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

Yıl 2025, Cilt: 28 Sayı: 2, 335 - 350, 27.03.2025

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

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

Öz

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.

Anahtar Kelimeler

Alzheimer disease Carbonic anhydrase Acetylcholinesterase Molecular docking Chalcone

Kaynakça

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  • Bale, A. T., Khan, K. M., Salar, U., Chigurupati, S., Fasina, T., Ali, F., & Perveen, S. (2018). Chalcones and -chalcones: As potential α-amylase inhibitors; synthesis, screening, and molecular modelling studies. Bioorganic Chemistry, 79, 179-189.
  • Bandgar, B. P., Gawande, S. S., Bodade, R. G., Totre, J. V., & Khobragade, C. N. (2010). Synthesis and biological evaluation of simple methoxylated chalcones as anticancer, anti-inflammatory and antioxidant agents. Bioorganic & Medicinal Chemistry, 18(3), 1364-1370.
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  • Demir, Y. (2020). Naphthoquinones, benzoquinones, and anthraquinones: Molecular docking, ADME and inhibition studies on human serum paraoxonase-1 associated with cardiovascular diseases. Drug Development Research, 81(5), 628-636
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Asetilkolinesterazı ve Karbonik Anhidraz Izoenzimlerini Hedef Alan Şalkonların Moleküler Yerleştirme Çalışmaları ve Biyolojik Aktiviteleri

Yıl 2025, Cilt: 28 Sayı: 2, 335 - 350, 27.03.2025

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

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

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

Alzheimer Hastalığı Karbonik Anhidraz Asetilkolinesteraz Moleküler Doking Şalkon

Destekleyen Kurum

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)

Teşekkür

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)

