ABSTRACT ABSTRACT Microwave induced synthesis has various - PowerPoint PPT Presentation

“ Microwave-assisted Facile Synthesis And Anticancer Evaluation Of N-((5-(substituted Methylene Amino)- 1,3,4-thiadiazol-2-yl)methyl) Benzamide Derivatives” Anna Pratima Nikalje*, Shailee Tiwari, Sumaiya Siddiqui, Y. B. CHAVAN COLLEGE OF PHARMACY, AURANGABAD.M Y. B. CHAVAN COLLEGE OF PHARMACY, AURANGABAD.M .MS. .MS. . INDIA . . INDIA . & Julio Seijas Vázquez, M. Pilar Vázquez UNIVERSIDAD DE SANTIAGO DE COMPOSTELA-LUGO (SPAIN)

ABSTRACT ABSTRACT Microwave induced synthesis has various advantages over conventional synthesis, such as highly accelerated reaction rate , reasonable better yields, simple open systems, no solvent or very less amount of solvents required, eco friendly method, clean heating system and control on reaction parameters .In the present work novel Schiff’s bases containing thiadiazole scaffold and benzamide group, through appropriate pharmacophore were designed and synthesized , because of the important biological properties associated with these three moieties/groups. The coupling of these important moieties was achieved under these three moieties/groups. The coupling of these important moieties was achieved under microwave irradiation. A facile, solvent-free synthesis of a series of N-((5-(substituted methylene amino)-1,3,4-thiadiazol-2-yl)methyl)benzamide was carried out under microwave-irradiation . Solvent free synthesis of novel Schiff bases was achieved by cyclo addition of various aromatic aldehydes (0.01 mol) and N-((5-amino-1,3,4-thiadiazol-2 yl)methyl)benzamide(0.01 mol)in presence of catalytic amount of glacial acetic acid Under microwave irradiation. The same compounds were also synthesized using conventional approach. The conventional method required 15-18 hrs, while microwave irradiation method required only 15-20 minutes and gave better yields. 2

Total 12 final compounds were synthesized as per the scheme reported. Structures of synthesized compounds were confirmed by IR, NMR, and Mass spectral study. All the designed hybrids were evaluated for their in vitro anticancer activity against a panel of four human cancer cell lines viz SK-MEL-2(melanoma), HL-60 (leukemia), HeLa (cervical) and MCF-7 using MTT assays method. Most of the synthesized compounds exhibited promising anticancer activity with the some compounds having GI 50 values similar to that of the Adriamycin. The compounds 7k , 7l, 7b , and 7a were found to be the most promising of the Adriamycin. The compounds 7k , 7l, 7b , and 7a were found to be the most promising in this study. A computational study of synthesized compounds 7(a–l) was performed for prediction of ADMET. The absorption, distribution, metabolism, excretion and Toxicity (ADMET) properties of all compounds were predicted using Qikprop v3.5 (Schrödinger LLC). Keywords: Micro-wave assisted synthesis, Schiff's bases, thiadiazoles, MTT assay, in-vitro anti-cancer activity 3

INTRODUCTION INTRODUCTION Cancer is a leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in 2008 h . Cancer is a generic term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumours and neoplasms. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs. This process is referred to as metastasis. Metastases are the major cause of death from cancer. major cause of death from cancer. Cancerogenesis 4

Review of literature shows that 1,3,4-Thiadiazole has gained prominence by • exhibiting a wide variety of biological activities. It has interesting pharmacophores that display a broad spectrum biological activity. The lower toxicity and in vivo stability of 1,3,4-thiadiazole nucleus are attributed to its aromaticity. Diverse chemical structures containing1,3,4-Thiadiazole nucleus have been reported with potential anticancer activity.The 1,3,4-thiadiazole ring in anticancer agents performs its role in pharmacophroes of apoptosis inducers and caspase activators, tyrosine kinase inhibitors, carbonic anhydrase inhibitors and etc. Hence, various mechanisms could beimagined for anticancer chemical structures that containing the 1,3,4-thiadiazole ring. In review of literature the Schiff base derivative shave been found to be more In review of literature the Schiff base derivative shave been found to be more • • potent molecules ininhibiting cancer cell lines. This is due to the presence of carbon–nitrogen double bond having potential receptor binding ability. Schiff bases are also one of the intensively investigated classes of aromatic and heteroaromatic compounds. This class of compounds showed a variety of applications ranging from anticancer, antibacterial, diuretic (Supran et al., 1996),antifungal and anti parasitic activity. They have also medicinal importance and are used in drug design due to their activity against a wide range of organisms. This importance of thiadiazole nucleus and Schiff’s bases and continuing demand for new anticancer agents, prompted us to synthesize 5 different Schiff base derivatives of 1, 3, 4-thiadiazole ring.

