Synthesis, biological evaluation and in silico studies of novel N-substituted phthalazine sulfonamide compounds as potent carbonic anhydrase and acetylcholinesterase inhibitors

Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Çoçaj, Liridon; Nixha, Arleta Rifati; Beydemır, Şükrü

doi:10.1016/j.bioorg.2019.103004

Cited by 121 publications

(62 citation statements)

References 75 publications

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“…Studied compounds displayed potential inhibition impact on hCA isoenzymes. K i constants were found as in the range of 6.80±0.10‐85.91±7.57 nM for hCA I and 6.32±0.06 to 128.93±23.11 nM for hCA II . In another study, novel 2‐aminopyridine liganded Pd(II) N‐heterocyclic carbene complexes were synthesized and tested inhibitory effects towards some methabolic enzymes such as α‐glycosidase, hCA I and II isoforms, butyrylcholinesterase, aldose reductase, and AChE.…”

Section: Resultsmentioning

confidence: 99%

New Isoindole‐1,3‐dione Substituted Sulfonamides as Potent Inhibitors of Carbonic Anhydrase and Acetylcholinesterase: Design, Synthesis, and Biological Evaluation

et al. 2019

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Herein, a series of isoindole‐1,3‐dione substituted sulfonamide derivatives (3, 4 a–k) were designed, synthesized, and biologically evaluated, as inhibitors of carbonic anhydrase (CA) and acetylcholinesterase (AChE). CA and AChE inhibitory activities of newly synthesized isoindole‐1,3‐dione substituted sulfonamides compounds (3, 4 a–k) towards the hCA I, II, and AChE were evaluated utilizing the Verpoorte's and Ellman's assays and checked against that of standard inhibitors, acetazolamide (AAZ) and tacrine (TAC). The developed compounds (3, 4 a–k) showed the potent hCA isoenzyme inhibitory effect with Ki constants ranging from 7.96 to 48.34 nM, compared to AAZ (Kis; 436.20 nM for hCA I and 93.53 nM for hCA II). Among these derivatives; 1,3‐dioxo‐1,3‐dihydroisobenzofuran‐5‐carbocyclic acid (3) and benzyl‐1,3‐dioxo‐2‐(4‐sulfomophenyl)isoindoline‐5‐carboxylate (4 i) determined to be effective AChE inhibitors (Kis, 103.51 and 108.92 nM, respectively); these compounds were almost as potent to TAC (Ki, 109.75 nM). Furthermore, molecular docking studies of derivatives 3 and 4 i were carried out utilizing the crystal structures of hCA I (PDB Code: 4WR7), II (PDB Code: 4HT0) isozymes and AChE (PDB Code: 4EY7) receptors to study their binding interactions.

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Section: Resultsmentioning

confidence: 99%

New Isoindole‐1,3‐dione Substituted Sulfonamides as Potent Inhibitors of Carbonic Anhydrase and Acetylcholinesterase: Design, Synthesis, and Biological Evaluation

et al. 2019

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“…After the enzyme purification, the purity degree of the enzyme was controlled according to Laemmli's method by using 3–8% batch sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE). The electrophoresis process was carried out according to previous papers …”

Section: Methodsmentioning

confidence: 99%

The behaviour of some antihypertension drugs on human serum paraoxonase-1: an important protector enzyme against atherosclerosis

Demir

2019

Journal of Pharmacy and Pharmacology

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Objectives Paraoxonase‐1 (PON1) enzyme is related to high‐density lipoprotein (HDL), which is calcium dependent. It has essential roles such as protecting LDL against oxidation and detoxification of highly toxic substances. It is a significant risk to reduce the levels of this enzyme in patients with diabetes mellitus, cardiovascular diseases, hyperthyroidism and chronic renal failure. Methods Here, it was reported that the purification of human serum PON1 using straightforward methods and determination of the interactions between some antihypertension drugs and the enzyme. Key finding It was found that these drugs exhibit potential inhibitor properties for human serum PON1 with IC50 values in the range of 131.40–369.40 μm and Ki values in the range of 56.24 ± 6.75–286.74 ± 28.28 μm. These drugs showed different inhibition mechanisms. It was determined that midodrine and nadolol were exhibited competitive inhibition, but atenolol and pindolol were exhibited non‐competitive inhibition. Conclusion Usage of these drugs would be hazardous in some cases.

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“…The drugs structures were retrieved from the chemical database (https://pubchem.ncbi.nlm.nih.gov; PubChem CID: 4679, 4594 and 9568614 for pantoprazole, omeprazole and esomeprazole, respectively). Converting and optimizing (OPLS3e) of the ligands from 2D to 3D were carried out using LigPrep . 2‐hydroxyquinoline was utilized as a reference inhibitor agent .…”

Section: Methodsmentioning

confidence: 99%

A potential risk factor for paraoxonase 1: in silico and in-vitro analysis of the biological activity of proton-pump inhibitors

Türkeş

2019

Journal of Pharmacy and Pharmacology

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Objectives Proton‐pump inhibitors (PPIs) are drugs commonly utilized by about 7% of adults in the world. Recent researches have shown that there are countless and severe side effects of these drugs. This situation has raised concern among clinicians and patients alike. The purpose of this study is to contribute the novel drug discovery and development technology and toxicology field by researching interactions of PPIs on paraoxonase 1. Methods In this study, the paraoxonase 1 enzyme was purified from human serum by using rapid and straightforward chromatographic techniques. Subsequently, the inhibition effects of pantoprazole, omeprazole, and esomeprazole, PPIs, were investigated on paraoxonase 1. Besides, molecular docking studies were performed to unravel the binding mechanism between the enzyme and drugs. Key findings All drugs showed potent inhibitory activities. IC50 of the drugs values were 54.780 ± 0.524, 86.470 ± 0.818 and 93.390 ± 0.885 mm and Ki constants were found as 39.895 ± 0.005 mm, 70.112 ± 0.010 mm and 78.868 ± 0.008 mm, respectively. The binding scores observed in silico studies were found to agree with the obtained from in‐vitro experimental results. Conclusions We observed that the drugs decreased PON1 activity at low concentrations. The results show that adjusting the dosages of these medications is a crucial case for each patient. The physicians should more carefully interpret whether there is an essential indication before prescribing PPIs and, if there is, to approve the proper dosing for the situation.

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Synthesis, biological evaluation and in silico studies of novel N-substituted phthalazine sulfonamide compounds as potent carbonic anhydrase and acetylcholinesterase inhibitors

Cited by 121 publications

References 75 publications

New Isoindole‐1,3‐dione Substituted Sulfonamides as Potent Inhibitors of Carbonic Anhydrase and Acetylcholinesterase: Design, Synthesis, and Biological Evaluation

New Isoindole‐1,3‐dione Substituted Sulfonamides as Potent Inhibitors of Carbonic Anhydrase and Acetylcholinesterase: Design, Synthesis, and Biological Evaluation

The behaviour of some antihypertension drugs on human serum paraoxonase-1: an important protector enzyme against atherosclerosis

A potential risk factor for paraoxonase 1: in silico and in-vitro analysis of the biological activity of proton-pump inhibitors

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