Abstract
Some promising 4-thiazolone derivatives as lipoxygenase inhibitors were designed, synthesized, characterized and evaluated for anti-inflammatory activity and respective ulcerogenic liabilities. Compounds (1b, 1e, 3b, and 3e) exhibited considerable in vivo anti-inflammatory activity (57.61, 79.35, 75.00, and 79.35%) against carrageenan-induced rat paw edema model, whereas compounds (1e, 3b, and 3e) were found active against the arachidonic acid-induced paw edema model (55.38, 55.38, and 58.46%). The most potent compound (3e) exhibited lesser ulcerogenic liability compared to the standard diclofenac and zileuton. Further, the promising compounds (1e and 3e) were evaluated for in vitro lipoxygenase (LOX; IC50 = 12.98 µM and IC50 = 12.67 µM) and cyclooxygenase (COX) inhibition assay (COX-1; IC50 > 50 µM and, COX-2; IC50 > 50 µM). The enzyme kinetics of compound 3e was evaluated against LOX enzyme and supported by in silico molecular docking and molecular dynamics simulations studies. Overall, the results substantiated that 5-benzylidene-2-phenyl-4-thiazolones are promising pharmacophore for anti-inflammatory activity.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ali AM, Saber GE, Mahfouz NM, El-Gendy MA, Radwan AA, Hamid MA (2007) Synthesis and three-dimensional qualitative structure selectivity relationship of 3, 5-disubstituted-2, 4-thiazolidinedione derivatives as COX2 inhibitors. Arch Pharm Res 30:1186–1204. https://doi.org/10.1007/BF02980259
Allaj V, Guo C, Nie D (2013) Non-steroid anti-inflammatory drugs, prostaglandins, and cancer. Cell Biosci 3:8. https://doi.org/10.1186/2045-3701-3-8
Aparoy P, Kumar Reddy K, Reddanna P (2012) Structure and ligand based drug design strategies in the development of novel 5-LOX inhibitors. Curr Med Chem 19:3763–3778. https://doi.org/10.2174/092986712801661112
Banerjee AG, Das N, Shengule SA, Srivastava RS, Shrivastava SK (2015) Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6–diphenyl–1, 2, 4–triazin–3 (2H)–one derivatives bearing 5–substituted 1, 3, 4–oxadiazole as potential anti–inflammatory and analgesic agents. Eur J Med Chem 101:81–95. https://doi.org/10.1016/j.ejmech.2015.06.020
Banerjee AG, Das N, Shengule SA, Sharma PA, Srivastava RS, Shrivastava SK (2016) Design, synthesis, evaluation and molecular modelling studies of some novel 5, 6-diphenyl-1, 2, 4-triazin-3 (2H)-ones bearing five-member heterocyclic moieties as potential COX-2 inhibitors: A hybrid pharmacophore approach. Bioorg Chem 69:102–120. https://doi.org/10.1016/j.bioorg.2016.10.003
Barreiro EJ, Fraga CA, Miranda AL, Rodrigues CR (2002) A química medicinal de N-acilidrazonas: Novos compostos-protótipos de fármacos analgésicos, antiinflamatórios e anti-trombóticos. Quim Nova 25:129–148. https://doi.org/10.1590/S0100-40422002000100022
Barzen S, Rödl CB, Lill A, Steinhilber D, Stark H, Hofmann B (2012) Synthesis and biological evaluation of a class of 5-benzylidene-2-phenyl-thiazolinones as potent 5-lipoxygenase inhibitors. Bioorg Med Chem 20:3575–3583. https://doi.org/10.1016/j.bmc.2012.04.003
Bekhit AA, Fahmy HT, Rostom SA, Bekhit AE-DA (2010) Synthesis and biological evaluation of some thiazolylpyrazole derivatives as dual anti-inflammatory antimicrobial agents. Eur J Med Chem 45:6027–6038. https://doi.org/10.1016/j.ejmech.2010.10.001
Berger W, De Chandt M, Cairns C (2007) Zileuton: clinical implications of 5-lipoxygenase inhibition in severe airway disease. Int J Clin Pract 61:663–676. https://doi.org/10.1111/j.1742-1241.2007.01320.x
Carter BZ, Wiseman AL, Orkiszewski R, Ballard KD, Ou C-N, Lieberman MW (1997) Metabolism of leukotriene C4 in γ-glutamyl transpeptidase-deficient mice. J Biol Chem 272:12305–12310. https://doi.org/10.1074/jbc.272.19.12305
