Some urea and thiourea derivatives bearing 1,2,4-triazole ring and their antiacetylcholinesterase activities

Year 2014, Volume: 4 Issue: 2, 85 - 89, 15.12.2014

Usama Abu Mohsen Bedia Kocyigit-kaymakcioglu , Ahmet Ozgur Celen Zafer Asim Kaplancikli

https://doi.org/10.5455/musbed.20140326030221

Abstract

Objective: Twenty different urea and thiourea derivatives were synthesized and evaluated for their ability to inhibit acetylcholinesterase (AChE) using a modification of Ellman’s spectrophotometric method. 

Methods: Anti-acetylcholinesterase activity was evaluated by using a modification of Ellman’s spectrophotometric method. The spectrophotometric method is based on the reaction of released thiocholine to give a coloured product with a chromogenic reagent 5,5-dithio-bis-(2-nitrobenzoic acid).

Results: The anti-acetylcholinesterase effects of the compounds (1a-e, 2a-e, 3a-e and 4a-4e) were determined by modified Ellman’s spectrophotometric method. Among these compounds, (4-{[(4-trifluoromethylphenyl)carbamoyl]amino}phenyl)acetic acid (1d), was found as the most active compound. The inhibition percentages were calculated 48.55% at 0.1 mM concentrations for compound 1d. 

Conclusion: The anti-acetylcholinesterase activity screening indicated that among the tested compounds, 1d bearing 4-trifluoromethyl group on the phenyl ring, showed noteworthy anti-acetylcholinesterase activity. Based on the activity results, it appears that halogen atoms on the phenyl ring have made good contribution to the anti-acetylcholinesterase activity.

Keywords

Urea, thiourea, 1, 2, 4-triazole, anti-acetylcholinesterase activity

1,2,4-Triazol halkası taşıyan bazı üre ve tiyoüre türevleri ve anti-asetilkolinesteraz aktiviteleri

Abstract

Amaç: Yirmi adet farklı tiyoüre ve üre türevleri sentezlenmiş ve asetilkolinesteraz enzimini (AChE) inhibe etme yetenekleri Ellman’ın modifiye spektrofotometrik yöntemi ile değerlendirilmiştir. 

Yöntem: Anti-asetilkolinesteraz aktivite tayini Ellman’ın modifiye edilmiş spektrofotometrik yöntemi kullanılarak yapılmıştır. Bu spektrofotometrik yöntem bir kromojenik reaktif olan 5,5- dithio-bis-(2-nitrobenzoik asit) ile salınan tiyokolinin renkli bir ürün vermesi esasına dayanır. 

Bulgular: Sentezlenen bileşiklerin (1a-e, 2a-e, 3a-e ve 4a-4e) anti-asetilkolinesteraz aktivite tayini Ellman’ın modifiye edilmiş spektrofotometrik yöntemi kullanılarak yapılmıştır. Test edilen bileşikler arasında, (4-{[(4-triflorometilfenil)karbamoil]amino}fenil)asetik asit (1d), en yüksek aktivite gösteren bileşik olmuştur. Bileşik 1d’nin 0.1mM konsantrasyonda inhibisyon oranı %48.55 olarak hesaplanmıştır.

Sonuç: Anti-asetilkolinesteraz aktivite tarama sonuçları incelediğinde, fenil halkasının 4. konumunda triflorometil grubu taşıyan bileşik 1d’nin kaydadeğer anti-asetilkolinesteraz aktivite gösterdiği tespit edilmiştir. Aktivite sonuçları incelendiğinde, fenil halkası üzerinde halojen taşıyan yapıların anti-asetilkolinesteraz aktiviteyi arttırıcı yönde katkı sağladığı gözlenmektedir.

