Nashrieh Shimi va Mohandesi Shimi Iran

Nashrieh Shimi va Mohandesi Shimi Iran

Design, Synthesis and Characterization of N-((4-((4-(2-Hydrazinylthiazol-4-yl)Phenoxy)Methyl)-1,2,3-Triazol-1-yl)Methyl)Benzamide Derivatives as Lead Compounds for Alzheimer's Treatment

Document Type : Research Article

Authors
Parisa Nikfar 1
Mehdi Asadi 1
Mina Saeedi 2
Seyedeh Sara Mirfazli 1
1 Department of Medicinal Chemistry, Faculty of Pharmacy, Iran University of Medical Sciences, Tehran, I.R. IRAN
2 Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, I.R. IRAN
Abstract
Heterocyclic triazole and thiazole rings can exert diverse biological effects in living organisms by forming chemical interactions with a variety of proteins, enzymes, and receptors. Chemical compounds containing these rings have anticancer, antibacterial, antifungal, anti-inflammatory, antituberculosis, anticonvulsant, antimalarial, anti-Alzheimer, and antiviral effects, and more than 18 FDA-approved drugs contain a thiazole ring. In addition, hydrazine is a very useful functional group that can act as a hydrogen bond donor and acceptor and as a key pharmacophore in molecules that inhibit enzymes, especially pyridoxal phosphate-dependent enzymes or metalloenzymes. Finally, the benzamide group is a common motif in drugs known for its favorable pharmacokinetic profile and is present in antiemetic drugs and anticancer agents. Therefore, due to the unique therapeutic effects of these cores as target groups in the design of drug structures, researchers are interested in them and using the method, rational scaffold hybridization, which is a powerful strategy in the design of lead compounds, a targeted integration of several different privileged pharmacophores, each of which adds specific properties to the entire molecule, has been carried out. Therefore, the present design was carried out to synergize the beneficial effects of each component to achieve a compound that can interact with multiple points on a biological target, which leads to increased potency, efficacy, and selectivity, and improved pharmacokinetic properties and a more favorable safety profile of the final compounds. As a result, in this study, the synthesis of a new hydrazino derivative of thiazole-phenoxy-1,2,3-triazole-benzamide using appropriate and optimized reagents and reaction conditions was presented in 4 steps, and the structure of the products in each step was confirmed using FT-IR and 1H-NMR spectroscopy methods. Docking study of the derivatives on AChE was investigated, and the results showed that these compounds can create key interactions with the enzyme's active site.
Keywords
Synthesis
Triazole
Thiazole
Rational scaffold hybridization
Lead compounds
Nucleophilic substitution
Click reaction
Docking study

