VIRTUAL SCREENING, SYNTHESIS OF NEWER HETEROCYCLES AS PPAR γ AGONISTS WITH ANTIDIABETIC ACTIVITYAbstract
Recent decades have experienced a sharp increase in the incidence and prevalence of diabetes mellitus. The major therapeutic approach is to diabetes is to reduce gastrointestinal glucose production and absorption through the inhibition of carbohydrate digesting enzymes such as α-amylase and α-glucosidase. The agonists of PPAR γ is of great interest to the pharmaceutical industry since they regulate the expression of genes Associated with diseases like cancer, diabetes, atherosclerosis and obesity The aim of the current study was to synthesize newer PPAR γ agonists with alleged antidiabetic properties for α-amylase and α-glucosidase inhibitory activities. Newer PPAR γ agonist ligands containing three parts acidic head, a linker, and a hydrophobic tail as Pharmacophore features were designed. Four different compounds containing thiazole as heterocyclic nucleus have been synthesised and characterised by analytical methods like IR, NMR, spectral data. All the synthesised molecules were Optimizied using Lipinksi’s rule of five and subjected to docking studies using ARGUS LAB 4.0. Docking studies showed the important interactions of lead molecules posses with some of the common active site residues like ARG 288, CYS 285, HIS 323, HIS 449, LEU 353, LYS 367, MET 364, MET 348, PHE 363 of different PPAR γ receptors like 3FEJ, 3V9V. The synthesised compounds were evaluated for their antidiabetic activity by α amylase and α glucosidase inhibitory methods and all were found to exhibit an effective inhibition against both the enzymes. Out of the four synthesised compounds, KPSV 4 was found to be most effective with percentage growth inhibition of 61.92% and 80..46% at 1000μg when compared with other three synthesised compounds like KPSV 1, KPSV2, KPSV3.
R. Priyadarsini *, V. Durga and Shahana Ahmed
Department of Pharmaceutical Chemistry, College of Pharmacy, Madras Medical College, Chennai, Tamilnadu India.
24 July, 2016
21 September, 2016
26 September, 2016
01 February, 2017