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Published on:February 2019
Indian Journal of Pharmaceutical Education and Research, 2019; 53(2):268-275
Original Article | doi:10.5530/ijper.53.2.35

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


Authors and affiliation (s):

Salih Ökten1,*, Makbule Ekiz2, Ahmet Tutar2, Burcu Bütün3, Ümit Muhammet Koçyiğit4, Gülaçtı Topçu5, İlhami Gülçin6

1Department of Maths and Science Education, Faculty of Education, Kırıkkale University, Yahşihan, Kırıkkale, TURKEY.

2Department of Chemistry, Faculty of Art and Science, Sakarya University, Serdivan, 54187, Sakarya, TURKEY.

3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093, İstanbul, TURKEY.

4Department of Medical Techniques, Vocational School of Health Services, Cumhuriyet University, 58140, Sivas, TURKEY.

5Department of Pharmacognosy/Phytochemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093, İstanbul, TURKEY.

6Department of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, TURKEY.

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.

Key words: Tacrine derivatives, Acetylcholinesterase, Butyrylcholinesterase, Carbonic anhydrase, Anticholinegic, SAR.

 

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IJPER - An Official Publication of Association of Pharmaceutical Teachers of India is pleased to announce continued growth in the 2019 Release of Journal Citation Reports (source: 2018 Web of Science Data).

 

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The Official Journal of Association of Pharmaceutical Teachers of India (APTI)
(Registered under Registration of Societies Act XXI of 1860 No. 122 of 1966-1967, Lucknow)

Indian Journal of Pharmaceutical Education and Research (IJPER) [ISSN-0019-5464] is the official journal of Association of Pharmaceutical Teachers of India (APTI) and is being published since 1967.

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