Kaynakça

  • Abdel-Halim, M., Keeton, A. B., Gurpinar, E., Gary, B. D., Vogel, S. M., Engel, M., & Abadi, A. H. (2013). Trisubstituted and tetrasubstituted pyrazolines as a novel class of cell-growth inhibitors in tumor cells with wild type p53. Bioorganic & Medicinal Chemistry, 21(23), 7343-7356.
  • Bale, A. T., Khan, K. M., Salar, U., Chigurupati, S., Fasina, T., Ali, F., & Perveen, S. (2018). Chalcones and -chalcones: As potential α-amylase inhibitors; synthesis, screening, and molecular modelling studies. Bioorganic Chemistry, 79, 179-189.
  • Bandgar, B. P., Gawande, S. S., Bodade, R. G., Totre, J. V., & Khobragade, C. N. (2010). Synthesis and biological evaluation of simple methoxylated chalcones as anticancer, anti-inflammatory and antioxidant agents. Bioorganic & Medicinal Chemistry, 18(3), 1364-1370.
  • Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry, 72, 248-254.
  • Choi, J. W., Jang, B. K., Cho, N. C., Park, J. H., Yeon, S. K., Ju, E. J., & Park, K. D. (2015). Synthesis of a series of unsaturated ketone derivatives as selective and reversible monoamine oxidase inhibitors. Bioorganic & Medicinal Chemistry, 23(19), 6486-6496.
  • Demir, Y. (2020). Naphthoquinones, benzoquinones, and anthraquinones: Molecular docking, ADME and inhibition studies on human serum paraoxonase-1 associated with cardiovascular diseases. Drug Development Research, 81(5), 628-636
  • Demir, Y., Ozturk N., Isıyel, M., Ceylan, H. (2024). Effects of Carnosic and Usnic Acid on Pentose Phosphate Pathway Enzymes: An Experimental and Molecular Docking Study. ChemistrySelect, 9, e202401067
  • Dennington, R., Keith, T., Millam, J. (2009). GaussView, version 5, Semichem Inc.: Shawnee Mission, KS. Ellman, G. L., Courtney, K. D., Andres Jr, V., & Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharma, 7(2), 88-90.
  • El-Sayed, N. A., Farag, A. E., Ezzat, M. A. F., Akincioglu, H., Gulcin, I., Abou-Seri, S. M. (2019). Design, synthesis, in vitro and in vivo evaluation of novel pyrrolizine-based compounds with potential activity as cholinesterase inhibitors and anti-Alzheimer's agents. Bioorg. Chem, 93, 10.3312
  • Erdogan, M., Onder, A., Demir Y., Onder, F. C. (2024). Novel Dibenzoazepine-Substituted Triazole Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors and Anticancer Agents: Synthesis, Characterization, Biological Evaluation, and In Silico Studies. ACS Omega, 9, 46860−46878.
  • Ferreira, L. G., Dos Santos, R. N., Oliva, G., Andricopulo, A. D. (2015). Molecular docking and structure-based drug design strategies, Molecules, 20(7), 13384-13421.
  • Ferri, C. P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., & Intl, A. D. (2005). Global prevalence of dementia: a Delphi consensus study. Lancet, 366(9503), 2112-2117.
  • Frisch, M.J., Trucks, G., Schlegel, H., Scuseria, G., Robb, M., Cheeseman, J., Scalmani, G., Barone, V., Mennucci, B., Petersson, G. (2009). Gaussian 09, Revision D. 01, Gaussian, Inc.: Wallingford, CT.
  • Galvin, J. E., Powlishta, K. K., Wilkins, K., McKeel, D. W., Xiong, C. J., Grant, E., & Morris, J. C. (2005). Predictors of-preclinical Alzheimer disease and dementia - A clinicopathologic study. Archives of Neurology, 62(5), 758-765.
  • Guney, M., Coskun, A., Topal, F., Dastan, A., Gulcin, I., Supuran, C.T. (2014). Oxidation of cyanobenzocycloheptatrienes: Synthesis, photooxygenation reaction and carbonic anhydrase isoenzymes inhibition properties of some new benzotropone derivatives. Bioorganic & Medicinal Chemistry, 22(13), 3537-3543.
  • Ivanova, J., Leitans, J., Tanc, M., Kazaks, A., Zalubovskis, R., Supuran, C. T., Tars, K. (2015). X-ray crystallography-promoted drug design of carbonic anhydrase inhibitors. Chemical Communications, 51(33), 7108-7111.
  • Kannan, K., Ramanadham, M., Jones, T. (1984). Structure, refinement, and function of carbonic anhydrase isozymes: refinement of human carbonic anhydrase I. Annals of the New York Academy of Sciences, 429(1), 49-60.
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  • Kocyigit, U. M., Budak, Y., Gurdere, M. B., et al. (2017). Synthesis, characterization, anticancer, antimicrobial and carbonic anhydrase inhibition profiles of novel (3aR,4S,7R,7aS)-2-(4-((E)-3-(3-aryl)acryloyl) phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives. Bioorganic Chemistry, 70, 118-125.
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  • Kovar, S. E., Fourman, C., Kinstedt, C., Williams, B., Morris, C., Cho, K. J., & Ketcha, D. M. (2020). Chalcones bearing a 3,4,5-trimethoxyphenyl motif are capable of selectively inhibiting oncogenic K-Ras signaling. Bioorganic & Medicinal Chemistry Letters, 30(11), 127144.
