolize polycyclic aromatic hydrocarbons, and aromatic amines to their final, mutagenic or carcinogenic metabolites. Furthermore, CYP1A1/2, which catalyzes EROD activity, is effective in producing ROS [3]. The protection of biological molecules (lipids, carbohy- drates, proteins and DNA) from oxidative stress is very im- portant to prevent inflammatory diseases, atherosclerosis, aging and cancer caused by high levels of ROS [4]. Antioxi- dants scavenge and prevent the formation of free radicals so they are highly important for the treatment of these kinds of diseases. For this reason, in recent years, there has been an increasing interest in finding new antioxidant compounds [5- 7]. Previously, we have reported the antioxidant properties of *Address correspondence to this author at the Department of Pharmaceuti- cal Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tandoan, Ankara, Turkey; Tel: +90 312 203 3075; Fax: + 90 312 213 1081; E-mail: kus@pharmacy.ankara.edu.tr some benzimidazole series by evaluation of their free radical scavenging activity and reducing power [8-11]. Ketoconazole, a well known azole antifungal drug, was reported as an inhibitor of lipid peroxidation (LP) in both microsomal and liposomal systems. The fungistatic effect of ketoconazole on Candida species was associated with its membrane stabilizing effects as indicated by inhibition of LP [12]. Moreover, recent studies have shown that Candida al- bicans possesses an ROS scavenger, superoxide dismutase, [13] and that endogenous ROS is an important mediator of miconazole antifungal effect [14]. There is a strong inverse correlation between the level of ROS production and the MIC values of miconazole sensitivity [14]. Synthesis and antimicrobial activity of a large number of benzimidazolecarboxamide derivatives have been already reported from our lab. [15-19]. Because of the resistance to antimicrobial agents it is important to find new antimicrobial drug classes. Taking into considerations these reports, in order to find new antimicrobial agents it was planned to con- nect two benzimidazole rings with a carboxyamide chain. In order to search, there is any correlation with antibacterial activity and antioxidant capacity of novel synthesized ben- zimidazole derivatives this study was attempted. In this study, the detailed design and synthetic pathway for prepara- tion, antimicrobial and antioxidant properties of benzimida- zole derivatives (8-10, 18-21) that have two benzimidazole rings in the same structure are described. CHEMISTRY In order to obtain the desired final products, according to the ref. [20], cyclization of 4-substituted-1,2-phenylenedia-