Volume 26, Issue 7 (Oct 2018)                   JSSU 2018, 26(7): 583-598 | Back to browse issues page

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Abstract:   (2251 Views)
Introdution: Lipoxygenase enzyme is responsible for biosynthesis of leukotrienes that possess various pharmacological effects in the body. The beneficial therapeutic effects of lipoxygenase inhibitors have been proved in some diseases such as asthma, cancer and Alzheimer’s disease. So, the lipoxygenase inhibitors could be used in the treatment of some diseases and pathological conditions. In this study, heteroaryl 2-phenoxypyridine-3-yl derivatives have been synthesized and evaluated as lipoxygenase inhibitors.
Methods: In this basic-applied study, the desired derivatives were synthesized in multiple steps using convenient methods. Then, the structure of compounds was validated using infrared, mass and nuclear magnetic resonance spectroscopy. Finally, lipoxygenase inhibitory activity of compounds was evaluated and molecular docking studies was performed on the most active compound.
Results: All target compounds were synthesized in good yields and showed good inhibitory activity against lipoxygenase (IC50 =100-179 mM) in comparison to Quercetin (IC50 = 58.5 mM) as standard inhibitor. The compound 7a (5-(2-phenoxypyridine-3-yl)-1, 3, 4-oxadiazole-2(3H)-thione) showed the most potent activity and the molecular docking studies showed that this compound was well fitted in the active site of enzyme.
Conclusion: The synthesized compounds have shown good inhibitory activity against lipoxygenase and the molecular docking studies show that these compounds are able to fit in the active site of enzyme. Therefore, the target compounds could be used as lead compounds for further studies to find novel lipoxygenase inhibitor drugs.
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Type of Study: Original article | Subject: other
Received: 2018/08/26 | Accepted: 2018/10/13 | Published: 2018/12/23

1. 1- Fürstenberger G, Epp N, Eckl K-M, Hennies HC, Jørgensen C, Hallenborg P. Role of epidermis-type lipoxygenases for skin barrier function and adipocyte differentiation. Prostaglandins Other lipid Med 2007; 82(1-4): 128-34.
2. 2- Kuhn H, Banthiya S, van Leyen K. Mammalian lipoxygenases and their biological relevance. Biochimica et Biophysica Acta 2015; 1851(4): 308-30.
3. 3- Mashima R, Okuyama T. The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol 2015; 6: 297-310.
4. 4- Schneider C, Pratt DA, Porter NA, Brash AR. Control of oxygenation in lipoxygenase and cyclooxygenase catalysis. Chemistry & Bio 2007; 14(5): 473-88.
5. 5- Mattsson N, Yaong M, Rosengren L, Blennow K, Månsson JE, Andersen O. Elevated cerebrospinal fluid levels of prostaglandin E2 and 15‐(S)‐hydroxyeicosatetraenoic acid in multiple sclerosis. J Intern Med 2009; 265(4): 459-64.
6. 6- Ackermann JA, Hofheinz K, Zaiss MM, Krönke G. The double-edged role of 12/15-lipoxygenase during inflammation and immunity. Biochimica et Biophysica Acta (BBA)-Mol Cell Biol Lipids 2017; 1862(4): 371-81.
7. 7- Kühn H, O’Donnell VB. Inflammation and immune regulation by 12/15-lipoxygenases. Prog lipid Res 2006; 45(4): 334-56.
8. 8- Uderhardt S, Krönke G. 12/15-lipoxygenase during the regulation of inflammation, immunity, and self-tolerance. J Mol Med 2012; 90(11): 1247-56.
9. 9- Larsen JS, Acosta EP. Leukotriene-receptor antagonists and 5-lipoxygenase inhibitors in asthma. Annals Pharmaco 1993; 27(7-8): 898-903.
10. 10- Blaho VA, Zhang Y, Hughes-Hanks JM, Brown CR. 5-Lipoxygenase–Deficient Mice Infected with Borrelia burgdorferi Develop Persistent Arthritis. J Immunology 2011; 186(5): 3076-84.
11. 11- Steinhilber D, Fischer AS, Metzner J, Steinbrink SD, Roos J, Ruthardt M, et al. 5-lipoxygenase: underappreciated role of a pro-inflammatory enzyme in tumorigenesis. Front Pharm 2010; 1: 143.