Deep A, Jain S, Sharma PC (2010) Synthesis and anti-inflammatory activity of some novel biphenyl-4-carboxylic acid 5-(arylidene)-2-(aryl)-4-oxothiazolidin-3-yl amides. Acta Pol Pharm 67:63–67
DiMartino M, Campbell G, Wolff C, Hanna N (1987) The pharmacology of arachidonic acid-induced rat paw edema. Inflamm Res 21:303–305. https://doi.org/10.1007/BF01966498
Drazen JM, Israel E, O’byrne PM (1999) Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 340:197–206. https://doi.org/10.1056/NEJM199901213400306
Franke L, Hofmann B, Schneider G, Steinhilber D (2009) Neue Inhibitoren der 5-lipoxygenase und deren Verwendungen New inhibitors of 5-lipoxygenase and their uses. In: Patent G (ed) German Patent. Johann Wolfgang Goethe-Universität Frankfurt am Main, German
Gilbert NC, Bartlett SG, Waight MT, Neau DB, Boeglin WE, Brash AR, Newcomer ME (2011) The structure of human 5-lipoxygenase. Science 331:217–219. https://doi.org/10.1126/science.1197203
Hofmann B, Franke L, Proschak E, Tanrikulu Y, Schneider P, Steinhilber D, Schneider G (2008) Scaffold-hopping cascade yields potent inhibitors of 5-lipoxygenase. ChemMedChem 3:1535–1538. https://doi.org/10.1002/cmdc.200800153
Hofmann B, Barzen S, Rödl CB, Kiehl A, Borig J, Živković A, Stark H, Schneider G, Steinhilber D (2011) A class of 5-benzylidene-2-phenylthiazolinones with high potency as direct 5-lipoxygenase inhibitors. J Med Chem 54:1943–1947. https://doi.org/10.1021/jm101165z
Hofmann B, Rödl C, Kahnt A, Maier T, Michel A, Hoffmann M, Rau O, Awwad K, Pellowska M, Wurglics M (2012) Molecular pharmacological profile of a novel thiazolinone-based direct and selective 5-lipoxygenase inhibitor. Br J Pharmacol 165:2304–2313
Liang Z-Q, Yi L, Chen K-Q, Ye S (2016) N-heterocyclic carbene-catalyzed [3 + 4] annulation of enals and alkenyl thiazolones: enantioselective synthesis of thiazole-fused ε-lactones. J Org Chem 81:4841–4846. https://doi.org/10.1021/acs.joc.6b00313
Lineweaver H, Burk D (1934) The determination of enzyme dissociation constants. J Am Chem Soc 56:658–666. https://doi.org/10.1021/ja01318a036
Martel-Pelletier J, Lajeunesse D, Reboul P, Pelletier J (2003) Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis 62:501–509. https://doi.org/10.1136/ard.62.6.501
Murphy RC, Gijón MA (2007) Biosynthesis and metabolism of leukotrienes. Biochem J 405:379–395. https://doi.org/10.1042/BJ20070289
Ottana R, Maccari R, Barreca ML, Bruno G, Rotondo A, Rossi A, Chiricosta G, Di Paola R, Sautebin L, Cuzzocrea S (2005) 5-Arylidene-2-imino-4-thiazolidinones: design and synthesis of novel anti-inflammatory agents. Bioorg Med Chem 13:4243–4252. https://doi.org/10.1016/j.bmc.2005.04.058
Pergola C, Werz O (2010) 5-Lipoxygenase inhibitors: a review of recent developments and patents. Expert Opin Ther Pat 20:355–375. https://doi.org/10.1517/13543771003602012
Pradelles P, Grassi J, Maclouf J (1985) Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay. Anal Chem 57:1170–1173. https://doi.org/10.1021/ac00284a003
Qiu J, Stevenson SH, O’Beirn MJ, Silverman RB (1999) 2, 6-difluorophenol as a bioisostere of a carboxylic acid: bioisosteric analogues of γ-aminobutyric acid. J Med Chem 42:329–332. https://doi.org/10.1021/jm980435l
Reddy KK, Rajan VKV, Gupta A, Aparoy P, Reddanna P (2015) Exploration of binding site pattern in arachidonic acid metabolizing enzymes, cyclooxygenases and lipoxygenases. BMC Res Notes 8:152. https://doi.org/10.1186/s13104-015-1101-4
Rossi A, Pergola C, Koeberle A, Hoffmann M, Dehm F, Bramanti P, Cuzzocrea S, Werz O, Sautebin L (2010) The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages. Br J Pharmacol 161:555–570. https://doi.org/10.1111/j.1476-5381.2010.00930.x