Subjects

[1] Kumari S., Carmona A.V., Tiwari A.K., Trippier P.C., Amide Bond Bioisosteres: Strategies, Synthesis, and Successes, J Med Chem, 63(22): 13633-60 (2020).
[2] Vardhan D.M.S., Mittal S., Scaffold Hybridization in Drug Discovery: A Review, Future Med Chem, 14(16): 1187-204 (2022).
[3] Morphy R., Rankovic Z., Designed Multiple Ligands. An Emerging Drug Discovery Paradigm, J Med Chem, 48(21): 6523-43 (2005).
[4] Cheke R.S., Shinde S.D., Ambhore J.P., Patil V.M., Molecular Hybridization: A Powerful Tool for Multi-Target Drug Discovery, Curr Top Med Chem, 22(11): 897-919 (2022).
[5] Saeedi M., Mohtadi-Haghighi D., Mirfazli S.S., Mahdavi M., Hariri R., Lotfian H., Edraki N., Iraji A., Firuzi O., Akbarzadeh T., Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole-Phenylpiperazine Derivatives. Chem Biodivers. 16(2): e1800433, (2019).
[6] Guimiao T., Qiuyi S., Ziwei L., Ju G., Shuang C., Sihui L., Recent Advances in 1,2,3- and 1,2,4-Triazole Hybrids as Antimicrobials and Their SAR: A Critical Review. Eur J Med Chem, 259: 115603 (2023).
[7] Petrou A., Fesatidou M., Geronikaki A., Thiazole Ring—A Biologically Active Scaffold. Molecules, 26(11): 3166 (2021).
[8] Maileen Gloriane, U., Simrit Kaur S., Samantha M., Alzheimer Disease, The Journal for Nurse Practitioners, 14(3): 129-135 (2018).
[9] McGeer P.L., McGeer E.G., The Amyloid Cascade-Inflammatory Hypothesis of Alzheimer Disease: Implications for Therapy, Acta neuropathologica, 126: 479-497 (2013).
[10] Vitali F., Branigan G.L., Brinton R.D., Preventing Alzheimer's disease within reach by 2025: Targeted‐Risk‐AD‐Prevention (TRAP) Strategy, Alzheimer's & Dementia: Translational Research & Clinical Interventions, 7(1): e12190 (2021).
[11] Iqbal K., Flory M., Soininen H., Clinical Symptoms and Symptom Signatures of Alzheimer's Disease Subgroups, Journal of Alzheimer's Disease, 37(3): 475-481 (2013).
[12] Hampel H., Vassar R., De Strooper B., Hardy J., Willem M., Singh N., Zhou J., Yan R., Vanmechelen E., De Vos A., Nisticò R., Corbo M., Imbimbo B.P., Streffer J., Voytyuk I., Timmers M., Tahami Monfared A.A., Irizarry M., Albala B., Koyama A., Watanabe N., Kimura T., Yarenis L., Lista S., Kramer L., Vergallo A., The β-Secretase BACE1 in Alzheimer's Disease, Biological Psychiatry, 89(8): 745-756 (2021).
[13] Bartus R.T., On Neurodegenerative Diseases, Models, and Treatment Strategies: Lessons Learned, and Lessons Forgotten a Generation Following the Cholinergic Hypothesis, Experimental neurology, 163(2): 495-529 (2000).
[14] Hampel H., Mesulam M.M., Cuello A.C., Farlow M.R., Giacobini E., Grossberg G.T., Khachaturian A.S., Vergallo A., Cavedo E., Snyder P.J., Khachaturian Z.S., The Cholinergic System in the Pathophysiology and Treatment of Alzheimer’s Disease, Brain, 141(7): 1917-1933 (2018).
[15] Joe E., Ringman J.M., Cognitive Symptoms of Alzheimer’s Disease: Clinical Management and Prevention, BMJ, 367 (2019).
[16] Guimiao T., Qiuyi S., Ziwei L., Jie G., Shuang C., Sihui L., Recent Advances in 1,2,3- and 1,2,4-Triazole Hybrids as Antimicrobials and Their SAR: A Critical Review, E. J. Med. Chem, 259: 115603 (2023).
[17] Zhang J., Wang S., Ba Y., Xu Z., 1,2,4-Triazole-Quinoline/Quinolone Hybrids as Potential Anti-Bacterial Agents, E. J. Med. Chem, 174: 1-8 (2019).