Microwave Induced Green Synthesis In the present work microwave-assisted synthetic protocol is reported. Microwave is an important tool in Green synthesis . Microwave reactions involve selective absorption of electromagnetic waves by polar molecules, non-polar molecules being inert to microwave. Microwave induced organic reaction enhanced more. Green synthesis is a simplest method for conducting microwave assisted reactions which involves irradiation of reactants in an open vessel at fixed frequency of 2.45GHz. This method was developed by Bose et al . Advantages of microwave induced synthesis: Microwave induced synthesis has various advantages over conventional synthesis. Microwave induced synthesis has various advantages over conventional synthesis. These are as follows: � Highly accelerated reaction rate � Reasonable good yields � Simple open systems � No solvent or very less amount of solvents required � Eco friendly method � Clean heating system � Control on reaction parameters 6

Mechanism Of Action Of Anticancer Drugs � Block nucleic acid (DNA, RNA) biosynthesis � Directly destroy DNA and inhibit DNA reproduction � Interfere transcription and block RNA synthesis � Interfere protein synthesis and function � Influence hormone homeostasis 7

Need For Study Need For Study Discovery of new anticancer agents is the need of the hour due to: 1. Development of resistance by cancer cells. 2. Abnormal nature of cancer cells. 3. High toxicity and side effects by anticancer agents. 4. High rate of mortality due to cancer. 5. 5. Changes in lifestyle. With the recent advent in technology, it is possible to Changes in lifestyle. With the recent advent in technology, it is possible to harness the presently available molecules for different pharmacological actions. 6. Anticancer drugs are one such class of drugs which still has a lot of scope for modulation and discovery. 7. Many heterocyclic compounds show multiple pharmacological activities including the anticancer activity. 8. Keeping the current medical needs in mind, the heterocyclic thiadiazole derivatives can be targeted for study. 8

Objective Objective � To design and synthesize Schiff base derivatives of heterocyclic 1,3,4 thiadiazole scaffold. � To conduct physicochemical characterization of intermediates and synthesized compounds. � To confirm the structures of synthesized compounds by chemical tests, and spectral techniques such as FT-IR, ES-MS and NMR. In-vitro anticancer screening of the synthesized compound on human cancer � cell lines viz. HL-60(leukemia), MCF-7 (breast), HeLa (cervical) and SK- MEL-2 (melanoma) 9

Scheme of Synthesis Scheme of Synthesis 10

EXPERIMENTAL EXPERIMENTAL Step I: General process for synthesis of 2-Benzamidoacetic acid 0.33mol of glycine (2) was dissolved in 250ml of 10% NaOH solution contained in a conical flask.0.385mol of benzoyl chloride (1) was added in 5-portion to the solution and shaken vigorously until all the chloride has reacted. The solution was transferred to a beaker containing crushed ice and dil. HCl was added until the solution was acidic to congored paper. The resulting crystalline solid was collected and boiled with 10 ml of CCl 4 for 10 min. The product was filtered and washed with CCl 4 . The solid product obtained was dried and recrystallized from washed with CCl . The solid product obtained was dried and recrystallized from ethanol. The melting point and yield were recorded. Step II: General procedure for synthesis of N-((5-amino-1,3,4-thiadiazol-2- yl)methyl) benzamide 2- Benzamidoacetic acid (3) (0.05mol) was refluxed with thiosemicarbazide (4) (0.05mol) and phosphorus oxychloride (15 ml) for 1hr. The mixture was cooled and diluted with water (90 ml) and again refluxed for 4 hrs. Then the mixture was filtered and filtrate was basified with potassium hydroxide solution. The precipitate was filtered off and recrystallized from ethanol. 11