Towards safer anti-inflammatory therapy: synthesis of new thymol–pyrazole hybrids as dual COX-2/5-LOX inhibitors

References

• Martel-Pelletier J, Lajeunesse D, Reboul P, Pelletier JP. Therapeutic role of dual inhibitors of 5-lox and cox, selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis. 2003;62(6):501–509.
   PubMed Web of Science ®Google Scholar
• Yoshimura H, Sekine S, Adachi H, Uematsu Y, Mitani A, Futaki N, Shimizu N. High levels of human recombinant cyclooxygenase-1 expression in mammalian cells using a novel gene amplification method. Protein Expr Purif. 2011;80(1):41–46.
   PubMed Web of Science ®Google Scholar
• Yao B, Xu J, Harris RC, Zhang MZ. Renal localization and regulation of 15-hydroxyprostaglandin dehydrogenase. Am J Physiol Ren Physiol. 2008;294(2):433–439.
   Web of Science ®Google Scholar
• Haruna H, Shimizu T, Ohtsuka Y, Yarita Y, Fujii T, Kudo T, Yamashiro Y. Expression of cox-1, cox-2, and ppar-γ in the gastric mucosa of children with helicobacter pylori infection. Pediatr Int. 2008;50(1):1–6.
   PubMed Web of Science ®Google Scholar
• Yoshida S, Ujiki M, Ding X-Z, Pelham C, Talamonti MS, Bell RH, Denham W, Adrian TE. Pancreatic stellate cells (pscs) express cyclooxygenase-2 (cox-2) and pancreatic cancer stimulates cox-2 in pscs. Mol Cancer. 2005;4:27–27.
   PubMed Web of Science ®Google Scholar
• Abdelall EKA, Kamel GM. Synthesis of new thiazolo-celecoxib analogues as dual cyclooxygenase-2/15-lipoxygenase inhibitors: determination of regio-specific different pyrazole cyclization by 2d nmr. Eur J Med Chem. 2016;118(:250–258.
   PubMed Web of Science ®Google Scholar
• Garcia-Rodriguez LA, Hernández-Diaz S. Nonsteroidal antiinflammatory drugs as a trigger of clinical heart failure. Epidemiology. 2003;14:240–246.
   PubMed Web of Science ®Google Scholar
• Ruan CH, So SP, Ruan KH. Inducible cox-2 dominates over cox-1 in prostacyclin biosynthesis: mechanisms of cox-2 inhibitor risk to heart disease. Life Sci. 2011;88(1–2):24–30.
   PubMed Web of Science ®Google Scholar
• Khan M, Fraser A. Cox-2 inhibitors and the risk of cardiovascular thrombotic events. Ir Med J. 2012;105(4):119–121.
   PubMedGoogle Scholar
• Singh P, Prasher P, Dhillon P, Bhatti R. Indole based peptidomimetics as anti-inflammatory and anti-hyperalgesic agents: dual inhibition of 5-lox and cox-2 enzymes. Eur J Med Chem. 2015;97:104–123.
   PubMed Web of Science ®Google Scholar
• Tries S, Neupert W, Laufer S. The mechanism of action of the new antiinflammatory compound ml3000: Inhibition of 5-lox and cox-1/2. Inflamm Res. 2002;51(3):135–143.
   PubMed Web of Science ®Google Scholar
• Rainsford K. The effects of 5-lipoxygenase inhibitors and leukotriene antagonists on the development of gastric lesions induced by nonsteroidal antiinflammatory drugs in mice. Agents Actions. 1987;21(3–4):316–319.
   PubMedGoogle Scholar
• Rainsford K. Leukotrienes in the pathogenesis of NSAID-induced gastric and intestinal mucosal damage. Agents Actions. 1993;39(S1):C24–C26.
   PubMedGoogle Scholar
• Laufer S. Discovery and development of ml3000. Inflammopharmacology. 2001;9(1–2):101–112.
   Google Scholar
• Hudson N, Balsitis M, Everitt S, Hawkey C. Enhanced gastric mucosal leukotriene b4 synthesis in patients taking non-steroidal anti-inflammatory drugs. Gut. 1993;34(6):742–747.
