Synthesis and in silico studies of triazene‐substituted sulfamerazine derivatives as acetylcholinesterase and carbonic anhydrases inhibitors

Abstract

A novel series of sulfonamides, 4‐(3‐phenyltriaz‐1‐en‐1‐yl)‐N‐(4‐methyl‐2‐pyrimidinyl)benzenesulfonamides (1–9), was designed and synthesized by the diazo reaction between sulfamerazine and substituted aromatic amines for the first time. Their chemical structures were characterized by 1H nuclear magnetic resonance (NMR), 13C NMR, and high‐resolution mass spectra. The newly synthesized compounds were evaluated in terms of acetylcholineasterase (AChE) and human carbonic anhydrases (hCA) I and II isoenzymes inhibitory activities. According to the AChE inhibition results, the Ki values of the compounds 1–9 were in the range of 19.9 ± 1.5 to 96.5 ± 20.7 nM against AChE. Tacrine was used as the reference drug and its Ki value was 49.2 ± 2.7 nM against AChE. The Ki values of the compounds 1–9 were in the range of 10.2 ± 2.6 to 101.4 ± 27.8 nM against hCA I, whereas they were 18.3 ± 4.4 to 48.1 ± 4.5 nM against hCA II. Acetazolamide was used as a reference drug and its Ki values were 72.2 ± 5.4 and 52.2 ± 5.7 nM against hCA I and hCA II, respectively. The most active compounds, 1 (nonsubstituted) against AChE, 5 (4‐ethoxy‐substituted) against hCA I, and 8 (4‐bromo‐substituted) against hCA II, were chosen and docked at the binding sites of these enzymes to explain the inhibitory activities of the series. The newly synthesized compounds presented satisfactory pharmacokinetic properties via the estimation of ADME properties.

Novel Mannich bases with strong carbonic anhydrases and acetylcholinesterase inhibition effects: 3-(aminomethyl)-6-{3-[4-(trifluoromethyl)phenyl]acryloyl}-2(3H)- benzoxazolones

“…Acetylcholinesterase enzyme inhibition assay was performed according to our previous studies [4,41,[51][52][53][54][55]. The inhibition effects of the compounds 1 and 1a-g on AChE enzyme, obtained from electric eel [56], were recorded in accordance with Ellman's method as demonstrated previously in detail [51,52,57].…”

“…CA inhibition assay was recorded according to previous studies [4,10,27,49,[60][61][62][63][64]. The hCA I and II isoenzymes were purified from human red blood cells by sepharose-4B-L-tyrosine-sulfanilamide affinity chromatography [65], which was used as an affinity matrix for selective retention of both hCA isoenzymes [27,66].…”

“…Although the disease cannot be cured, its progression can be stopped. According to the cholinergic hypothesis, which is one of the theses to understand the pathogenesis of the disease, losses occur both in the level of acetylcholine and cholinergic neurons in the cerebral cortex in AD [3][4][5]. For this purpose, many cholinesterase inhibitors such as donepezil, tacrine, and rivastigmine are used in the clinic.…”

“…Among hCAs, hCA I has an important function in the regulation of retinal edema [15,16]. Besides, hCA II isozyme inhibitor compounds are used in clinics as antiedema, antiglaucoma, and antiepileptic agents [4,12,[15][16][17][18]. However, the hCA inhibitors used have undesired side effects because of having low selectivity to these isoenzymes [12,[16][17][18].…”

Transition‐Metal Complexes of Bidentate Schiff‐Base Ligands: In Vitro and In Silico Evaluation as Non‐Classical Carbonic Anhydrase and Potential Acetylcholinesterase Inhibitors

“…Especially in recent years, the development of hCAIs has attracted significant attention as it shows that hCAIs can be supportive in anti-cancer treatment and inhibition of hCAs associated with hypoxic cancers offer therapeutic potential. [15][16][17] Acetylcholinesterase (AChE) is found mostly in blood, striated muscle, and brain. AChE enzyme is the most significant enzyme in living organisms associate with synapse cholinergic and other neural mechanisms.…”