4-(3-(4-溴苯基)-3-氧代-1-芳基丙氨基)-N-(5-甲基异噁唑-3-基)苯磺酰胺的合成与抗糖尿病活性的初步研究

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

由磺胺甲噁唑、对溴苯乙酮和芳香醛反应合成了17个未见报道的β-氨基酮化合物,制备方法简便、反应条件温和,产物收率32%～90%。通过1HNMR、13CNMR、MS和HR-MS对目标分子进行了结构表征。生物活性试验显示,在低浓度范围,所得化合物不仅显示一定的蛋白质酪氨酸磷酸酶1B(PTP1B)和α-葡萄糖苷酶抑制活性,而且具有中等强度的过氧化物酶体增殖物激活受体反应元件(PPRE)的激动活性,7个化合物的激动活性超过40%,化合物12活性达到了66.35%,值得进一步研究。

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） benzene-sulfonamide containing sulfamethoxazole moiety exhibited antidiabetic activity for the first time.