Synthesis and preliminary evaluation of antidiabetic activity of 4-(3-(4-bromophenyl)-3-oxo-1-arylpropylamino)- N-(5-methylisoxazol-3-yl)benzenesulfonamide

Diabetes mellitus is a common metabolic disease with a high and growing prevalence affecting 4% of the population worldwide, the development of safe and effective therapeutic drug is the major thrust for chemists and pharmacists.  To search for active antidiabetic lead compound, we designed and synthesized some novel β-amino ketone derivatives containing sulfamethoxazole moiety directly through Mannich reaction of  sulfamethoxazole, 4-bromoacetophenone and some aromatic aldehydes catalyzed by concentrated hydogen  chloride or iodine in the solution of ethanol at 24−40 ℃ with convenient operation, mild reaction condition   and satisfactory yield (32%−90%).  Their chemical structures were characterized by ¹H NMR, ¹³C NMR, MS and HR-MS.  Biological activity tests showed that, in the range of low concentration (5−10 μg·mL⁻¹), these    title compounds to a certain degree possess protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and α-glucosidase inhibitory activity, moreover, some could activate peroxisome proliferator-activated receptor   response element (PPRE) moderately.  The PPRE agonist activities of seven compounds are almost 40% of that of Pioglitazone (the positive control), compound 12 shows the strongest activity (66.35%) among them.  Thus, it was found that some of 4-(3-(4-bromophenyl)-3-oxo-1-arylpropylamino)-N-(5-methyl-isoxazol-3-yl) benzenesulfonamide containing sulfamethoxazole moiety exhibited antidiabetic activity for the first time.