   PubMed Web of Science ®Google Scholar
• Burnett BP, Levy RM. 5-lipoxygenase metabolic contributions to NSAID-induced organ toxicity. Adv Ther. 2012;29(2):79–98.
   PubMed Web of Science ®Google Scholar
• Sala A, Zarini S, Bolla M. Leukotrienes: lipid bioeffectors of inflammatory reactions. Biochem NY Eng Trans Biokhimiya. 1998;63(1):84–92.
   PubMed Web of Science ®Google Scholar
• Charlier C, Michaux C. Dual inhibition of cyclooxygenase-2 (cox-2) and 5-lipoxygenase (5-lox) as a new strategy to provide safer non-steroidal anti-inflammatory drugs. Eur J Med Chem. 2003;38(7–8):645–659.
   PubMed Web of Science ®Google Scholar
• Young RN. Inhibitors of 5-lipoxygenase: a therapeutic potential yet to be fully realized? Eur J Med Chem. 1999;34(9):671–685.
   Web of Science ®Google Scholar
• Lamie PF, Ali WAM, Bazgier V, Rárová L. Novel n-substituted indole schiff bases as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase enzymes: synthesis, biological activities in vitro and docking study. Eur J Med Chem. 2016;123:803–813.
   PubMed Web of Science ®Google Scholar
• Alvaro-Gracia JM. Licofelone—clinical update on a novel lox/cox inhibitor for the treatment of osteoarthritis. Rheumatology. 2004;43(90001):21i–25.
   Google Scholar
• Botelho MA, Barros G, Queiroz DB, Carvalho CF, Gouvea J, Patrus L, Bannet M, Patrus D, Rego A, Silva I, et al. Nanotechnology in phytotherapy: antiinflammatory effect of a nanostructured thymol gel from lippia sidoides in acute periodontitis in rats. Phytother Res. 2016;30(1):152–159.
   PubMed Web of Science ®Google Scholar
• Marsik P, Kokoska L, Landa P, Nepovim A, Soudek P, Vanek T. In vitro inhibitory effects of thymol and quinones of nigella sativa seeds on cyclooxygenase-1- and -2-catalyzed prostaglandin e2 biosyntheses. Planta Med. 2005;71(8):739–742.
   PubMed Web of Science ®Google Scholar
• Meeran N, Fizur M, Javed H, Al Taee H, Azimullah S, Ojha SK. Pharmacological properties and molecular mechanisms of thymol: prospects for its therapeutic potential and pharmaceutical development. Front Pharmacol. 2017;8:380.
   PubMed Web of Science ®Google Scholar
• Tsai ML, Lin CC, Lin WC, Yang CH. Antimicrobial, antioxidant, and anti-inflammatory activities of essential oils from five selected herbs. Biosci Biotechnol Biochem. 2011;75(10):1977–1983.
   PubMed Web of Science ®Google Scholar
• Menozzi G, Merello L, Fossa P, Mosti L, Piana A, Mattioli F. 4-substituted 1, 5-diarylpyrazole, analogues of celecoxib: synthesis and preliminary evaluation of biological properties. Farmaco. 2003;58(9):795–808.
   PubMedGoogle Scholar
• Hwang SH, Wagner KM, Morisseau C, Liu JY, Dong H, Wecksler AT, Hammock BD. Synthesis and structure − activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase. J Med Chem. 2011;54(8):3037–3050.
   PubMed Web of Science ®Google Scholar
• Abdelazeem AH, Safi El-Din AG, Abdel-Fattah MM, Amin NH, El-Moghazy SM, El-Saadi MT. Discovery of novel urea-diarylpyrazole hybrids as dual cox-2/seh inhibitors with improved anti-inflammatory activity and highly reduced cardiovascular risks. Eur J Med Chem. 2020;205:112662.
   PubMed Web of Science ®Google Scholar
• Li Z, Wang ZC, Li X, Abbas M, Wu SY, Ren SZ, Liu QX, Liu Y, Chen PW, Duan YT, et al. Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual cox-2/5-lox inhibitors and antitumor agents. Eur J Med Chem. 2019;169:168–184.