12. 12- Park SW, Heo DS, Sung MW. The shunting of arachidonic acid metabolism to 5-lipoxygenase and cytochrome p450 epoxygenase antagonizes the anti-cancer effect of cyclooxygenase-2 inhibition in head and neck cancer cells. Cell Oncol 2012; 35(1): 1-8.
13. 13- Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, et al. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice. J Clin Invest 1999; 103(11): 1597-604.
14. 14- Harats D, Shaish A, George J, Mulkins M, Kurihara H, Levkovitz H, et al. Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor–deficient mice. Arteriosclerosis, Thrombosis, Vascular Biol 2000; 20(9): 2100-5.
15. 15- Kelavkar U, Glasgow W, Eling TE. The effect of 15-lipoxygenase-1 expression on cancer cells. Current urology reports 2002; 3(3): 207-14.
16. 16- Schewe T. 15-lipoxygenase-1: a prooxidant enzyme. Biol Chem 2002; 383(3-4): 365-74.
17. 17- Rothe T, Gruber F, Uderhardt S, Ipseiz N, Rössner S, Oskolkova O, et al. 12/15-lipoxygenase–mediated enzymatic lipid oxidation regulates DC maturation and function. J Clin Invest 2015; 125(5): 1944-54.
18. 18- Sultana C, Shen Y, Rattan V, Kalra VK. Lipoxygenase metabolites induced expression of adhesion molecules and transendothelial migration of monocyte‐like HL‐60 cells is linked to protein kinase C activation. J Cell Physiol 1996; 167(3): 477-87.
19. 19- Rubab K, Abbasi MA, Siddiqui SZ, Ashraf M, Shaukat A, Ahmad I, et al. S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1, 3, 4-oxadiazole-5-thiol derivatives. 2. Anti-bacterial, enzymeinhibitory and hemolytic activities. Tropical J Pharma Res 2016; 15(7): 1525-33.
20. 20- Nafeesa K, Abbasi MA, Siddiqui SZ, Rasool S, Shah SA. Synthesis, characterization and pharmacological evaluation of different 1, 3, 4-oxadiazole and acetamide derivatives of ethyl nipecotate. Bulletin of Faculty of Pharmacy, Cairo Uni 2017; 55(2): 333-43. [Persian]
21. 21- Sattar A, Aziz-ur-Rehman, Abbasi MA, Siddiqui SZ, Rasool S, Ahmad I. Synthesis of some novel enzyme inhibitors and antibacterial agents derived from 5-(1-(4-tosyl) piperidin-4-yl)-1, 3, 4-oxadiazol-2-thiol. Brazilian J Pharmaceutical Sci 2016; 52(1): 77-85.
22. 22- Pelcman B, Sanin A, Nilsson P, No K, Schaal W, Öhrman S, et al. 3-Substituted pyrazoles and 4-substituted triazoles as inhibitors of human 15-lipoxygenase-1. Bioorganic & Med Chem Letters 2015; 25(15): 3024-9.
23. 23- Cai H, Huang X, Xu S, Shen H, Zhang P, Huang Y, et al. Discovery of novel hybrids of diaryl-1, 2, 4-triazoles and caffeic acid as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for cancer therapy. Eur J Med Chem 2016; 108: 89-103.
24. 24- Jiang B, Huang X, Yao H, Jiang J, Wu X, Jiang S, et al. Discovery of potential anti-inflammatory drugs: diaryl-1, 2, 4-triazoles bearing N-hydroxyurea moiety as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase. Organic Biomol Chem 2014; 12(13): 2114-27.
25. 25- Mohamed MS, Mansour YE, Amin HK, El-Araby ME. Molecular modelling insights into a physiologically favourable approach to eicosanoid biosynthesis inhibition through novel thieno [2, 3-b] pyridine derivatives. J Enzyme Inhib Med Chem 2018; 33(1): 755-67.
26. 26- Aliabadia A, Mohammadi-Farania A, Roodabehb S, Ahmadia F. Synthesis and Biological Evaluation of N-(5-(pyridin-2-yl)-1, 3, 4-thiadiazol-2-yl) benzamide Derivatives as Lipoxygenase Inhibitor with Potential Anticancer Activity. Iran J Pharm Res 2017; 16(1): 165-72. [Persian]
27. 27- Li Y, Chen SH, Ou TM, Tan JH, Li D, Gu LQ, Huang ZS. Syntheses and characterization of nimesulide derivatives for dual enzyme inhibitors of both cyclooxygenase-1/2 and 5-lipoxygenase. Bioorg Med Chem 2011; 19(6): 2074-83.
