Nitrofurantoin with Anticholinergic Effect: A Different in Vitro Approach to Alzheimer's Disease

Yıl 2024, Cilt: 1 Sayı: 1, 1 - 12, 10.10.2024

Şeyma Kandemir , Cüneyt Türkeş

Öz

Alzheimer's disease (AD), a leading cause of dementia, severely affects cognitive function, with the depletion of acetylcholine being a pivotal factor in its pathogenesis. This study delves into the inhibitory potential of the nitrofuran analogue, nitrofurantoin on cholinesterases (ChEs) using comprehensive in vitro approaches. Our findings indicate that nitrofurantoin exhibits differential inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with inhibition constants (KI) of 6.77 ± 0.56 μM for AChE and 9.48 ± 0.69 μM for BChE. These values, although less potent than those of the reference drug tacrine (KIs of 0.17 ± 0.01 μM for AChE and 0.13 ± 0.01 μM for BChE), suggest a noteworthy anticholinergic capability. By providing detailed insights into the enzyme inhibition dynamics, this study lays the groundwork for optimizing nitrofuran derivatives in the therapeutic landscape of AD. The implications of these findings extend to the broader context of pharmacological advancements, highlighting the significance of targeted enzyme inhibition in managing neurodegenerative diseases. Future research building on these results could lead to the development of more effective treatments, enhancing the quality of life for individuals affected by AD and offering new avenues for clinical intervention.

Anahtar Kelimeler

Acetylcholinesterase, Butyrylcholinesterase, Alzheimer, Nitrofuran derivative, Enzyme-ligand interactions

Antikolinerjik etkili nitrofuranlar: Alzheimer hastalığının tedavisine in vitro yaklaşım

Öz

Demansın önde gelen nedenlerinden biri olan Alzheimer hastalığı (AD), bilişsel işlevi ciddi şekilde etkiler ve asetilkolinin tükenmesi patogenezinde önemli bir faktördür. Bu çalışma, kapsamlı in vitro yaklaşımlar kullanarak nitrofuran analoğu olan nitrofurantoinin kolinesterazlar (ChE'ler) üzerindeki inhibitör potansiyelini araştırmaktadır. Bulgularımız, nitrofurantoinin asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BChE) üzerinde farklı inhibisyon gösterdiğini, AChE için 6,77 ± 0,56 μM ve BChE için 9,48 ± 0,69 μM inhibisyon sabitleri (KI)’ne sahip olduğunu göstermektedir. Bu değerler, referans ilaç takrinin KI değerlerinden (AChE için 0,17 ± 0,01 μM ve BChE için 0,13 ± 0,01 μM) daha az etkili olsa da, dikkate değer bir antikolinerjik kapasiteye işaret etmektedir. Bu çalışma, enzim inhibisyon dinamiklerine dair ayrıntılı içgörüler sağlayarak, nitrofuran türevlerinin AD'nin terapötik manzarasında optimize edilmesi için temel oluşturmaktadır. Bu bulguların çıkarımları, farmakolojik gelişmelerin daha geniş bağlamına uzanmakta ve nörodejeneratif hastalıkların yönetiminde hedeflenen enzim inhibisyonunun önemini vurgulamaktadır. Bu sonuçlara dayanarak yapılacak gelecekteki araştırmalar, daha etkili tedavilerin geliştirilmesine, AD'den etkilenen bireylerin yaşam kalitesinin artırılmasına ve klinik müdahale için yeni yollar sunulmasına yol açabilir.

Anahtar Kelimeler

Asetilkolinesteraz, Bütirilkolinesteraz, Alzheimer hastalığı, Nitrofuran türevi, Enzim-ligand etkileşimleri

