Molecular Docking Studies and Biological Activities of Chalcones Targeting Acetylcholinesterase, and Carbonic Anhydrase Isoenzymes

Mehtap Tuğrak Sakarya; Halise İnci Gül; Yusuf Sert; Hülya Akıncıoğlu; İlhami Gülçin; Mustafa Gül

doi:10.18016/ksutarimdoga.vi.1591728

TR EN

Asetilkolinesterazı ve Karbonik Anhidraz Izoenzimlerini Hedef Alan Şalkonların Moleküler Yerleştirme Çalışmaları ve Biyolojik Aktiviteleri

Öz

Şalkon molekülleri, medisinal kimyada önemli farmakoforlar olup, karbonik anhidraz (CA) ve asetilkolinesteraz (AChE) enzimleri üzerindeki inhibitör etkiler de dahil çeşitli biyolojik fonksiyonlara sahiptir. Karbonik anhidraz I ve II inhibitörleri, retina ve serebral ödem (CAI), epilepsi ve glokom (CA II) gibi bozuklukların tedavisinde kullanılır. Ayrıca, başlangıçta Alzheimer hastalığını tedavi etmek için oluşturulan asetilkolinesteraz inhibitörlerinin Parkinson hastalığıyla ilişkili hafıza sorunları, davranış bozuklukları ve bilişsel gerileme çeken hastalar için de yararlı olduğu kanıtlanmıştır. Piyasadaki ilaçların olumsuz etkileri bulunmaktadır. Bu nedenle, ortaya çıkan sorunları ele almak için yeni ilaç adaylarına ihtiyaç vardır. Bu çalışmada, CA ve AChE inhibitör etkilerini araştırmak için şalkon bileşikleri sentezlenmiş ve kimyasal yapıları NMR kullanılarak doğrulanmıştır. Bu çalışma ile sentezlenen bileşiklerin karbonik anhidraz ve asetilkolin esteraz enzimleri üzerindeki inhibitör etkileri ilk kez sunulmuştur. Bileşik 1-21'in CA ve AChE inhibitör etkileri açıklanan metodolojiler kullanılarak araştırılmıştır. Yapılan araştırmalar sonucunda bileşiklerin hCA I için 2.65-82.33 µM ve hCA II için 2.63-74.89 µM inhibisyon aralığında olduğu tespit edilirken, referans AZA'nın IC50 değerlerinin ise 46.75 µM (hCA I) ve 38.25 µM (hCA II) olduğu görülmüştür. Dahası, bu bileşikler AChE'yi 15.53-177.46 aralığında inhibe ederken, referans ilaç Tacrin'in IC50 değeri ise 25.78 nM olarak ölçülmüştür. Sentezlenen şalkon türevleri arasında, bileşik 5 hCA I ve AChE için en etkili inhibitör olarak ortaya çıkarken, bileşik 13 hCA II için en güçlüsüydü. AutoDock Vina ile yapılan molecular docking sonuçlarına göre, bileşik 5 hCA I (-8.0 kcal mol⁻¹) ve AChE (-7.0 kcal mol⁻¹) için en güçlü afiniteyi gösterirken, bileşik 13 hCA II (-8.1 kcal mol⁻¹) için en güçlü inhibitör olarak belirlendi. Kilit katalitik kalıntılarla etkileşimleri, halojen ve metoksi gruplarının enzim bağlanmasını, stabilitesini ve hidrojen bağlarını güçlendirdiğini göstermektedir. Bu bulgular, bu bileşiklerin CA ve AChE ile ilişkili bozukluklar için potansiyel ilaç adayları olarak umut vadettiğini göstermektedir.