Sandmeyer T (1884) Ueber die Ersetzung der Amid-gruppe durch Chlor, Brom und Cyan in den aromatischen Substanzen. Eur J Inorg Chem 17:2650–2653. https://doi.org/10.1002/cber.188401702202
Schneider G, Steinhilber D, Franke L, Hofmann B (2009) 5-arylalkylidene-2-arylalkyl-thiazol-4-one derivatives as inhibitors of 5-lipoxygenase and uses thereof. In: Patent W (ed) World Patent. Johann Wolfgang Goethe-Universität, Frankfurt Am Main
Scholz M, Ulbrich HK, Soehnlein O, Lindbom L, Mattern A, Dannhardt G (2009) Diaryl-dithiolanes and-isothiazoles: COX-1/COX-2 and 5-LOX-inhibitory, OH scavenging and anti-adhesive activities. Bioorg Med Chem 17:558–568. https://doi.org/10.1016/j.bmc.2008.11.074
Shrivastava SK, Srivastava P, Bendresh R, Tripathi PN, Tripathi A (2017) Design, synthesis, and biological evaluation of some novel indolizine derivatives as dual cyclooxygenase and lipoxygenase inhibitor for anti-inflammatory activity. Bioorg Med Chem. https://doi.org/10.1016/j.bmc.2017.06.027
Srivastava P, Vyas VK, Variya B, Patel P, Qureshi G, Ghate M (2016) Synthesis, anti-inflammatory, analgesic, 5-lipoxygenase (5-LOX) inhibition activities, and molecular docking study of 7-substituted coumarin derivatives. Bioorg Chem 67:130–138. https://doi.org/10.1016/j.bioorg.2016.06.004
Szelenyi I, Thiemer K (1978) Distention ulcer as a model for testing of drugs for ulcerogenic side effects. Arch Toxicol 41:99–105. https://doi.org/10.1007/BF00351774
Tsurumi K, Kyuki K, Niwa M, Kokuba S, Fujimura H (1986) Pharmacological investigations of the new antiinflammatory agent 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid. 1st communication: inhibitory effects of rat paw edema. Arzneimittelforschung 36:1796–1800
Wenzel SE, Kamada AK (1996) Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann Pharmacother 30:858–864. https://doi.org/10.1177/106002809603000725
Winter CA, Risley EA, Nuss GW (1962) Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med 111:544–547. https://doi.org/10.3181/00379727-111-27849
Zaitsu M, Hamasaki Y, Matsuo M, Ichimaru T, Fujita I, Ishii E (2003) Leukotriene synthesis is increased by transcriptional up-regulation of 5-lipoxygenase, leukotriene A4 hydrolase, and leukotriene C4 synthase in asthmatic children. J Asthma 40:147–154. https://doi.org/10.1081/JAS-120017985
Zayed E, Elbannany A, Ghozlan S (1985) Studies on thiazolin-4-one: synthesis of some pyrano [2, 3-b]-thiazole derivatives. Pharmazie 40:194–196
Acknowledgements
The authors gratefully acknowledge Indian Institute of Technology (BHU) for providing financial assistance through Institute Research Project (IRP) scheme and Design Innovation Center (DIC) scheme. Grant No. IIT (BHU)/R&D/IRP/2015-16/3471/L and Grant No. DIC-IIT(BHU)/L-11, respectively. The authors are also thankful to Department of Health Research, Ministry of Health and Family Welfare for providing the Young Scientist Project in newer areas of Drugs Chemistry (DHR/HRD/YS-15-2015-16).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary material 1
Spectral studies (FT-IR, 1H-NMR, and 13C-NMR) of some of the synthesized compounds along with the RMSD and RMSF graphs of molecular dynamics simulations can be found in the supplementary material. (DOCX 3096 kb)
Rights and permissions
About this article
Cite this article
Shrivastava, S.K., Patel, B.K., Tripathi, P.N. et al. Synthesis, evaluation and docking studies of some 4-thiazolone derivatives as effective lipoxygenase inhibitors. Chem. Pap. 72, 2769–2783 (2018). https://doi.org/10.1007/s11696-018-0520-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11696-018-0520-9