Keywords

Üre, tiyoüre, 1, 2, 4-triazol, anti-asetilkolinesteraz aktivite

References

• Mehta M, Ademand A, Sabbagh M. New acetylcholinesterase inhibitors for Alzheimer disease. Int J Alzheimers Dis. 2012; 2012: 1-9.
• Perry EK, Tomilinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J. 1978; 6150: 1457- 1459.
• Bartus RL, Dean RT, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982; 217: 408–417.
• Terry AV, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003; 306: 821–827.
• Weinstock M, Groner E. Rational design of a drug for Alzheimer’s disease with cholinesterase inhibitory and neuroprotective activity. Chem Biol Interact. 2008; 175: 216-221.
• Zhang J, Zhu D, Sheng R, Wu H, Hu Y, Wang F, Chai T, Yang B, He Q. BZYX, a novel acetylcholinesterase inhibitor, significantly improved chemicals-induced learning and memory impairments on rodents and protected PC12 cells from apoptosis induced by hydrogen peroxide. Eur J Pharmacol. 2009; 613:1-9.
• Mustazza C, Borioni A, Del Giudice MR, Gatta F, Ferretti R, Menequz A, Volpe MD, Lorenzini P. Synthesis and cholinesterase activity of phenylcarbamates related to Rivastigmine, a therapeutic agent for Alzheimer’s disease. Eur J Med Chem. 2002; 37:91-109.
• Kryger G, Israel S, Sussman JL. Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure. 1999; 3: 297-307.
• Araşjo JQ, de Brito MA, Hoelz LV, de Alencastro RB, Castro HC, Rodrigues CR, Albuquerque MG. Receptor-dependent (RD) 3D-QSAR approach of a series of benzylpiperidine inhibitors of human acetylcholinesterase (HuAChE). Eur J Med Chem. 2011; 46: 39-51.
• Vidaluc JL, Calmel F, Bigg D, Carilla E, Stenger A, Chopin P, Briley M. Novel [2-(4-piperidinyl)ethyl](thio)ureas: synthesis and antiacetylcholinesterase activity. J Med Chem. 1994; 37(5): 689-695.
• Darvesh S, Pottie IR, Darvesh KV, Mcdonald RS, Walsh R, Conrad S, Penwell A, Mataija D, Martin E. Differential binding of phenothiazine urea derivatives to wild-type human cholinesterases and butyrylcholinesterase mutants. Bioorg Med Chem. 2010; 18: 2232- 2244.
• Holan G, Virgona, CT, Watson KG. Synthesis and anti- acetylcholinesterase activity of some 5-substituted-1-methyl-1H- 1,2,4-triazole-3-yl methanesulfonates. Aust J Chem. 1997; 50 (1): 53-57.
• Mohsen UA. Biological evaluation of some triazole and triazolothiadiazine derivatives, Marmara Pharm J. 2012; 16: 229-234.
• Khan I, Hanif M, Hussain MT, Khan AA, Aslam MAS, Rama NH, Iqbal J. Synthesis, acetylcholinesterase and alkaline phosphatase inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Aust J Chem. 2012; 65(10): 1413-1419.
• Celen AÖ, Koçyiğit-Kaymakçıoğlu B, Gümrü S, Toklu HZ, Arıcıoğlu F. Synthesis and anticonvulsant activity of substituted thiourea derivatives. Marmara Pharm J. 2011; 15: 43-47.
• Koçyigit-Kaymakcioglu B, Celen AÖ, Tabanca N, Ali A, Khan SI, Khan IA, Wedge DE. Synthesis and biological activity of substituted urea and thiourea derivatives containing 1,2,4-triazole moieties. Molecules. 2013; 18: 3562-3576.
• Ellman GL, Courtney KD, Andres V, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961; 7: 88-95.
• Perry NSL, Houghton PJ, Theobald AE, Jenner P, Perry EK. In-vitro inhibition of human erythrocyte acetylcholine esterase by Salvia lavandulae folia essential oil and constituent terpenes. J Pharm Pharmacol. 2000; 52: 895-902.