SAR Evaluation of Disubstituted Tacrine Analogues as Promising Cholinesterase and Carbonic Anhydrase Inhibitors
By: Okten, Salih
.
Contributor(s): Ekiz, Makbule.
Publisher: Bengaluru Indian journal of pharmaceutical education and research 2019Edition: Vol.53(2), Apr-Jun.Description: 268-275p.Subject(s): PHARMACEUTICSOnline resources: Click here
In:
Indian journal of pharmaceutical education and researchSummary: 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 investigatedinhibition 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 (IC50= 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 Ki in the range of 43.81–471.67 nM, as well as a moderate selectivity toward hCA II isoenzyme with Kiin 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 memberedhydrocycle 3 derivativesmay be novel hCA I and II enzyme inhibitors
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School of Pharmacy Archieval Section | Not for loan | 2019990 |
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 investigatedinhibition 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 (IC50= 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 Ki in the range of 43.81–471.67 nM, as well as a moderate selectivity toward hCA II isoenzyme with Kiin 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 memberedhydrocycle 3 derivativesmay be novel hCA I and II enzyme inhibitors
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