Abstract: Diabetes Mellitus is one of the most widespread metabolic disorders in the world and nearly 200 million global population is affected from diabetes. Type I diabetes is caused because of insulin deficiency and it has affected nearly 5-10% of the diabetic population. However, type II diabetes which is most common is mainly due to insulin resistance. Diabetes is characterized by hyperglycemia that is associated with various complications such as cardiac and vascular diseases, thrombosis, cerebral and renal disorders. The worldwide prevalence of diabetes in all age groups has been rising and it is estimated that it might increase from 2.8% (171 million) in the year 2000 to 4.4% (~ 400 million) in 2030. In case of Type II diabetes inhibition of alpha-glucosidase enzyme is an effective therapeutic approach which involves controlling postprandial hyperglycemia by delaying the digestion of carbohydrates. Therefore, inhibition of alpha-glucosidase enzyme slows down the carbohydrate absorption. This stabilizes the blood glucose level among diabetic patients, thereby preventing hyperglycemia. Effective treatment of diabetes mellitus is currently limited to oral alpha-glucosidase inhibitors viz. acarbose, miglitol and voglibose, However they are impaired by efficacy problems and unwanted side effects. These drugs were discovered more than three decades ago with no further significant progress in the drug development area of anti-diabetic alpha-glucosidase inhibitors. Hence, it is the need of the hour to identify a novel alpha-glucosidase inhibitor. This thesis mainly consist of five chapters describing the evaluation of potent alpha-glucosidase inhibitor for treatment of diabetes. First chapter introduces diabetes and it’s therapeutic approaches and also it describes various existing potent inhibitors. Second chapter involves design, synthesis, in vitro and in vivo studies of a novel library of a-arylketones as potential inhibitors of a-glucosidase. Chapter three includes detailed study of design, synthesis and in vitro study of densely functionalized oxindoles as potent alpha-glucosidase inhibitors. Fourth and fifth chapter describes the design and synthesis of novel pyridone based alpha-glucosidase inhibitors along with their biological evaluation, in vitro ADME-Tox, in vivo pharmacokinetics and efficacy studies.
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Ph.D. dissertation, Shiv Nadar University 2019 "Design of Novel Molecular Libraries as Inhibitors of alpha-glucosidase- Potent Hybrid Compounds Against Type II Diabetes"
List of Publications (to be included in the thesis):
Tania Luthra, Rahul Agarwal, Uma Adepally,* Mamidala, Estari, Subhabrata Sen*, A novel library of alpha-arylketones as potential inhibitors of alpha-glucosidase: Their design, synthesis, in vitro and in vivo studies, Scientific Reports, 2017, 7, 13246.
Tania Luthra, K. Naga Lalitha, Rahul Agarwal, Uma Adepally and Subhabrata Sen*, Synthesis, design and in vitro study of densely functionalized oxindoles as potent alpha-glucosidase inhibitors. Bioorganic Med. Chem., 2018, 26, 4996-5005.
Tania Luthra, Venkana Bonuthu, Uma Adepally, Krishna Kumar, Swathi M, Saikat Chakrabarti, Srinivas R. Maddi and Subhabrata Sen*, Discovery of novel pyrido-pyrrolidine hybrid compounds as alpha-glucosidase inhibitors and alternative agent for control of Type 1 diabetes. (Manuscript in Submission)
Research Advisor: Dr. Subhabrata Sen