Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin‐4(<scp>3<i>H</i></scp>)‐one derivatives as potential aldose reductase inhibitors

Tokalı, Feyzi Sinan; Demir, Yeliz; Demircioğlu, İbrahim Hakkı; Türkeş, Cüneyt; Kalay, Erbay; Şendil, Kıvılcim; Beydemır, Şükrü

doi:10.1002/ddr.21887

Cited by 54 publications

(90 citation statements)

References 116 publications

(134 reference statements)

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“…Several studies have been designed for the identification of novel inhibitors of ALR2, including designing derivatives of chemical inhibitors [ 44 ]. Compounds that inhibit ALR2 in a pattern similar to Epalrestat are much needed to control complications in DR. Inhibition of ALR2 by the identified phytocompounds in ARPE-19 cells was performed to validate the IC 50 concentration of the identified compounds on ALR2 from human lens.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Aldose Reductase by Novel Phytocompounds: A Heuristic Approach to Treating Diabetic Retinopathy

Julius

Renuka

Hopper

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Aldose reductase (ALR2) activation in the polyol pathway has been implicated as the primary mechanism for the progression of diabetic retinopathy. Most of the aldose reductase inhibitors (ARIs), used for the treatment of diabetic complications, were withdrawn due to ineffective treatment and adverse side effects caused by nonspecificity. Epalrestat, a carboxylic acid inhibitor, is the only ARI used for the treatment of diabetic neuropathy, though associated with minor side effects to 8% of the treated population. Our study exploited the interactions of Epalrestat-ALR2 crystal structure for the identification of specific phytocompounds that could inhibit human lens ALR2. 3D structures of plant compounds possessing antidiabetic property were retrieved from PubChem database for inhibition analysis, against human lens ALR2. Among the shortlisted compounds, Agnuside and Eupalitin-3-O-galactoside inhibited lens ALR2 with IC50 values of 22.4 nM and 27.3 nM, respectively, compared to the drug Epalrestat (98 nM), indicating high potency of these compounds as ALR2 inhibitors. IC50 concentration of the identified ARIs was validated in vitro using ARPE-19 cells. The in silico and in vitro approaches employed to identify and validate specific and potent ALR2 inhibitors resulted in the identification of phytocompounds with potency equal to or better than the ALR2 inhibiting drug, Epalrestat.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Aldose Reductase by Novel Phytocompounds: A Heuristic Approach to Treating Diabetic Retinopathy

Julius

Renuka

Hopper

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…When the p-value was less than 0.05, differences between data sets were considered statistically significant as in our earlier investigations. [34][35][36]…”

Section: Discussionmentioning

confidence: 99%

Design, synthesis, and biological activity of novel dithiocarbamate‐methylsulfonyl hybrids as carbonic anhydrase inhibitors

Osmaniye

Türkeş

Demir

et al. 2022

Archiv der Pharmazie

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Carbonic anhydrase (CA) enzymes are involved in many physiological events. These enzymes, which contain Zn 2+ in their structure, can be easily inhibited by dithiocarbamate compounds. In addition, CA enzyme inhibitory activities are known in groups such as sulfonamide and methylsulfonyl. For this purpose, in this study, a series of 23 new dithiocarbamate-methylsulfonyl derivatives were synthesized and their CA enzyme inhibitory activities were investigated. The inhibition potentials of the obtained compounds against the human CA I and CA II enzymes were investigated by the in vitro enzyme isolation method. It is seen that the compounds show activity at the nanomolar level. Molecular docking studies of the compounds were carried out by in silico methods. The poses of compounds 2a, 2e, 2o, and 2t are presented.

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“…To investigate the in vitro inhibitory mechanisms of the novel synthesized N -substituted sulfonyl amides ( 6a–j ) incorporating 1,3,4-oxadiazol structural motif, kinetic studies were made with the variable compound and substrate concentrations, and IC 50 curves, Michaelis–Menten graphs [ 49 – 51 ], and Lineweaver–Burk curves [ 52 – 54 ] were generated as previously reported by Türkeş et al . [ 55 – 57 ].…”

Section: Methodsmentioning

confidence: 99%

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif

et al. 2022

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The acetylcholinesterase and carbonic anhydrase inhibitors (AChEIs and h CAIs) remain key therapeutic agents for many bioactivities such as anti-Alzheimer and antiobesity antiepileptic, anticancer, antiinfective, antiglaucoma, and diuretic effects. Here, it has been attempted to discover novel multi-target AChEIs and h CAIs that are highly potent, orally bioavailable, may be brain penetrant, and have higher effectiveness at lower doses than tacrine and acetazolamide. After detailed investigations both in vitro and in silico, novel N -substituted sulfonyl amide derivatives ( 6a–j ) were determined to be highly potent inhibitors for AChE and h CAs ( K I s are in the range of 23.11–52.49 nM, 18.66–59.62 nM, and 9.33–120.80 nM for AChE, h CA I, and h CA II, respectively). Moreover, according to the cytotoxic effect studies, such as the ADME-Tox, cortex neuron cells, and neuroblastoma SH-SY5Y cell line, compounds 6a , 6d , and 6h , which are the most potent representative versus the target enzymes, were identified as orally bioavailable, highly selective, and brain preferentially distributed AChEIs and h CAIs. The docking studies revealed precise binding modes between 6a , 6d , and 6h and h CA II, h CA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and h CAIs. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10422-8.

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Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin‐4(3H)‐one derivatives as potential aldose reductase inhibitors

Cited by 54 publications

References 116 publications

Inhibition of Aldose Reductase by Novel Phytocompounds: A Heuristic Approach to Treating Diabetic Retinopathy

Inhibition of Aldose Reductase by Novel Phytocompounds: A Heuristic Approach to Treating Diabetic Retinopathy

Design, synthesis, and biological activity of novel dithiocarbamate‐methylsulfonyl hybrids as carbonic anhydrase inhibitors

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif

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