28. 28- El-Din MM, El-Gamal MI, Abdel-Maksoud MS, Yoo KH, Oh CH. Synthesis and broad-spectrum antiproliferative activity of diarylamides and diarylureas possessing 1, 3, 4-oxadiazole derivatives. Bioorg Med Chem 2015; 25(8): 1692-9.
29. 29- Tan TMC, Chen Y, Kong Kh, Bai J, Li Y, Lim SG, et al. Synthesis and the biological evaluation of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1, 3, 4]-oxadiazoles as potential anti-hepatitis B virus agents. Antiviral Res 2006; 71(1): 7-14.
30. 30- Zhang K, Wang P, Xuan LN, Fu XY, Jing F, Li S, et al. Synthesis and antitumor activities of novel hybrid molecules containing 1, 3, 4-oxadiazole and 1, 3, 4-thiadiazole bearing Schiff base moiety. Bioorg Med Chem letters 2014; 24(22): 5154-6.
31. 31- Kumar D, Sundaree S, Johnson EO, Shah K. An efficient synthesis and biological study of novel indolyl-1, 3, 4-oxadiazoles as potent anticancer agents. Bioorg Med Chem letters 2009; 19(15): 4492-4.
32. 32- Omar FA, Mahfouz N, Rahman M. Design, synthesis and antiinflammatory activity of some 1, 3, 4-oxadiazole derivatives. Eur J Med Chem 1996; 31(10): 819-25.
33. 33- Abel S, Russell D, Whitlock LA, Ridgway CE, Nedderman AN, Walker DK. Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects. Br J Clin Pharmacol 2008; 65: 60-7.
34. 34- Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-García J, Lazzarin A, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. New England J Med 2004; 351(5): 438-50.
35. 35- Turan-Zitouni G, Kaplancıklı ZA, Yıldız MT, Chevallet P, Kaya D. Synthesis and antimicrobial activity of 4-phenyl/cyclohexyl-5-(1-phenoxyethyl)-3-[N-(2-thiazolyl) acetamido] thio-4H-1, 2, 4-triazole derivatives. Eur J Med Chem 2005; 40(6): 607-13.
36. 36- Tehranchian S, Akbarzadeh T, Fazeli MR, Jamalifar H, Shafiee A. Synthesis and antibacterial activity of 1-[1, 2, 4-triazol-3-yl] and 1-[1, 3, 4-thiadiazol-2-yl]-3-methylthio-6, 7-dihydrobenzo [c] thiophen-4 (5H) ones. Bioorg Med Chem Lett 2005; 15(4): 1023-5.[Persian]
37. 37- Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. New England J Med 2002; 347(6): 408-15.
38. 38- Akbarzadeh T, Tabatabai SA, Khoshnoud MJ, Shafaghi B, Shafiee A. Design and synthesis of 4H-3-(2-phenoxy) phenyl-1, 2, 4-triazole derivatives as benzodiazepine receptor agonists. Bioorg Med Chem 2003; 11(5): 769-73. [Persian]
39. 39- Tozkoparan B, Küpeli E, Yeşilada E, Ertan M. Preparation of 5-aryl-3-alkylthio-l, 2, 4-triazoles and corresponding sulfones with antiinflammatory–analgesic activity. Bioorg Med Chem 2007; 15(4): 1808-14.
40. 40- Salgın-Gökşen U, Gökhan-Kelekçi N, Göktaş Ö, Köysal Y, Kılıç E, Işık Ş, et al. 1-Acylthiosemicarbazides, 1, 2, 4-triazole-5 (4H)-thiones, 1, 3, 4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones: synthesis, analgesic-anti-inflammatory and antimicrobial activities. Bioorg Med Chem 2007; 15(17): 5738-51.
41. 41- Bhaskaruni SV, Maddila S, Gangu KK, Jonnalagadda SB. A Review on multi-component green synthesis of N-containing heterocycles using mixed oxides as heterogeneous catalysts. Arabian J Chem 2017.
42. 42- Amir M, Kumar H, Javed S. Condensed bridgehead nitrogen heterocyclic system: Synthesis and pharmacological activities of 1, 2, 4-triazolo-[3, 4-b]-1, 3, 4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid. Eur J Chem 2008; 43(10): 2056-66.
