Design, synthesis, molecular docking and biological evaluation of new dithiocarbamates substituted benzimidazole and chalcones as possible chemotherapeutic agents Keerthana Bacharaju a , Swathi Reddy Jambula a , Sreekanth Sivan b , Saritha JyostnaTangeda a , Vijjulatha Manga b,⇑ a Sarojini Naidu Vanitha Pharmacy Maha Vidyalaya, Osmania University, Hyderabad 500001, Andhra Pradesh, India b Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, Nizam College, Osmania University, Hyderabad 500001, Andhra Pradesh, India article info Article history: Received 29 December 2011 Revised 3 March 2012 Accepted 6 March 2012 Available online 11 March 2012 Keywords: Benzimidazole Chalcone Dithiocarbamate Antimitotic Molecular docking abstract A series of novel dithiocarbamates with benzimidazole and chalcone scaffold have been designed syn- thesised and evaluated for their antimitotic activity. Compounds 4c and 9d display the most promising antimitotic activity with IC 50 of 1.66 lM and 1.52 lM respectively. Ó 2012 Elsevier Ltd. All rights reserved. Benzimidazoles are one of the most extensively studied classes of heterocyclic compounds known for their wide range of biologi- cal activities. 1,2 Extensive studies have been carried out on benzim- idazoles and their chemotherapeutic activity. 3,4 On the other side, dithiocarbamates are a common class of organic molecules, that form mono and bidentate coordination with transition metals. Transition metal complexes of dithiocarbamate present a wide range of biological activities 5 and are recently applied in the treat- ment of cancer. 6,7 Since brassinin (Fig. 1), a phytoalexin first iso- lated from cabbage had cancer preventive activity, structural modification on this compound led to the synthesis of isobrassinin (Fig. 1) 8 and a series of dithiocarbamates, some of these were found to have antitumor activity. 9 Beside the compounds mentioned above chalcones are the bio- genetic precursors of all known flavonoids and isoflavanoids and are abundant in edible plants. 10 They exhibit a broad spectrum of pharmacological activities such as anticancer, 11 antiinflamma- tary, 12 antimalarial, 13 antifungal, 14 antilipidemic, 15 antiviral, 16 antileshmanial, 17 antiulcer 18 and antioxidant activities. 19 Recently Yong Qian and coworkers reported a series of chalcone derivatives (Fig. 1), with dithiocarbamate moieties which possessed potential antiproliferative and anti-tubulin properties. 20 Microtubules are among the most important molecular targets for cancer chemo- therapeutic agents. These small molecules bind to the tubulin, interfering with the polymerisation or depolymerisation of micro- tubules and there by inducing cell cycle arrest, resulting in cell death or apoptosis. Although many new chalcone derivatives have been synthesized as potential antitumor agents, there is very scarce recent literature data on antitumor potentials of dithiocarbamate-substituted chalcones. This combination should provide favourable structural properties of both dithiocarbamate and chalcone moieties. It improves their binding affinities with the protein via hydrogen bonding, hydrophobic contact and to further explore their chemotherapeutic properties. New molecules were designed in which indole moiety, is isosterically replaced with benzimid- azole. A series of novel derivatives containing both benzimidazole nucleus and dithiocarbamate as side chain possessing different substituents on nitrogen linked through methylene group at second position of benzimidazole were synthesized. Route applied for the synthesis of a various dithiocarbamate analogues is summarized in Schemes 1 and 2. Key intermediate 2-chloromethylbenzimidazole (2) (Scheme 1) was prepared by the addition of chloroaceticacid to o-phenylenediamine in 4 N hydrochloric acid as reported earlier. 21 Dithiocarbamates were synthesized from various amines and carbon disulfide, using dimethylformamide as solvent and anhydrous potassium phosphate as base, followed by treatment with 2-chloromethyl- benzimidazoles. 22 Chalconedithiocarbamates were obtained by 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.03.018 ⇑ Corresponding author. Tel.: +91 040 23234321; fax: +91 040 23240806. E-mail address: vijjulathamanga@gmail.com (V. Manga). Bioorganic & Medicinal Chemistry Letters 22 (2012) 3274–3277 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl