A novel series comprising of 10 derivatives of two chemical entities thiazolidinedione and rhodanine were synthesized and characterized physicochemically as well as by spectral means. The synthesized derivatives (THP, RHP, RHB, MB01-MB09) were then screened for anti-hyperglycemic activity in fructose-induced diabetic animal model. It can be concluded that presence of piperazine and N-methyl piperazine at N-3 of thiazolidinedione and rhodanine derivatives have shown significant activity in comparison to aromatic amine substitution. The presence of ether linkage is the primary requisite for anti-hyperglycemic activity. Condensation of benzylidene with lipophilic moiety i.e. benzothiazole enhanced the activity of the synthesized derivatives. Piperazine substituted compound, MB01was most potent anti-hyperglycemic activity that might be due to the availability of free nitrogen at receptor site.