  • Kumar, R., Sharma, P., Shard, A., Tewary, D. K., Nadda, G., & Sinha, A. K. (2012). Chalcones as promising pesticidal agents against diamondback moth (Plutella xylostella): microwave-assisted synthesis and structure-activity relationship. Medicinal Chemistry Research, 21(6), 922-931.
  • Le Duc, Y., Licsandru, E., Vullo, D., Barboiu, M., & Supuran, C. T. (2017). Carbonic anhydrases activation with 3-amino-1H-1,2,4-triazole-1-carboxamides: Discovery of subnanomolar isoform II activators. Bioorganic & Medicinal Chemistry, 25(5), 1681-1686.
  • Mahmudov, I., Demir, Y., Sert, Y., Abdullayev, Y., Sujayev, A., Alwasel, S. H., Gulcin, I. (2022). Synthesis and inhibition profiles of N-benzyl-and N-allyl aniline derivatives against carbonic anhydrase and acetylcholinesterase–A molecular docking study. Arabian Journal of Chemistry, 15(3), 103645
  • Mai, C. W., Yaeghoobi, M., Abd-Rahman, N., Kang, Y. B., & Pichika, M. R. (2014). Chalcones with electron-withdrawing and electron-donating substituents: Anticancer activity against TRAIL resistant cancer cells, structure-activity relationship analysis and regulation of apoptotic proteins. European Journal of Medicinal Chemistry, 77, 378-387.
  • Marucci, G., Buccioni, M., Dal Ben, D., Lambertucci, C., Volpini, R., & Amenta, F. (2021). Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology, 1(190), 108352.
  • Mazumder, R., Ichudaule, Ghosh, A., Deb, S., & Ghosh, R. (2024). Significance of chalcone scaffolds in medicinal chemistry. Topics in Current Chemistry, 382(3), 22.
  • Meng, X. Y., Zhang, H. X., Mezei, M., Cui, M. (2011). Molecular docking: a powerful approach for structure-based drug discovery. Current Computer-aided Drug Design, 7(2), 146-157.
  • Mert, S., Demir, Y., Sert, Y., Kasımoğulları, R., Gulcin I. (2025). Synthesis, biological evaluation and molecular docking of novel pyrazole derivatives as multitarget acetylcholinesterase and carbonic anhydrase inhibitors. Journal of Molecular Structure, 1319, 139472.
  • Mikus, P., Krajciová, D., Mikulová, M., Horváth, B., Pecher, D., Garaj, V., & Supuran, C. T. (2018). Novel sulfonamides incorporating 1,3,5-triazine and amino acid structural motifs as inhibitors of the physiological carbonic anhydrase isozymes I, II and IV and tumor-associated isozyme IX. Bioorganic Chemistry, 81, 241-252.
  • Ouyang, Y., Li, J. J., Chen, X. Y., Fu, X. Y., Sun, S., & Wu, Q. (2021). Chalcone Derivatives: Role in Anticancer Therapy. Biomolecules, 11(6), 894.
  • Patil, P. S., Dharmaprakash, S. M., Ramakrishna, K., Fun, H. K., Kumar, R. S. S., & Rao, D. N. (2007). Second harmonic generation and crystal growth of new chalcone derivatives. Journal of Crystal Growth, 303(2), 520-524.
  • Petersen, R. C., Parisi, J. E., Dickson, D. W., Johnson, K. A., Knopman, D. S., Boeve, B. F., & Kokmen, E. (2006). Neuropathologic features of amnestic mild cognitive impairment. Archives of Neurology, 63(5), 665-672.
  • Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G., & Kokmen, E. (1999). Mild cognitive impairment - Clinical characterization and outcome. Archives of Neurology, 56(3), 303-308.
  • Poyraz, S., Döndas, H. A., Yamali, C., Belveren, S., Demir, Y., Aydinoglu, S., & Sansano, J. M. (2024). Design, synthesis, biological evaluation and docking analysis of pyrrolidine-benzenesulfonamides as carbonic anhydrase or acetylcholinesterase inhibitors and antimicrobial agents. Journal of Biomolecular Structure & Dynamics, 42(7), 3441-3458.
  • Protein data Bank. https://www.rcsb.org/.
  • Raghavan, S., Manogaran, P., Kuppuswami, B. K., Venkatraman, G., & Narasimha, K. K. G. (2015). Synthesis and anticancer activity of chalcones derived from vanillin and isovanillin. Medicinal Chemistry Research, 24(12), 4157-4165.
  • Roman, B. I., De Ryck, T., Patronov, A., Slavov, S. H., Vanhoecke, B. W. A., Katritzky, A. R., & Stevens, C. V. (2015). 4-Fluoro-3′,4′,5′-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an metastasis model. European Journal of Medicinal Chemistry, 101, 627-639.
  • Russell, A. (1934). The constitution of tannins. Part I. Reduction products of chalkones and the synthesis of a typical phlobatannin. 218-221. Scientific Software http://www.3dsbiovia.com/.
  • Schultze, S., & Grubmüller, H. (2021). Time-lagged independent component analysis of random walks and protein dynamics. Journal of Chemical Theory and Computation, 17(9), 5766-5776.
