Identification of 9<i>H</i>‐purin‐6‐amine derivatives as novel aldose reductase inhibitors for the treatment of diabetic complications

Zhu, Junkai; Qi, Guoyuan; Ke, Ya; Zhao, Yaping; Sun, Xinjie; Zhu, Changjin; Hao, Xin; Han, Zhongfei

doi:10.1002/ardp.202200043

Cited by 3 publications

(1 citation statement)

References 22 publications

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“…The docking behavior of 5g with the AKR1A1/NADP + /fidarestat complex (PDB code: 3H4G) was also investigated. [ 28 ] However, the binding mode showed that 5g could neither fit with the binding site nor show any hydrogen bonding with AKR1A1. As shown in Figure 4, docking results reveal that the N3 benzyl was mismatched floating out of the active site of AKR1A1, and no hydrogen bond was formed.…”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of novel quinazolin‐4(1H)‐one derivatives as potent and selective inhibitors targeting AKR1B1

Han

et al. 2023

Archiv der Pharmazie

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Inhibition of aldose reductase (AKR1B1) is a promising option for the treatment of diabetic complications. However, most of the developed small molecule inhibitors lack selectivity or suffer from low bioactivity. To address this limitation, a novel series of quinazolin-4(1H)-one derivatives as potent and selective inhibitors of AKR1B1 were designed and synthesized. Aldose reductase inhibitory activities of the novel compounds were characterized by IC 50 values ranging from 0.015 to 31.497 μM. Markedly enhanced selectivity of these derivatives was also recorded, which was further supported by docking studies. Of these inhibitors, compound 5g exhibited the highest inhibition activity with selectivity indices reaching 1190.8. The structure-activity relationship highlighted the importance of N1-acetic acid and N3benzyl groups with electron-withdrawing substituents on the quinazolin-4(1H)-one scaffold for the construction of efficient and selective AKR1B1 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Design and synthesis of novel quinazolin‐4(1H)‐one derivatives as potent and selective inhibitors targeting AKR1B1

Han

et al. 2023

Archiv der Pharmazie

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Exploration of Some Bis‐Sulfide and Bis‐Sulfone Derivatives as Non‐Classical Aldose Reductase İnhibitors

et al. 2023

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Aldose reductase (AR, ALR2; EC 1.1.1.21), an enzyme that converts glucose to fructose on the polyol pathway, is an important member of the Aldo-keto reductase superfamily. ALR2 is part of the rate-limiting step, which is associated with diabetic complications in this process, and plays a role in regulating reactive oxygen species induced by growth factors and cytokines. Despite the fact that sulfides and sulfones have been discovered to have a variety of other biological functions, in the current study, we assessed the ALR2 inhibitory potential of the derivatives of bis-sulfide (5 a-i) and bis-sulfone (6 a-i) in order to further our interest in designing and discovering powerful ALR2 inhibitors. The results of the biological investigations showed that all of the derivatives exhibit activity against ALR2, with K I values ranging from 0.53 � 0.03 to 4.20 � 0.06 μM.Among these agents, 2,6-bis((4-chlorophenyl)(phenylthio)methyl)cyclohexan-1-one (5 h), 2,6bis((3-nitrophenyl)(phenylthio)methyl)cyclohexan-1-one (5 c), and 2,6-bis((3-chlorophenyl)(phenylthio)methyl)cyclohexan-1one (5 g) exhibited prominent inhibitory activity with K I constants of 0.53 � 0.03 μM, 0.65 � 0.04 μM, and 0.71 � 0.05 μM, respectively, against ALR2 and were found to be more potent than epalrestat (K I = 0.79 � 0.01 μM) is currently, the only ALR2 inhibitor (ALR2I) utilized in treatment. Additionally, in silico molecular docking experiments were carried out to explain how these bis-sulfides (5 a-i) and bis-sulfones (6 a-i) interacted with the target enzyme ALR2's binding site. According to the ADME-Tox study, these compounds are predicted to be ALR2Is with appropriate drug-like characteristics. The study's findings on sulfides and sulfones could be exploited to create innovative therapeutics that prevent diabetes complications.

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Aldose reductase with quinolone antibiotics interaction: In vitro and in silico approach of its relationship with diabetic complications

Türkeş

2024

Archives of Biochemistry and Biophysics

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Identification of 9H‐purin‐6‐amine derivatives as novel aldose reductase inhibitors for the treatment of diabetic complications

Cited by 3 publications

References 22 publications

Design and synthesis of novel quinazolin‐4(1H)‐one derivatives as potent and selective inhibitors targeting AKR1B1

Design and synthesis of novel quinazolin‐4(1H)‐one derivatives as potent and selective inhibitors targeting AKR1B1

Exploration of Some Bis‐Sulfide and Bis‐Sulfone Derivatives as Non‐Classical Aldose Reductase İnhibitors

Aldose reductase with quinolone antibiotics interaction: In vitro and in silico approach of its relationship with diabetic complications

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