43. 43- Navidpour L, Shafaroodi H, Abdi K, Amini M, Ghahremani MH, Dehpour AR, et al. Design, synthesis, and biological evaluation of substituted 3-alkylthio-4, 5-diaryl-4H-1, 2, 4-triazoles as selective COX-2 inhibitors. Bioorg Med Chem 2006; 14(8): 2507-17. [Persian]
44. 44- Helal M, El-Awdan S, Salem M, Abd-Elaziz T, Moahamed Y, El-Sherif A, et al. Synthesis, biological evaluation and molecular modeling of novel series of pyridine derivatives as anticancer, anti-inflammatory and analgesic agents. Spectrochim Acta A Mol Biomol Spectrosc 2015; 135: 764-73.
45. 45- Hill MD. Recent strategies for the synthesis of pyridine derivatives. Chemistry–A Eur J 2010; 16(40): 12052-62.
46. 46- Bernardino AMR, de Azevedo AR, da Silva Pinheiro LC, Borges JC, Carvalho VL, Miranda MD, et al. Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl) amino]-1-phenyl-1H-pyrazolo [3, 4-b] pyridine-4-carboxylic acids derivatives. Med Chem Res 2007; 16(7-9): 352-69.
47. 47- Gaonkar S, Rai KL, Prabhuswamy B. Synthesis of novel 3-[5-ethyl-2-(2-phenoxy-ethyl)-pyridin]-5-substituted isoxazoline libraries via 1, 3-dipolar cycloaddition and evaluation of antimicrobial activities. Med Chem Res 2007; 15(7-8): 407-17.
48. 48- Patel NB, Patel HR. Synthesis and pharmacological studies of 5-ethyl pyridin-2-ethanol analogs derivatives. ARKIVOC 2009; 12: 302-21.
49. 49- Xu M, Wang Y, Yang F, Wu C, Wang Z, Ye B, et al. Synthesis and biological evaluation of a series of novel pyridinecarboxamides as potential multi-receptor antipsychotic drugs. Bioorg Med Chem Lett 2018; 28(4): 606-11.
50. 50- Loso MR, Benko Z, Buysse A, Johnson TC, Nugent BM, Rogers RB, et al. SAR studies directed toward the pyridine moiety of the sap-feeding insecticide sulfoxaflor (Isoclast™ active). Bioorg Med Chem 2016; 24(3): 378-82.
51. 51- Ng HP, Buckman BO, Eagen KA, Guilford WJ, Kochanny MJ, Mohan R, et al. Design, synthesis, and biological activity of novel factor Xa inhibitors: 4-aryloxy substituents of 2, 6-diphenoxypyridines. Bioorg Med Chem 2002; 10(3): 657-66.
52. 52- Chao H, Turdi H, Herpin TF, Roberge JY, Liu Y, Schnur DM, et al. Discovery of 2-(phenoxypyridine)-3-phenylureas as small molecule P2Y1 antagonists. J Med Chem 2013; 56(4): 1704-14.
53. 53- Markley LD, Tong YC, Dulworth JK, Steward DL, Goralski CT, Johnston H, et al. Antipicornavirus activity of substituted phenoxybenzenes and phenoxypyridines. J Med Chem 1986; 29(3): 427-33.
54. 54- Song X, Chen W, Lin L, Ruiz CH, Cameron MD, Duckett DR, et al. Synthesis and SAR of 2-phenoxypyridines as novel c-Jun N-terminal kinase inhibitors. Bioorg Med Chem lett 2011; 21(23): 7072-5.
55. 55- Pavia MR, Taylor CP, Hershenson FM, Lobbestael SJ, Butler DE. 3-Phenoxypyridine 1-oxides as anticonvulsant agents. J Med Chem 1988; 31(4): 841-7.
56. 56- Malterud KE, Rydland KM. Inhibitors of 15-lipoxygenase from orange peel. J Agric Food Chem 2000; 48(11): 5576-80.
57. 57- Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Computational Chem 2010; 31(2): 455-61.
58. 58- Sanner MF. Python: a programming language for software integration and development. J Mol Graph Model 1999; 17(1): 57-61.
59. 59- O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Chem Inf 2011; 3: 33.
60. 60-Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 2004; 25(13):1605-12.