Abstract
Diabetes mellitus is a chronic metabolism disorder characterized by hyperglycemia due to insulin deficiency or insulin resistance. Associated complications include Myocardial infarction, cardiomyopathy, retinopathy, neuropathy, nephropathy, etc. Cinnamic acid analogs (SSPC0-SSPC20) containing different amino acids were designed and docked into crystal structure of AMPK and PPARs. Among the 20 designed compounds five compounds namely SSPC5, SSPC8, SSPC11, SSPC14, SSPC15 showed good docking scores using Glide 5.0 Maestro program and were subjected to ADME prediction by using software Quickprop version 3.1. These were then selected for synthesis, characterized and antidiabetic activity carried out using Alloxan induced diabetic rat model by measuring blood glucose levels using glucometer at 0, 1, 2, 4, 6, 8 and 24 hrs through the tail vein puncture method. SSPC5, SSPC8, SSPC11, SSPC14 showed % reduction in blood glucose of 23.02%, 37.02%, 14.04% and 15.96% as compared to standard with 33.53% reduction. As SSPC14 had good and comparable docking scores in both AMPK and PPAR γ receptor, so it was subjected for the Diabetic as well as diabetic cardiomyopathy activity by recording the electrocardiogram of both diabetic and control rat. It was found to be very efficient at low dose and had a prolong duration of action on the heart (Up to 54 hrs). Thus this study indicated that such hybrid antidiabetic drug with dual action on hyperglycemia and cardiac function is desirable and cost effective.
Highlights
The epidemic of obesity and sedentary lifestyle is projected to result in over 300 million people with diabetes mellitus by 2025 [1].Diabetes Mellitus is a syndrome of disordered metabolism usually due to a combination of hereditary and environmental causes resulting in hyperglycemia (fasting plasma glucose >7.0 mmol/lit (126 mg dl-1) or plasma glucose >10 mmol/lit, two hours after a meal) due to insulin deficiency and/or insulin resistance [2].Diabetes is associated with a number of complications both microvascular and macrovascular
Diabetic Cardiomyopathy is responsible for 80% of deaths among diabetic patients much of which has been attributed to CAD
SSPC5, SSPC8, SSPC11, SSPC14 showed % reduction in blood glucose of 37.02%, 12.5, 14.04, 15.96% and 2.51% as compared to standard with 33.53% reduction
Summary
The epidemic of obesity and sedentary lifestyle is projected to result in over 300 million people with diabetes mellitus by 2025 [1]. Diabetic Cardiomyopathy is responsible for 80% of deaths among diabetic patients much of which has been attributed to CAD (coronary artery disease). Studies showed that a hexapeptide (Gly-Ala-Gly-Val-Gly-Tyr) had improved glucose transport and exerts beneficial lipid metabolic effects [11]. Because of this a series of cinnamic acid-amino-acid hybrid series were designed, docked using Glide 5.0 and the best docked five compounds were synthesized. Antidiabetic activity of the five compounds was done on alloxanised rats and a new non-invasive animal model was developed to study the diabetic cardiomyopathy
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