Kaynakça

• AlFadly, E. D., Elzahhar, P. A., Tramarin, A., Elkazaz, S., Shaltout, H., Abu-Serie, M. M., . . . & Belal, A. S. F. (2019). Tackling neuroinflammation and cholinergic deficit in Alzheimer's disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase. European Journal of Medicinal Chemistry, 167, 161-186.
• Bailly, C. (2019). Toward a repositioning of the antibacterial drug nifuroxazide for cancer treatment. Drug Discovery Today, 24(9), 1930-1936.
• Bandyopadhyay, S. (2021). Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction. Frontiers in Aging Neuroscience, 13.
• Bortolami, M., Rocco, D., Messore, A., Di Santo, R., Costi, R., Madia, V. N., . . . & Pandolfi, F. (2021). Acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease – a patent review (2016–present). Expert Opinion on Therapeutic Patents, 31(5), 399-420.
• De Boer, D., Nguyen, N., Mao, J., Moore, J., & Sorin, E. J. (2021). A Comprehensive Review of Cholinesterase Modeling and Simulation. Biomolecules, 11(4), 580.
• Ding, Z., Li, F., Zhong, C., Li, F., Liu, Y., Wang, S., . . . & Li, W. (2020). Structure-based design and synthesis of novel furan-diketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer. Bioorganic & Medicinal Chemistry, 28(10), 115435.
• El-Wakil, M. H., Meheissen, M. A., & Abu-Serie, M. M. (2021). Nitrofurazone repurposing towards design and synthesis of novel apoptotic-dependent anticancer and antimicrobial agents: Biological evaluation, kinetic studies and molecular modeling. Bioorganic Chemistry, 113, 104971.
• Ellman, G. L., Courtney, K. D., Andres Jr, V., & Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology, 7(2), 88-95.
• Fernando da Silva Santos-Júnior, P., Rocha Silva, L., José Quintans-Júnior, L., & Ferreira da Silva-Júnior, E. (2022). Nitro compounds against trypanosomatidae parasites: Heroes or villains? Bioorganic & Medicinal Chemistry Letters, 75, 128930.
• Foscolos, A.-S., Papanastasiou, I., Foscolos, G. B., Tsotinis, A., Kellici, T. F., Mavromoustakos, T., . . . & Kelly, J. M. (2016). New hydrazones of 5-nitro-2-furaldehyde with adamantanealkanohydrazides: synthesis and in vitro trypanocidal activity. Medicinal Chemistry Communications, 7(6), 1229-1236.
• Gallardo-Garrido, C., Cho, Y., Cortés-Rios, J., Vasquez, D., Pessoa-Mahana, C. D., Araya-Maturana, R., . . . & Faundez, M. (2020). Nitrofuran drugs beyond redox cycling: Evidence of Nitroreduction-independent cytotoxicity mechanism. Toxicology and Applied Pharmacology, 401, 115104.
• Gantner, M. E., Prada Gori, D. N., Llanos, M. A., Talevi, A., Angeli, A., Vullo, D., . . . & Gavernet, L. (2022). Identification of New Carbonic Anhydrase VII Inhibitors by Structure-Based Virtual Screening. Journal of Chemical Information and Modeling, 62(19), 4760-4770.
• Gao, H., Jiang, Y., Zhan, J., & Sun, Y. (2021). Pharmacophore-based drug design of AChE and BChE dual inhibitors as potential anti-Alzheimer’s disease agents. Bioorganic Chemistry, 114, 105149.
• Hampel, H., Mesulam, M.-M., Cuello, A. C., Farlow, M. R., Giacobini, E., Grossberg, G. T., . . . & Khachaturian, Z. S. (2018). The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 141(7), 1917-1933.
• Huang, L., Huang, C., Yan, Y., Sun, L., & Li, H. (2022). Urinary Tract Infection Etiological Profiles and Antibiotic Resistance Patterns Varied Among Different Age Categories: A Retrospective Study From a Tertiary General Hospital During a 12-Year Period. Frontiers in Microbiology, 12.
• Kalinin, S., Vedekhina, T., Paramonova, P., & Krasavin, M. (2021). Antimicrobial activity of 5-membered nitroheteroaromatic compounds beyond nitrofurans and nitroimidazoles: Recent progress. Current Medicinal Chemistry, 28(29), 5926-5982.
