Vol 10, Issue 4, 2017 Online - 2455-3891 Print - 0974-2441 IN SILICO DESIGN, SYNTHESIS AND CHARACTERIZATION OF SOME NOVEL BENZOTHIAZOLE DERIVATIVES AS ANTICANCER AGENTS LEENA K PAPPACHEN*, SUBIN MARY ZACHARIAH, DEEPTHY CHANDRAN Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham University, AIMS Health Sciences Campus, Kochi, Kerala, India. Email: leenakpappachen@aims.amrita.edu. Received: 30 November 2016, Revised and Accepted: 23 January 2017 ABSTRACT Objectives: Cancer is a disease characterized by uncontrollable, irreversible, independent, autonomous, uncoordinated, relatively unlimited, and abnormal overgrowth of tissues. Breast cancer is the second most common type of cancer after lung cancer. The aim of the study is to carry out the docking studies, synthesis, and antitumor activities of benzothiazole derivatives containing oxadiazole groups or amino groups. Methods: The docking studies of benzothiazole derivatives were done with known anticancer targets like estrogen receptor using Argus lab and AutoDock programs and compared with the standard drug tamoxifen. Based on the results obtained from the molecular modeling studies, the derivatives were selected for the synthesis. The synthesized compounds were characterized by melting point, thin layer chromatography, InfraRed, 1 H NMR, 13 CNMR, mass spectral data, and screened for their in-vitro anticancer activities. Results: The docking scores obtained for benzothiazole derivatives (BT1, BT2, BT3, BT4) and std. tamoxifen from the preliminary docking program using Argus Lab were −9.68, −9.4, −9.59, −11.1988, −9.71 and using AutoDock program were −6.29, −5.25, −7.19, −7.48, −3.86, respectively. All the four derivatives were synthesized, characterized, and subjected to in vitro anticancer screening by MTT assay in breast cancer (MCF-7) cell lines. Compounds DBT1, DBT2, and DBT3 were the most active compounds against MCF-7 cell lines with inhibitory concentration 50% of 70.0, 64.0 and 65.0, respectively. Conclusion: All the four derivatives show good docking scores when compared to standard drug tamoxifen and can be concluded that all the synthesized benzothiazole ligands show good anticancer property. Keywords: Benzothiazole, Oxadiazole, Estrogen receptor, Anticancer targets. INTRODUCTION Benzothiazole is a heterocyclic compound which possesses various biological activities. It is of great scientific interest nowadays. Benzothiazoles are fused membered rings which consist of thiazole ring fused with benzene ring. They are widely found in bio-organic and medicinal chemistry with application in drug discovery [1]. Benzothiazole moieties are part of compounds showing numerous biological activities such as antifungal [2], antiepileptic [3] anticancer [4], anti-inflammatory (COX-inhibitors) [5], antidiabetic [6], anticonvulsant [7], antimicrobial [8] , diuretic [9], antitubercular [10], schictosomicidal [11], and anthelmintic [12] activities. Benzothiazole is used in research as a starting material for the synthesis of various bioactive structures. Its aromaticity makes it a relatively stable compound [13]. Drug design, sometimes referred to as rational drug design or more simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient [14] Docking is a method which predicts the preferred orientation of one molecule to the second when bound to each other to form a stable complex. Breast cancer is a type of cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. METHODS In silico molecular modeling In silico drug, designing is a technique used for the design of new drug molecules, and the identification of drug targets using various bioinformatic tools with the help of computers. Analysis of Lipinski’s rule of five and determination of toxicity parameter was carried out. Target identification and retrieval Crystallographic structures of the target of interest were obtained from Protein Data Bank (PDB) and saved in standard three dimensional (3D) coordinate format. The selected target and its PDB ID are mentioned in Table 1. Estrogen receptor (ER) [15] Breast cancer, the most common malignancy in women, was already known to be associated with the steroid hormone estrogen. The discovery of the ER provided us not only with a powerful predictive and prognostic marker but also an efficient target for the treatment of hormone-dependent breast cancer with antiestrogens [16]. 3D structures of inhibitors The chemical structures of inhibitors were designed, and the structure was analyzed using Chemsketch. Molecular docking and visual inspection are carried out. The list of compounds undergone for docking studies was mentioned in Table 2. Experimental part Preparation of 4, 6-disubstituted-1,3-benzothiazol-2-amine derivatives Substituted aniline and potassium thiocyanate were dissolved in ethanol containing 2 ml concentrated hydrochloric acid (HCL). To this, bromine in glacial acetic acid was added, and the reaction mixture was refluxed for 1 hr. Then, the mixture was poured into crushed ice. The precipitate obtained was strained well. It was then filtered, washed © 2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2017.v10i4.16407 Research Article