SAR Evaluation of Disubstituted Tacrine Analogues as Promising Cholinesterase and Carbonic Anhydrase Inhibitors

Abstract

Background: The inhibition of both hydrolysis products of acetylcholine (ACh), Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE), is essential for successful treatment of Alzhemier patients. Objectives: This study was investigated inhibition potentials of recently synthesized disubstituted tacrines derivatives on going our research against AChE, BChE and carbonic anhydrase cyctosolic (hCA I and II) enzymes to explore the Structure activity relationship (SAR). Methods: Inhibitory activities of tested compounds against AChE and BChE were measured by spectrophotometric method, developed by Ellman et al. Furthermore, the disubstituted tacrines were determined as inhibitors of two physiologically relevant CA isoforms, the cytosolic hCA I and II by an esterase assay method. Results: The silyl, thiomethyl and cyano substituted seven membered hydrocycle tacrines (9, 11 and 14) significantly inhibited AChE, compared with starting compound 3 (6,8-dibromo-2,3,4,5-teytrahydro-1H-cyclohepta[1,2-b] quinoline) and reference compounds, galantamine and tacrine, while methoxy substituted seven membered hydrocycle tacrine derivative 10 showed selective inhibition against BChE (IC 50 = 563 nM). Interestingly, disubstituted tacrines displayed higher or parallel inhibition to galantamine. Additionally, all these tacrine analogues were recorded to be powerful inhibitor compounds of the cytosolic isoenzyme hCA I with K i in the range of 43.81-471.67 nM, as well as a moderate selectivity toward hCA II isoenzyme with K i in the range from 87.14 to 614.68 nM compared with AZA, as standard. Conclusion: The disubstituted seven membered hydrocycle tacrine analogues 9-12 and 14 may have promising anti Alzhemier drug candidate and dibromo six membered hydrocycle 2 and dibromo seven membered hydrocycle 3 derivatives may be novel hCA I and II enzyme inhibitors.

The inhibition profile of sesamol against α-glycosidase and acetylcholinesterase enzymes

“…Comparing current results with previous results, it was found that novel bromophenols (Ki: 159.6-924.2 nM) [4] , oxazolidinone (Ki: 16.5-35.6 nM) [48] , pyrazolines (Ki: 48.2-84.1 nM) [76] , hydrazones (Ki: 66-128 nM) [77] , tacrine derivatives (Ki: 68-8480 nM) [78] , sulfamides (Ki: 0.027-0.076 nM) [79] , olivetol (Ki: 3.40 nM) [73] , and benzenesulfonamides (Ki: 22.7-109.1 nM) [80] effectively inhibited AChE enzyme. As seen in Figure 4, α-glycosidase enzyme, which released from intestine cells, hydrolyzes the oligosaccharides and polysaccharide to monosaccharide units, such as glucose and fructose in small intestine.…”

Quinoline‐based promising anticancer and antibacterial agents, and some metabolic enzyme inhibitors

“…An esterase assay method [41,42] was used to investigate the inhibition potentials of substituted quinoline derivatives against two physiologically relevant CA isoforms, the slower cytosolic isoform (hCA I) and the more rapid cytosolic isoenzyme (hCA II). In this assay, acetazolamide (AZA) was used as a standard drug due to its utilization in clinical application as a carbonic anhydrase inhibitor.…”

“…In our recent studies, [6][7][8]15] the antiproliferative activities of 6,8-dibromo-1,2,3,4tetrahydroquinoline (3), 5,7-dibromo-8-hydroxyquinoline (17), 6bromo-8-cyano-1,2,3,4-tetrahydroquinoline, and nitrated 3,6,8tribromoquinoline (5) against HeLa, HT29, and C6 cell lines using sulforhodamine-B stain (SRB) and BCPE assays were determined. In the present study, the substituted quinoline derivatives (Table 1) were prepared according to reported procedures [6,30,[39][40][41][42] Table 1 and 2). Our previous results obtained by SRB assay [15] confirmed that 6-bromo-8-cyanotetrahydroquinoline (7) did not display an antiproliferative activity against HeLa and HT29 cells.…”

Synthesis, characterization, molecular docking, and biological activities of coumarin–1,2,3‐triazole‐acetamide hybrid derivatives

“…As a result of this mechanism, dominant CA II isoform is responsible for regulating the intraocular pressure (IOP) that leads to a secondary chronic open‐angle glaucoma. [ 59,60 ] The high IOP is harmful for the optic nerve in the eye. Thus, CA II inhibition reduces a high IOP normally accompanying glaucoma.…”