Anahtar Kelimeler

Molecular Docking Studies and Biological Activities of Chalcones Targeting Acetylcholinesterase, and Carbonic Anhydrase Isoenzymes

Abstract

Chalcone molecules are important pharmacophores in medicinal chemistry and have various biological functions, including inhibitory effects on the enzymes carbonic anhydrase (CA) and acetylcholinesterase (AChE). Carbonic anhydrase I and II inhibitors are used in the treatment of disorders such as retinal and cerebral edema (CAI), epilepsy, and glaucoma (CA II). Furthermore, acetylcholinesterase inhibitors, which were originally created to treat Alzheimer's disease, have proven useful for patients suffering from Parkinson's disease-related memory problems, behavioral disorders, and cognitive decline. The drugs on the market have adverse effects. Therefore, new drug candidates are required to address the issues raised. In this study, chalcone compounds were synthesized to investigate their CA and AChE inhibitory effects and their chemical structures were confirmed using NMR. The inhibitory effects of the synthesized compounds on carbonic anhydrase and acetylcholine esterase enzymes were presented for the first time in this study. Carbonic anhydrases and AChE inhibitory effects of 1-21 were investigated using described methodologies. As a result of the studies, it was determined that the compounds were in the inhibition range of 2.65-82.33 µM for hCA I and 2.63-74.89 µM for hCA II, while the IC50 values of the reference AZA were 46.75 µM (hCA I) and 38.25 µM (hCA II). Moreover, these compounds inhibited AChE in the range of 15.53-177.46, while the IC50 value of the reference drug Tacrin was measured as 25.78 nM. Among the synthesized chalcone derivatives, compound 5 emerged as the most potent inhibitor for hCA I and AChE, while compound 13 was the strongest for hCA II. AutoDock Vina docking results showed that compound 5 had the strongest affinity for hCA I (-8.0 kcal mol⁻¹) and AChE (-7.0 kcal mol⁻¹), while compound 13 was most potent for hCA II (-8.1 kcal mol⁻¹). Key interactions with catalytic residues suggest that halogen and methoxy groups enhance enzyme binding, stability, and hydrogen bonding. These findings suggest that these compounds hold promise as potential drug candidates for CA and AChE related disorders.

Keywords

Supporting Institution

The authors especially thanks to Prof. Dr. Fatih UCUN for his helpful contribution for Gaussian calculations, Dr. Barıs Anıl for contributions and TUBITAK for financial support (Project Number: 117S939)

Thanks

The authors especially thanks to Prof. Dr. Fatih UCUN for his helpful contribution for Gaussian calculations, Dr. Barıs Anıl for contributions and TUBITAK for financial support (Project Number: 117S939)

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Details

Primary Language

English

Subjects

Biochemistry and Cell Biology (Other)

Journal Section

Research Article

Authors

Mehtap Tuğrak Sakarya ^*
0000-0002-6535-6580
Türkiye

Halise İnci Gül
0000-0001-6164-9602
Türkiye

Yusuf Sert
0000-0001-8836-8667
Türkiye

Hülya Akıncıoğlu
0000-0001-5453-0953
Türkiye

İlhami Gülçin
0000-0001-5993-1668
Türkiye

Mustafa Gül
0000-0002-0042-890X
Türkiye

Early Pub Date

March 20, 2025

Publication Date

March 27, 2025

Submission Date

November 26, 2024

Acceptance Date

February 15, 2025

Published in Issue

Year 2025 Volume: 28 Number: 2

DOI

https://doi.org/10.18016/ksutarimdoga.vi.1591728

IZ

https://izlik.org/JA75MW87UK

Cite

RIS / Bibtex

APA

Tuğrak Sakarya, M., Gül, H. İ., Sert, Y., Akıncıoğlu, H., Gülçin, İ., & Gül, M. (2025). Molecular Docking Studies and Biological Activities of Chalcones Targeting Acetylcholinesterase, and Carbonic Anhydrase Isoenzymes. Kahramanmaraş Sütçü İmam Üniversitesi Tarım Ve Doğa Dergisi, 28(2), 335-350. https://doi.org/10.18016/ksutarimdoga.vi.1591728

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https://doi.org/10.1016/j.molstruc.2026.145363