  • Schwartz, M. A., Rose, B. F., Holton, R. A., Scott, S. W., & Baburao, V. (1977). Intramolecular oxidative coupling of diphenolic, monophenolic, and nonphenolic substrates. Journal of the American Chemical Society, 99(8), 2571-2577.
  • Shibata, K., Katsuyama, I., Matsui, M., & Muramatsu, H. (1991). Synthesis of 3-cyano-2-methylpyridines substituted with heteroaromatics. Journal of Heterocyclic Chemistry, 28(1), 161-165.
  • Shinichi, I., Minako, S., & Ito, K. (1990). Polymer-supported poly(amino acids) as new asymmetric epoxidation catalyst of αβ-unsaturated ketones. Journal of Organic Chemistry, 55(24), 6047-6049.
  • Supuran, C. T. (2008). Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nature Reviews: Drug Discovery, 7(2), 168–181
  • Taylor, R. D., Jewsbury, P. J., Essex, J. W. (2002). A review of protein-small molecule docking methods. Journal of Computer-aided Molecular Design, 16,151-166.
  • Temperini, C., Scozzafava, A., & Supuran, C. T. (2008). Carbonic anhydrase activation and the drug design. Current Pharmaceutical Design, 14(7), 708-715.
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  • Trott, O., Olson, A. J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, Journal of Computational Chemistry, 31(2), 455-461.
  • Tugrak, M., Gul, H. I., Akincioglu, H., & Gulcin, I. (2021a). New chalcone derivatives with pyrazole and sulfonamide pharmacophores as carbonic anhydrase inhibitors. Letters in Drug Design and Discovery, 18(2), 191-198.
  • Tugrak, M., Gul, H. I., Anil, B., & Gülçin, I. (2020). Synthesis and pharmacological effects of novel benzenesulfonamides carrying benzamide moiety as carbonic anhydrase and acetylcholinesterase inhibitors. Turkish Journal of Chemistry, 44(6), 1601.
  • Tugrak, M., Gul, H. I., Demir, Y., & Gulcin, I. (2021b). Synthesis of benzamide derivatives with thiourea-substituted benzenesulfonamides as carbonic anhydrase inhibitors. Archiv Der Pharmazie, 354(2).
  • Tugrak, M., Gul, H. I., Demir, Y., Levent, S., & Gulcin, I. (2021c). Synthesis and in vitro carbonic anhydrases and acetylcholinesterase inhibitory activities of novel imidazolinone-based benzenesulfonamides. Archiv Der Pharmazie, 354(4.
  • Tugrak, M., Gul, H. I., Sakagami, H., Gulcin, I., & Supuran, C. T. (2018). New azafluorenones with cytotoxic and carbonic anhydrase inhibitory properties: 2-Aryl-4-(4-hydroxyphenyl)-5-indeno[1,2-]pyridin-5-ones. Bioorganic Chemistry, 81, 433-439.
  • Tugrak, M., Gul, H. I., Sakagami, H., & Mete, E. (2017). Synthesis and anticancer properties of mono Mannich bases containing vanillin moiety. Medicinal Chemistry Research, 26(7), 1528-1534.
  • Tugrak, M., Yamali, C., Sakagami, H., & Gul, H. I. (2016). Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one and evaluation of their cytotoxicities. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(5), 818-823.
  • Umesha, B., Basavaraju, Y. B., & Mahendra, C. (2015). Synthesis and biological screening of pyrazole moiety containing analogs of podophyllotoxin. Medicinal Chemistry Research, 24(1), 142-151.
  • Vaidya, S. S., Vinaya, H., & Mahajan, S. S. (2012). Microwave-assisted synthesis, pharmacological evaluation, and QSAR studies of 1,3-diaryl-2-propen-1-ones. Medicinal Chemistry Research, 21(12), 4311-4323.
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  • Wu, J. Z., Li, J. L., Cai, Y. P., Pan, Y., Ye, F. Q., Zhang, Y. L., & Liang, G. (2011). Evaluation and discovery of novel synthetic chalcone derivatives as anti-inflammatory agents. Journal of Medicinal Chemistry, 54(23), 8110-8123.
  • Yurt, B., Saglamtas, R., Demir, Y., İzol, E., Diril, H., Caglayan, C. (2024). Determination of in vitro antioxidant, anticholinergic, and antiepileptic activities of some medicinal and aromatic plant extracts. KSU Journal of Agricalture and Nature, 27, (Suppl. 1), 1-15.
Toplam 62 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Biyokimya ve Hücre Biyolojisi (Diğer)
Bölüm ARAŞTIRMA MAKALESİ (Research Article)
Yazarlar

Mehtap Tuğrak Sakarya 0000-0002-6535-6580

Halise İnci Gül 0000-0001-6164-9602

Yusuf Sert 0000-0001-8836-8667

Hülya Akıncıoğlu 0000-0001-5453-0953

İlhami Gülçin 0000-0001-5993-1668

Mustafa Gül 0000-0002-0042-890X

Erken Görünüm Tarihi 20 Mart 2025
Yayımlanma Tarihi 27 Mart 2025
Gönderilme Tarihi 26 Kasım 2024
Kabul Tarihi 15 Şubat 2025
Yayımlandığı Sayı Yıl 2025Cilt: 28 Sayı: 2

Kaynak Göster

APA Tuğrak Sakarya, M., Gül, H. İ., Sert, Y., Akıncıoğlu, H., vd. (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
 Kapak Resmi İndir

21082



2022-JIF = 0.500

2022-JCI = 0.170

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