• Kannigadu, C., Aucamp, J., & N'Da, D. D. (2022). Exploring novel nitrofuranyl sulfonohydrazides as anti-Leishmania and anti-cancer agents: Synthesis, in vitro efficacy and hit identification. Chemical Biology & Drug Design, 100(2), 267-279.
• Konwar, M., Gogtay, N. J., Ravi, R., Thatte, U. M., & Bose, D. (2022). Evaluation of efficacy and safety of fosfomycin versus nitrofurantoin for the treatment of uncomplicated lower urinary tract infection (UTI) in women – A systematic review and meta-analysis. Journal of Chemotherapy, 34(3), 139-148.
• Kumar Sahoo, S., Maddipatla, S., Nageswara Rao Gajula, S., Naiyaz Ahmad, M., Kaul, G., Nanduri, S., … & Madhavi Yaddanapudi, V. (2022). Identification of nitrofuranylchalcone tethered benzoxazole-2-amines as potent inhibitors of drug resistant Mycobacterium tuberculosis demonstrating bactericidal efficacy. Bioorganic & Medicinal Chemistry, 64, 116777.
• Lewkowski, J., Rogacz, D., & Rychter, P. (2019). Hazardous ecotoxicological impact of two commonly used nitrofuran-derived antibacterial drugs: Furazolidone and nitrofurantoin. Chemosphere, 222, 381-390.
• Li, Q., Chen, Y., Xing, S., Liao, Q., Xiong, B., Wang, Y., . . . & Sun, H. (2021). Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection. Journal of Medicinal Chemistry, 64(10), 6856-6876.
• Li, Q., Xing, S., Chen, Y., Liao, Q., Xiong, B., He, S., . . . & Sun, H. (2020). Discovery and Biological Evaluation of a Novel Highly Potent Selective Butyrylcholinsterase Inhibitor. Journal of Medicinal Chemistry, 63(17), 10030-10044.
• Lineweaver, H., & Burk, D. (1934). The determination of enzyme dissociation constants. Journal of the American chemical society, 56(3), 658-666.
• Lolak, N., Akocak, S., Durgun, M., Duran, H. E., Necip, A., Türkeş, C., . . . & Beydemir, Ş. (2023). Novel bis-ureido-substituted sulfaguanidines and sulfisoxazoles as carbonic anhydrase and acetylcholinesterase inhibitors. Molecular Diversity, 27(4), 1735-1749.
• Melekhin, A. O., Tolmacheva, V. V., Shubina, E. G., Dmitrienko, S. G., Apyari, V. V., & Grudev, A. I. (2021). Determination of nitrofuran metabolites in honey using a new derivatization reagent, magnetic solid-phase extraction and LC–MS/MS. Talanta, 230, 122310.
• Mohamed, M. S., Elamin, K. M., Alenazy, R., Mohamed Eltayib, E., Timan Idriss, M., Alhudaib, N. A. A., . . . & Awadalla Mohamed, M. (2023). Synthesis, Antimicrobial, and Anticancer Activities of Novel Nitrofuran Derivatives. Journal of Chemistry, 2023(1), 1481595.
• Molognoni, L., Daguer, H., & Hoff, R. B. (2021). Chapter 12 - Analysis of nitrofurans residues in foods of animal origin. In C. M. Galanakis (Ed.), Food Toxicology and Forensics (pp. 379-419): Academic Press.
• Muğlu, H., Yakan, H., Erdoğan, M., Topal, F., Topal, M., Türkeş, C., & Beydemir, Ş. (2024). Novel asymmetric biscarbothioamides as Alzheimer's disease associated cholinesterase inhibitors: synthesis, biological activity, and molecular docking studies. New Journal of Chemistry, 759, 110099.
• Munsimbwe, L., Seetsi, A., Namangala, B., N’Da, D. D., Inoue, N., & Suganuma, K. (2021). In Vitro and In Vivo Trypanocidal Efficacy of Synthesized Nitrofurantoin Analogs. Molecules, 26(11), 3372.
• Murugasu-Oei, B., & Dick, T. (2000). Bactericidal activity of nitrofurans against growing and dormant Mycobacterium bovis BCG. Journal of Antimicrobial Chemotherapy, 46(6), 917-919.
• Mushtaq, A., Wu, P., & Naseer, M. M. (2024). Recent drug design strategies and identification of key heterocyclic scaffolds for promising anticancer targets. Pharmacology & Therapeutics, 254, 108579.
• Ndlovu, K., Kannigadu, C., Aucamp, J., van Rensburg, H. D. J., & N'Da, D. D. (2023). Exploration of ethylene glycol linked nitrofurantoin derivatives against Leishmania: Synthesis and in vitro activity. Archiv der Pharmazie, 356(5), 2200529.
