A series of aminated- (1–9) and sulfonamide-containing diarylpentadienones (10–18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were non-associated PAINS compounds. The sulfonamide-containing series (compounds 10–18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC₅₀ value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of α-glucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients.

一系列aminated-（1 - 9）和含有磺酰胺的diarylpentadienones（10 - 18）的合成，结构特点，并评价它们在体外对α葡糖苷酶和DPP-4酶的抗糖尿病的潜力。发现所有新分子都是非缔合的PAINS化合物。含磺酰胺的系列（化合物10 – 18）比DPP-4选择性抑制α-葡萄糖苷酶，其中化合物18表现出最高的IC ₅₀活性通过竞争性抑制机制获得的值为5.69±0.5 µM。结构活性关系（SAR）研究得出的结论是，引入三氟甲基苯磺酰胺部分对于抑制α-葡萄糖苷酶至关重要。然后使用斑马鱼动物模型进一步测试最具活性的化合物18的体内毒性，在斑马鱼的正常胚胎发育，血管形成和细胞凋亡中未检测到毒性作用。还进行了对接模拟研究，以更好地理解化合物18的结合相互作用建模的α-葡萄糖苷酶和人类溶酶体α-葡萄糖苷酶之间的同源性。总体结果表明，新的含磺酰胺的二芳基戊二烯酮化合物18可能是寻找新的α-葡萄糖苷酶抑制剂的有希望的候选物，并且可以作为体内涉及铅到铅优化的进一步研究的基础动物模型中的功效和安全性评估以及T2DM患者治疗的作用机理。