Design Synthesis And Evaluation Of Antidiabetic Activity Of Some Thiadiazole Derivatives

Abstract

Diabetes mellitus is observed when there is a rise of glucose level in blood. Now a day s diabetes become a major health problem and is increasing day by day. Diabetes mellitus is divided into Insulin dependent and non -insulin dependent diabetes. Our aim is to design and synthesize some novel antidiabetic compound with minimum toxic effect. newlineThis dissertation included the designing and synthesis of some novel 1, 3, 4 thiadiazole newlinederivatives for the treatment of diabetes. Designing of novel 1, 3, 4 thiadiazole derivatives was done with the help of QSAR tool. A total newlineof 21 compounds were selected which were used to develop potent QSAR models. Through selection of data sets randomly and manually QSAR models were established. Four predictive models were generated in which one model by manual SA- kNN-MFA, Random selection newlinemethod with 80% followed by PLS regression analysis and the other two models were generated newlineby SW- kNN- MFA. Model 1 was achieved by means of manual data selection for test set newlinefollowed by simulated annealing as a variable selection method. Model one provides effective newlineinternal as well as external projecting capability of ~79% and ~91% respectively. Another model newline4 was achieved through selection method randomly for test set and associated with genetic newlinealgorithm method. Model 4 was found to be ~70% as worthy internal projecting ability and newline~80% of external projecting ability. Through kNN-MFA outline plans it is concluded that there newlinewas a liaison among substituted thiadiazole products structural features and their activities, which newlineought to be appropriate for designing innovative potent antidiabetic molecule. From QSAR results, a synthetic scheme was established to synthesize potent thiadiazole newlinederivatives for the treatment of diabetes. The synthetic scheme was divided into two series in newlinewhich first series was contained the aromatic amide, 4-substituted-N-(5-(4-(1-piperidino)1- newlinepiperidinyl)-1,3,4-(2-thiadiazolyl)benzamide (4a-f) and second series was contained the aromatic newlineurea, 1-(4-substitutedphenyl)-3-(5-(4-(1-piperidino)1-piperidinyl)-1,3,4-(2-thiadiazolyl)urea (6a- newlinef). newlineThe evaluation of antidiabetic activity or Blood glucose lowering study was performed for all the synthesized compounds (4a-f, 6a-f) and compared with standard compound gliclazide, newlineii newlinepioglitazone and control. From the in vivo study it was found that the urea series (6a-f) was more newlineeffectively lowered the blood glucose level than the amide derivatives (4a-f). newlineAmong all the synthesized compounds, the compound 1-(5-(4-(1-piperidino)1-piperidinyl)-1,3,4- newline(2-thiadiazolyl)-3-p-tolylureaof urea series (6f) showed most significant effect on the percentage inhibition in rise of blood glucose level which was 89.7% and also more than the standard compound gliclazide (87.8%) and pioglitazone (86.3%). The second effective compound was 4- newlinemethyl-N-(5-(4-(1-piperidino)1-piperidinyl)-1,3,4-(2-thiadiazolyl)benzamide of amide series(4f). newline