   PubMed Web of Science ®Google Scholar
• Çalışkan B, Luderer S, Özkan Y, Werz O, Banoglu E. Pyrazol-3-propanoic acid derivatives as novel inhibitors of leukotriene biosynthesis in human neutrophils. Eur J Med Chem. 2011;46(10):5021–5033.
   PubMed Web of Science ®Google Scholar
• Gorantla V, Gundla R, Jadav SS, Anugu SR, Chimakurthy J, Nidasanametla SK, Korupolu R. Molecular hybrid design, synthesis and biological evaluation of n-phenyl sulfonamide linked n-acyl hydrazone derivatives functioning as cox-2 inhibitors: new anti-inflammatory, anti-oxidant and anti-bacterial agents. New J Chem. 2017;41(22):13516–13532.
   Web of Science ®Google Scholar
• Cordeiro NDM, Freitas RHCN, Fraga CAM, Fernandes PD. New 2-amino-pyridinyl-n-acylhydrazones: synthesis and identification of their mechanism of anti-inflammatory action. Biomed Pharmacother. 2020;123:109739.
   PubMed Web of Science ®Google Scholar
• Ju Z, Su M, Hong J, La Kim E, Moon HR, Chung HY, Kim S, Jung JH. Design of balanced cox inhibitors based on anti-inflammatory and/or cox-2 inhibitory ascidian metabolites. Eur J Med Chem. 2019;180:86–98.
   PubMed Web of Science ®Google Scholar
• Hernández P, Cabrera M, Lavaggi ML, Celano L, Tiscornia I, Rodrigues da Costa T, Thomson L, Bollati-Fogolín M, Miranda ALP, Lima LM, et al. Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl n-acylhydrazone derivatives. Bioorg Med Chem. 2012;20(6):2158–2171.
   PubMed Web of Science ®Google Scholar
• Drysdale MJ, Hind SL, Jansen M, Reinhard JF. Synthesis and sar of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and esters and 2-amino-4-aryl-4-oxobut-2-enoic acids and esters: potent inhibitors of kynurenine-3-hydroxylase as potential neuroprotective agents. J Med Chem. 2000;43(1):123–127.
   PubMed Web of Science ®Google Scholar
• Sheverdov V, Nasakin O, Andreev AY, Gein V, Tafeenko V. Synthesis of methyl 3-acyl-6-amino-5-cyano-4-phenyl-4h-pyran-2-carboxylates and their rearrangement into 2-hydroxy-4-[hydroxy (r) methylidene]-3-oxo-5-phenylcyclopent-1-ene-1-carbonitriles. Russ J Org Chem. 2011;47(7):1117–1118.
   Web of Science ®Google Scholar
• Dias LRS, Salvador RRS. Pyrazole carbohydrazide derivatives of pharmaceutical interest. Pharmaceuticals (Basel). 2012;5(3):317–324. (
   PubMedGoogle Scholar
• Rajput J, Bagul S, Tadavi S, Karandikar P, Bendre R. Design, synthesis and biological evaluation of novel class diindolyl methanes (dims) derived from naturally occurring phenolic monoterpenoids. Med Chem. 2016;6(2):123–128.
   Google Scholar
• Duff JC. A new general method for the preparation of o-hydroxyaldehydes from phenols and hexamethylenetetramine. J Chem Soc. 1941;547–550.
   Google Scholar
• Casiraghi G, Casnati G, Cornia M, Pochini A, Puglia G, Sartori G, Ungaro R. Selective reactions using metal phenoxides. Part 1. Reactions with formaldehyde. J Chem Soc Perkin Trans 1. 1978;9(4):318–321.
   Google Scholar
• Casnati G, Casiraghi G, Puglia G, Sartori G, Terenghi G. Process for preparing 2-hydroxybenzoic aldehydes. Process for preparing 2-hydroxybenzoic aldehydes. Google Patents. 1979.
   Google Scholar
• Soliman R. Preparation and antidiabetic activity of some sulfonylurea derivatives of 3, 5-disubstituted pyrazoles. J Med Chem. 1979;22(3):321–325.
   PubMed Web of Science ®Google Scholar
• Coleman GH. Phenylhydrazine. Org Synth Coll. 1941;1:432–435.
