Recently we have developed novel oxotriazinoindole inhibitors (OTIs) of aldose reductase (ALR2), characterized by high efficacy and selectivity. Herein we describe novel OTI derivatives design of which is based on implementation of additional intermolecular interactions within an unoccupied pocket of the ALR2 enzyme. Four novel derivatives, OTI-(7–10), of the previously developed N-benzyl(oxotriazinoindole) inhibitor OTI-6 were synthetized and screened. All of them revealed 2 to 6 times higher ALR2 inhibitory efficacy when compared to their non-substituted lead compound OTI-6. Moreover, the most efficient ALR2 inhibitor OTI-7 (IC₅₀ = 76 nM) possesses remarkably high inhibition selectivity (S_F ≥ 1300) in relation to structurally related aldehyde reductase (ALR1). Derivatives OTI-(8–10) bearing the substituents –CONH₂, –COOH and –CH₂OH, possess 2–3 times lower inhibitory efficacy compared to OTI-7, but better than the reference inhibitor OTI-6. Desolvation penalty is suggested as a possible factor responsible for the drop in ALR2 inhibitory efficacy observed for derivatives OTI-(8–10) in comparison to OTI-7.

最近，我们已经开发了新的oxotriazinoindole抑制剂（奥蒂斯）醛糖还原酶的（ALR2），其特征在于，高功效和选择性。在此，我们描述了新的OTI衍生物设计，其基于在 ALR2 酶的未占用口袋内实施额外的分子间相互作用。合成并筛选了先前开发的N-苄基（氧代三嗪基吲哚）抑制剂OTI-6 的四种新型衍生物OTI-(7 – 10)。与未取代的先导化合物OTI-6相比，它们的 ALR2 抑制功效均高出 2 至 6 倍。此外，最有效的 ALR2 抑制剂OTI-7 (IC₅₀  = 76纳米）具有显着的高抑制选择性（S _˚F 相对于结构上相关的醛还原酶（ALR1）≥1300）。带有取代基–CONH ₂、–COOH 和–CH ₂ OH 的衍生物OTI-(8 – 10)的抑制效果比OTI-7低2–3 倍，但优于参考抑制剂OTI-6。与OTI-7相比，对衍生物OTI-(8 – 10)观察到的 ALR2 抑制功效下降的可能因素是去溶剂化惩罚。