Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: novel sulfamoylcarbamates and sulfamides derived from acetophenones.
In this study, several novel sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9±8.9-687.5±84.3 pM for hCA I, and 48.80±8.2-672.2±71.9pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52±0.61-38.28±6.84pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17-21 and sulfamide derivatives 22-26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity.
Ağrı İbrahim Çeçen University, Central Researching Laboratory, Ağrı, Turkey; Atatürk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey.
Akın
A
Akıncıoğlu
Ağrı İbrahim Çeçen University, Central Researching Laboratory, Ağrı, Turkey; Atatürk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey.
Hülya
H
Akıncıoğlu
Atatürk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey; Fetal Programming of Diseases Research Chair, Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia.
İlhami
İ
Gülçin
Department of Biophysics, School of Medicine, Bahçeşehir University, İstanbul, Turkey.
Serdar
S
Durdagi
Università degli Studi di Firenze, Neurofarba dept., Via U Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy.
Claudiu T
CT
Supuran
Atatürk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey. Electronic address: sgoksu@atauni.edu.tr.
Süleyman
S
Göksu
D000098:Acetophenones / Q000737:chemistry*; D000110:Acetylcholinesterase / Q000737:chemistry*; D000586:Amination; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors* / Q000737:chemistry; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D017953:Isocyanates; D007700:Kinetics; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry*
D000098:Acetophenones; D002257:Carbonic Anhydrase Inhibitors; D002800:Cholinesterase Inhibitors; D017953:Isocyanates; D013449:Sulfonamides; C487390:chlorosulfonyl isocyanate; D000110:Acetylcholinesterase; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II
Acetylcholine esterase; Carbonic anhydrase; Enzyme inhibition; Hybrid molecules; Molecular docking; Sulfamide; Sulfamoylcarbamate