Kousaxidis Antonios, Kalfagianni Konstantina-Malamati, Seretouli Eleni, Nicolaou Ioannis
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Medicines (Basel). 2025 Jun 23;12(3):16. doi: 10.3390/medicines12030016.
BACKGROUND/OBJECTIVES: Diabetes mellitus is a group of chronic metabolic disorders characterized by persistent hyperglycemia. Aldose reductase, the first enzyme in the polyol pathway, plays a key role in the onset of long-term diabetic complications. Aldose reductase inhibition has been widely established as a potential pharmacotherapeutic approach to prevent and treat diabetes mellitus-related comorbidities. Although several promising aldose reductase inhibitors have been developed over the past few decades, they have failed in clinical trials due to unacceptable pharmacokinetic properties and severe side effects. This paper describes the design, synthesis, and pharmacological evaluation of four novel 5-halogenated -indolylsulfonyl-2-fluorophenol derivatives (-) as aldose reductase inhibitors.
The design of compounds was based on a previously published lead compound (IIc) developed by our research group to enhance its inhibitory capacity. Compounds - were screened for their ability to inhibit in vitro partially purified aldose reductase from rat lenses, and their binding modes were investigated through molecular docking.
The presence of a sulfonyl linker between indole and o-fluorophenol aromatic rings is mandatory for potent aldose reductase inhibition. The 5-substitution of the indole core with halogens resulted in a slight decrease in the inhibitory power of - compared to IIc. Among halogens, bromine was the most capable of filling the selectivity pocket through hydrophobic interactions with Thr113 and Phe115 residues.
Although our strategy to optimize the inhibitory potency of IIc via inserting halogen atoms in the indole scaffold was not fruitful, aromatic ring halogenation can be still utilized as a promising approach for designing more potent aldose reductase inhibitors.
背景/目的：糖尿病是一组以持续性高血糖为特征的慢性代谢紊乱疾病。醛糖还原酶是多元醇途径中的首个酶，在长期糖尿病并发症的发病过程中起关键作用。抑制醛糖还原酶已被广泛确立为预防和治疗糖尿病相关合并症的一种潜在药物治疗方法。尽管在过去几十年中已开发出几种有前景的醛糖还原酶抑制剂，但由于不可接受的药代动力学性质和严重的副作用，它们在临床试验中失败了。本文描述了四种新型5-卤代-吲哚基磺酰基-2-氟苯酚衍生物（-）作为醛糖还原酶抑制剂的设计、合成及药理评价。
化合物的设计基于我们研究小组先前发表的先导化合物（IIc），以增强其抑制能力。筛选化合物-抑制大鼠晶状体中部分纯化的醛糖还原酶的体外能力，并通过分子对接研究它们的结合模式。
吲哚和邻氟苯酚芳香环之间存在磺酰基连接子是有效抑制醛糖还原酶所必需的。与IIc相比，吲哚核心的5-位用卤素取代导致-的抑制能力略有下降。在卤素中，溴最能够通过与Thr113和Phe115残基的疏水相互作用填充选择性口袋。
尽管我们通过在吲哚支架中插入卤素原子来优化IIc抑制效力的策略没有成效，但芳香环卤化仍可作为设计更有效醛糖还原酶抑制剂的一种有前景的方法。