[18] Chekir S., Debbabi M., Regazzetti A., Dargère D., Laprévote O., Ben Jannet H., Gharbi R., Design, Synthesis and Biological Evaluation of Novel 1,2,3-Triazole Linked Coumarinopyrazole Conjugates as Potent Anticholinesterase, Anti-5-Lipoxygenase, Anti-Tyrosinase and Anti-Cancer Agents, Bioorg. Chem, 80: 189-194 (2018).
[19] Carreiro E.P., Costa A.R., Antunes C.M., Ernesto S., Pinto F., Rodrigues B., Burke A.J., Quercetin-1, 2, 3-Triazole Hybrids as Multifunctional Anti-Alzheimer’s Agents, Molecules, 28(22): 7495 (2023).
[20] Najafi Z., Mahdavi M., Saeedi M., Karimpour-Razkenari E., Edraki N., Sharifzadeh M., Khanavi M., Akbarzadeh T., Novel Tacrine-Coumarin Hybrids Linked to 1, 2, 3-Triazole as Anti-Alzheimer’s Compounds: In Vitro and in Vivo Biological Evaluation and Docking Study, Bioorg. Chem, 83: 303-316 (2019).
[21] Rahim F., Ullah H., Taha M., Hussain R., Sarfraz M., Iqbal R., Iqbal N., Khan S., Ali Shah S.A., Albalawi M.A., Abdelaziz M.A., Alatawi F.S., Alasmari A., Sakran M.I., Zidan N., Jafri I., Khan K.M., Synthesis of New Triazole-Based Thiosemicarbazone Derivatives as Anti-Alzheimer’s Disease Candidates: Evidence-Based in Vitro Study, Molecules, 28(1): 21 (2022).
[22] Saeedi M., Maleki A., Iraji A., Hariri R., Akbarzadeh T., Edraki N., Firuzi O., Mirfazli S. S., Synthesis and Bio-Evaluation of New Multifunctional Methylindolinone-1,2,3-Triazole Hybrids as Anti-Alzheimer's Agents, J Mol Struct, 1229:129828 (2021).
[23] Silalai P., Jaipea S., Tocharus J., Athipornchai A., Suksamrarn A., Saeeng R., New 1, 2, 3-Triazole-Genipin Analogues and Their Anti-Alzheimer’s Activity, ACS omega, 7(28): 24302-24316 (2022).
[24] Petrou A., Fesatidou M., Geronikaki A., Thiazole Ring—A Biologically Active Scaffold, Molecules, 26(11): 3166 (2021).
[25] Gümüş M., Yakan M., Koca İ., Recent Advances of Thiazole Hybrids in Biological Applications, Future Med. Chem, 11(16): 1979-1998 (2019).
[26] Budak Y., Kocyigit U.M., Burcu Gürdere M., Özcan K., Taslimi P., Gülçin İ., Ceylan M., Synthesis and Investigation of Antibacterial Activities and Carbonic Anhydrase and Acetyl Cholinesterase Inhibition Profiles of Novel 4, 5-Dihydropyrazol and Pyrazolyl-Thiazole Derivatives Containing Methanoisoindol-1, 3-Dion Unit, Synth. Comm, 47(24): 2313-2323 (2017).
[27] Bardakkaya M., Kilic B., Sagkan R.I., Aksakal F., Shakila S., Dogruer D.S.,  Synthesis and Evaluation of Multitarget New 2‐Aminothiazole Derivatives as Potential Anti‐Alzheimer's Agents, Archiv der Pharmazie, e2300054 (2023).
[28] Zhao L., Mao L., Hong G., Yang X., Liu T., Design, Synthesis and Anticancer Activity of Matrine–1H-1, 2, 3-Triazole–Chalcone Conjugates, Bioorg. Med. Chem. Lett, 25(12): 2540-4 (2015).
[29] Laufer S.A., Hauser D.R., Liedtke A.J., Regiospecific and Highly Flexible Synthesis of 1, 4, 5-Trisubstituted 2-Sulfanylimidazoles from Structurally Diverse Ethanone Precursors, Synthesis, (02): 253-66 (2008).
[30] Mohan R.B., Reddy N.G., Regioselective α-Bromination of Aralkyl Ketones Using N-Bromosuccinimide in the Presence of Montmorillonite K-10 Clay: A Simple and Efficient Method. Synth. Comm, 43(19): 2603-14 (2013).
[31] Carradori S., Rotili D., De Monte C., Lenoci A., D'Ascenzio M., Rodriguez V., Filetici P., Miceli M., Nebbioso A., Altucci L., Secci D., Evaluation of a Large Library of (Thiazol-2-yl) Hydrazones and Analogues as Histone Acetyltransferase Inhibitors: Enzyme and Cellular Studies, E.J. Med. Chem, 80: 569-78 (2014).