   Google Scholar
• Karczmarzyk Z, Mojzych M, Rykowski A. Synthesis and structure of p-chlorophenylhydrazone of 3-(methylthio)-5-propanoyl-1, 2, 4-triazine. J Chem Crystallogr. 2000;30(6):423–427.
   Web of Science ®Google Scholar
• Kumar V, Kaur K, Gupta GK, Sharma AK. Pyrazole containing natural products: synthetic preview and biological significance. Eur J Med Chem. 2013;69(:735–753.
   PubMed Web of Science ®Google Scholar
• Cayman colorimetric COX (ovine) inhibitor screening assay kit (Catalog No. 560131) supplied by Cayman chemicals, 1180 E. Ann Arbor, MI, USA.
   Google Scholar
• Lipoxygenase inhibitor screening assay kit (Catalog No. 760700) supplied by Cayman chemicals, 1180 E. Ann Arbor, MI, USA.
   Google Scholar
• Razmi A, Zarghi A, Arfaee S, Naderi N, Faizi M. Evaluation of anti-nociceptive and anti-inflammatory activities of novel chalcone derivatives. Iran J Pharm Res. 2013;12:153–159.
   PubMed Web of Science ®Google Scholar
• Lakshmi V, Mishra V, Palit G. A new gastroprotective effect of limonoid compounds xyloccensins x and y from xylocarpus molluccensis in rats. Nat Prod Bioprospect. 2014;4(5):277–283.
   PubMedGoogle Scholar
• Hazzaa AA-E. Synthesis and biological evaluation of novel terpene derivatives. AlexU-IACUC (Member of ICLAS) 2019:AU-06-2019-9-30-2-58.
   Google Scholar
• Srivastava S, Nath C, Gupta M, Vrat S, Sinha J, Dhawan K, Gupta G. Protection against gastric ulcer by verapamil. Pharmacol Res. 1991;23(1):81–86.
   PubMed Web of Science ®Google Scholar
• Molecular operating environment (moe) 2016.08, chemical computing group inc. 1010 Sherbrooke St. West suite #910, Montreal, QC, Canada, h3a2r7. www.Chemcomp.Com.
   Google Scholar
• Rafinejad A, Fallah Tafti A, Tiwari R, Shirazi AN, Mandal D, Parang K, Foroumadi A, Akbarzadeh T. Synthesis and evaluation of ethyl 2,4-dioxo-4-arylbutanoate derivatives as src kinase inhibitors. J Sci Islamic Republic Iran. 2015;26:321–325.
   Google Scholar
• Yoon JY, Lee SG, Shin H. Recent advances in the regioselective synthesis of pyrazoles. Curr Org Chem. 2011;15(5):657–674.
   Web of Science ®Google Scholar
• Soliman WM, Abdellatif KRA, Knaus EE. Design, synthesis, biological evaluation, and nitric-oxide release studies of a novel series of celecoxib prodrugs possessing a nitric-oxide donor moiety. Braz J Pharm Sci. 2018;54(4):1–10.
   Web of Science ®Google Scholar
• Wang JL, Limburg D, Graneto MJ, Springer J, Hamper JRB, Liao S, Pawlitz JL, Kurumbail RG, Maziasz T, Talley JJ, et al. The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: the second clinical candidate having a shorter and favorable human half-life. Bioorg Med Chem Lett. 2010; 20(23):7159–7163.
   PubMed Web of Science ®Google Scholar
• Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996;384(6610):644–648.
   PubMed Web of Science ®Google Scholar
• Gilbert NC, Rui Z, Neau DB, Waight MT, Bartlett SG, Boeglin WE, Brash AR, Newcomer ME. Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at serine-663. FASEB J. 2012;26(8):3222–3229.
   PubMed Web of Science ®Google Scholar
• Hsu KC, HuangFu WC, Lin TE, Chao MW, Sung TY, Chen YY, Pan SL, Lee JC, Tzou SC, Sun CM, et al. A site-moiety map and virtual screening approach for discovery of novel 5-lox inhibitors. Sci Rep. 2020;10(1):10510.
   PubMed Web of Science ®Google Scholar