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

Indian Journal of Pharmaceutical Education and Research

  • Salih Ökten1Department of Maths and Science Education, Faculty of Education, Kırıkkale University, Yahşihan, Kırıkkale, TURKEY.
  • Makbule Ekiz2Department of Chemistry, Faculty of Art and Science, Sakarya University, Serdivan, 54187, Sakarya, TURKEY.
  • Ahmet Tutar2Department of Chemistry, Faculty of Art and Science, Sakarya University, Serdivan, 54187, Sakarya, TURKEY.
  • Burcu Bütün3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093, İstanbul, TURKEY.
  • Ümit Muhammet Koçyiğit4Department of Medical Techniques, Vocational School of Health Services, Cumhuriyet University, 58140, Sivas, TURKEY.
  • Gülaçtı Topçu5Department of Pharmacognosy/Phytochemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093, İstanbul, TURKEY.
  • İlhami Gülçin6Department of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, TURKEY.

Volume 53 Issue 2 Pages 268-275

DOI: 10.5530/ijper.53.2.35

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 (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 Ki 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.

Keywords

  • Tacrine derivatives
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Carbonic
  • anhydrase
  • Anticholinegic
  • SAR
IJOPP

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