Drug Design, Docking Studies And Synthesis of Certain Coumarin Derivatives and Evaluation of their α - Amylase Inhibitory Activity

Lekha, P (2017) Drug Design, Docking Studies And Synthesis of Certain Coumarin Derivatives and Evaluation of their α - Amylase Inhibitory Activity. Masters thesis, Sri Ramakrishna Institute of Paramedical Sciences, Coimbatore.


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INTRODUCTION:In Drug discovery, natural, synthetic and semisynthetic heterocyclic compounds play an important role in chemical biology. The heterocycles are mainly of the classes of alkaloids, flavones, isoflavones, chromans, chromones, coumarins and chromenes. It has been established that oxygen-containing heterocyclic compounds play an important role in designing new class of structural entities for medicinal applications. Among oxygen heterocyclic compounds, coumarin (2H-chromen-2-one or 2H-1-benzopyran-2-one) and its derivatives are significant because of their wide spectrum of biological activities.PURPOSE OF THE STUDY:Diabetes mellitus is a major endocrine disorder affecting nearly 10% of the population all over the World. It is characterised by hyperglycemia and disturbances of carbohydrate, protein and fat metabolisms, secondary to an abosolute or relative lack of the hormone insulin. The number of people in the world with diabetes has increased dramatically over recent years. It is also predicted that by 2030, India, China, and the United States will have the largest number of people with diabetes. Currently treatment of diabetes, in addition to insulin supplement includes many oral hypoglycemic agents along with appropriate diet and exercise. The treatment goal of diabetic patients is to maintain near normal levels of glycemic control, in both fasting and post-prandial conditions. Postprandial hyperglycemia has been proposed as an independent risk factor for diabetes mellitus. Therefore, control of postprandial hyperglycemia is suggested to be important in the treatment of diabetes. One of the effective method to control diabetes is to inhibit the activity of α-amylase enzyme which is responsible for the breakdown of starch to more simple sugars( dextrin, maltotriose, maltose, and glucose). This is contributed by α-amylase inhibitors, which delays the glucose absorption rate thereby maintaining the serum blood glucose in hyperglycemic individuals. This study is focussed to investigate the inhibitory potentials of the synthesised coumarin derivatives on α-amylase, the key enzyme responsible for carbohydrate hydrolysis.SUMMARY:The present work was focused on the designing and synthesis of novel isoxazole and pyrazole derivatives incorporated with coumarin moiety having α-amylase enzyme inhibitory activity. For this, following approach has been adopted. PHASE I: LITERATURE REVIEW Literature survey showed that coumarin is a drug like scaffold and is a core skeleton for the active sites involved in enzyme inhibiton in Type 2 diabetes. It also revealed that isoxazole, pyrazole posses enzyme inhibition for Type 2 diabetes. PHASE II: DRUG DESIGN APPROACH It involves the following stages: Stage 1: Identification of target α-amylase was selected as the target enzyme as its inhibition will prevent carbohydrate hydrolysis. The target enzyme (1UA7) was downloaded from RCBs Protein Databank. Stage 2: Virtual screening Virtual screening was done by iGEMDOCK v.2 software. More than 500 compounds from the pubchem and zinc database were screened from which 50 lead compounds were selected. From this, based on the bioactivity score, Coumarin was selected as the lead molecule Stage 3: Lead optimization Lead optimisation was done by computation of drug likness score. Isoxazole and Pyrazole derivatives of coumarin were the desired compounds with good molecular properties and bioactivity score, ie., the compounds I1-5 and T1-5, showed good scores.CONCLUSION:The present study establishes that computational tools help in minimizing the tedious process of drug discovery and delivers new drug candidate more quickly. α-amylase enzyme was selected as target and virtual screening made selection of lead compounds easier and coumarin was selected as lead molecule. The drug likeness score established the compounds to be pharmacokinetically active. The proposed ten compounds of isoxazole and pyrazole derivatives with coumarin ring system were synthesised in good yield using the developed schemes. All the reactions were monitored by TLC one spot technique and the structures of the synthesised compounds were confirmed by UV, IR, 1H NMR, Mass spectra. Compounds I4, T1 and T3 exhibited maximum α-amylase inhibitory activity. Among the synthesized compounds, I4 and T1 can be taken for further studies as the lead molecule and acute toxicity studies are to be done on these promising compounds.

Item Type: Thesis (Masters)
Additional Information: REG.No.261515103
Uncontrolled Keywords: Drug Design ; Docking Studies ; Synthesis ; Coumarin Derivatives ; α - Amylase Inhibitory Activity
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Ravindran C
Date Deposited: 16 Mar 2018 09:03
Last Modified: 16 Mar 2018 09:03
URI: http://repository-tnmgrmu.ac.in/id/eprint/6317

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