• Penning, T. M., Su, A. L., & El-Bayoumy, K. (2022). Nitroreduction: A Critical Metabolic Pathway for Drugs, Environmental Pollutants, and Explosives. Chemical Research in Toxicology, 35(10), 1747-1765.
• Popiołek, Ł., Rysz, B., Biernasiuk, A., & Wujec, M. (2020). Synthesis of promising antimicrobial agents: hydrazide-hydrazones of 5-nitrofuran-2-carboxylic acid. Chemical Biology & Drug Design, 95(2), 260-269.
• Reid, G. A., & Darvesh, S. (2024). Interaction of exogenous acetylcholinesterase and butyrylcholinesterase with amyloid-β plaques in human brain tissue. Chemico-Biological Interactions, 395, 111012.
• Roca, C., Requena, C., Sebastián-Pérez, V., Malhotra, S., Radoux, C., Pérez, C., . . . & Campillo, N. E. (2018). Identification of new allosteric sites and modulators of AChE through computational and experimental tools. Journal of Enzyme Inhibition and Medicinal Chemistry, 33(1), 1034-1047.
• Rossi, M., Freschi, M., de Camargo Nascente, L., Salerno, A., de Melo Viana Teixeira, S., Nachon, F., . . . & Bolognesi, M. L. (2021). Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer’s Disease. Journal of Medicinal Chemistry, 64(8), 4972-4990.
• Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C. E., . . . & van der Flier, W. M. (2021). Alzheimer's disease. The Lancet, 397(10284), 1577-1590.
• Squella, J. A., Letelier, M. E., Lindermeyer, L., & Nuñez-Vergara, L. J. (1996). Redox behaviour of nifuroxazide: generation of the one-electron reduction product. Chemico-Biological Interactions, 99(1), 227-238.
• Suarez-Torres, J. D., Orozco, C. A., & Ciangherotti, C. E. (2021). The numerical probability of carcinogenicity to humans of some antimicrobials: Nitro-monoaromatics (including 5-nitrofurans and 5-nitroimidazoles), quinoxaline-1,4-dioxides (including carbadox), and chloramphenicol. Toxicology in Vitro, 75, 105172.
• Turgutalp, B., Bhattarai, P., Ercetin, T., Luise, C., Reis, R., Gurdal, E. E., . . . & Yarim, M. (2022). Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease. Journal of Medicinal Chemistry, 65(18), 12292-12318.
• Türkan, F. (2021). Investigation of the toxicological and inhibitory effects of some benzimidazole agents on acetylcholinesterase and butyrylcholinesterase enzymes. Archives of Physiology and Biochemistry, 127(2), 97-101.
• Uddin, T. M., Chakraborty, A. J., Khusro, A., Zidan, B. M. R. M., Mitra, S., Emran, T. B., . . . & Koirala, N. (2021). Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects. Journal of Infection and Public Health, 14(12), 1750-1766.
• Vasudevan, S., Thamil Selvan, G., Bhaskaran, S., Hari, N., & Solomon, A. P. (2020). Reciprocal Cooperation of Type A Procyanidin and Nitrofurantoin Against Multi-Drug Resistant (MDR) UPEC: A pH-Dependent Study. Frontiers in Cellular and Infection Microbiology, 10.
• Wu, J., Pistolozzi, M., Liu, S., & Tan, W. (2020). Design, synthesis and biological evaluation of novel carbamates as potential inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorganic & Medicinal Chemistry, 28(5), 115324.
• Xing, S., Li, Q., Xiong, B., Chen, Y., Feng, F., Liu, W., & Sun, H. (2021). Structure and therapeutic uses of butyrylcholinesterase: Application in detoxification, Alzheimer's disease, and fat metabolism. Medicinal Research Reviews, 41(2), 858-901.
• Yan, M., Xu, L., Wang, Y., Wan, J., Liu, T., Liu, W., . . . & Li, Q. (2020). Opportunities and challenges of using five-membered ring compounds as promising antitubercular agents. Drug Development Research, 81(4), 402-418.
• Zuma, N. H., Smit, F. J., Seldon, R., Aucamp, J., Jordaan, A., Warner, D. F., & N'Da, D. D. (2020). Single-step synthesis and in vitro anti-mycobacterial activity of novel nitrofurantoin analogues. Bioorganic Chemistry, 96, 103587.