Design, Synthesis and Pharmacological Evaluation of Novel Antiinflammatory and Analgesic O-Benzyloxime Compounds Derived From Natural Eugenol

Author(s): Rodrigo César da Silva, Fabiano Veiga, Fabiana Cardoso Vilela, André Victor Pereira, Thayssa Tavares da Silva Cunha, Roberta Tesch, Claudio Viegas Jr., Danielle Ferreira Dias, Alexandre Giusti-Paiva, Marcia Paranho Veloso, Carlos Alberto Manssour Fraga*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 10 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: A new series of O-benzyloximes derived from eugenol was synthesized and was evaluated for its antinociceptive and anti-inflammatory properties.

Methods: The target compounds were obtained in good global 25-28% yields over 6 steps, which led us to identify compounds (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-(4- (methylthio)benzyloxime (8b), (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- bromobenzyloxime (8d) and (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- (methylsulfonyl)benzyloxime (8f) as promising bioactive prototypes.

Results: These compounds have significant analgesic and anti-inflammatory effects, as evidenced by formalin-induced mice paw edema and carrageenan-induced mice paw edema tests. In the formalin test, compounds 8b and 8f evidenced both anti-inflammatory and direct analgesic activities and in the carrageenan-induced paw edema, with compounds 8c, 8d, and 8f showing the best inhibitory effects, exceeding the standard drugs indomethacin and celecoxib.

Conclusion: Molecular docking studies have provided additional evidence that the pharmacological profile of these compounds may be related to inhibition of COX enzymes, with slight preference for COX-1. These results led us to identify the new O-benzyloxime ethers 8b, 8d and 8f as orally bioactive prototypes, with a novel structural pattern capable of being explored in further studies aiming at their optimization and development as drug candidates.

Keywords: O-benzyloxime, eugenol, indanone derivatives, anti-inflammatory, analgesic, drug design.

[1]
Marnett, L.J.; Kalgutkar, A.S. Cyclooxygenase 2 inhibitors: discovery, selectivity and the future. Trends Pharmacol. Sci., 1999, 20(11), 465-469.
[http://dx.doi.org/10.1016/S0165-6147(99)01385-1] [PMID: 10542447]
[2]
Medzhitov, R. Origin and physiological roles of inflammation. Nature, 2008, 454(7203), 428-435.
[http://dx.doi.org/10.1038/nature07201] [PMID: 18650913]
[3]
Chen, Q.H.; Rao, P.N.P.; Knaus, E.E. Synthesis and biological evaluation of a novel class of rofecoxib analogues as dual inhibitors of cyclooxygenases (COXs) and lipoxygenases (LOXs). Bioorg. Med. Chem., 2006, 14(23), 7898-7909.
[http://dx.doi.org/10.1016/j.bmc.2006.07.047] [PMID: 16904331]
[4]
El-Gamal, M.I.; Bayomi, S.M.; El-Ashry, S.M.; Said, S.A.; Abdel-Aziz, A.A.; Abdel-Aziz, N.I. Synthesis and anti-inflammatory activity of novel (substituted)benzylidene acetone oxime ether derivatives: molecular modeling study. Eur. J. Med. Chem., 2010, 45(4), 1403-1414.
[http://dx.doi.org/10.1016/j.ejmech.2009.12.041] [PMID: 20079558]
[5]
Zheng, L.W.; Li, Y.; Ge, D.; Zhao, B.X.; Liu, Y.R.; Lv, H.S.; Ding, J.; Miao, J.Y. Synthesis of novel oxime-containing pyrazole derivatives and discovery of regulators for apoptosis and autophagy in A549 lung cancer cells. Bioorg. Med. Chem. Lett., 2010, 20(16), 4766-4770.
[http://dx.doi.org/10.1016/j.bmcl.2010.06.121] [PMID: 20637610]
[6]
Abd-Ellah, H.S.; Abdel-Aziz, M.; Shoman, M.E.; Beshr, E.A.M.; Kaoud, T.; Ahmed, A.F.F. New 1,3,4-oxadiazole/oxime hybrids: Design, synthesis, anti-inflammatory, COX inhibitory activities and ulcerogenic liability. Bioorg. Chem., 2017, 74, 15-29.
[http://dx.doi.org/10.1016/j.bioorg.2017.06.003] [PMID: 28738249]
[7]
Mohassab, A.M.; Hassan, H.A.; Abdelhamid, D.; Abdel-Aziz, M.; Dalby, K.N.; Kaoud, T.S. Novel quinoline incorporating 1,2,4-triazole/oxime hybrids: Synthesis, molecular docking, anti-inflammatory, COX inhibition, ulceroginicity and histopathological investigations. Bioorg. Chem., 2017, 75, 242-259.
[http://dx.doi.org/10.1016/j.bioorg.2017.09.018] [PMID: 29032325]
[8]
deSouza, T.B.; Orland, M.; Coelho, L.F.L.; Malaquias, L.C.C.; Dias, A.L.T.; Carvalho, R.R.; Silva, N.C.; Carvalho, D.T. Synthesis and in vitro evaluation of antifungal and cytotoxic activities of eugenol glycosides. Med. Chem. Res., 2014, 23, 496-502.
[http://dx.doi.org/10.1007/s00044-013-0669-2]
[9]
Sheridan, H.; Walsh, J.J.; Cogan, C.; Jordan, M.; McCabe, T.; Passante, E.; Frankish, N.H. Diastereoisomers of 2-benzyl-2, 3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol: potential anti-inflammatory agents. Bioorg. Med. Chem. Lett., 2009, 19(20), 5927-5930.
[http://dx.doi.org/10.1016/j.bmcl.2009.08.060] [PMID: 19740655]
[10]
De Clercq, E. Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int. J. Antimicrob. Agents, 2009, 33(4), 307-320.
[http://dx.doi.org/10.1016/j.ijantimicag.2008.10.010] [PMID: 19108994]
[11]
Sheridan, H.; Frankish, N.; Farrell, R. Smooth muscle relaxant activity of pterosin Z and related compounds. Planta Med., 1999, 65(3), 271-272.
[http://dx.doi.org/10.1055/s-2006-960775] [PMID: 10232079]
[12]
Frankish, N.; Sheridan, H. 6-(methylamino)hexane-1,2,3,4,5-pentanol 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1'H-[2,2-biinden]-2-yl)methyl)benzoate (PH46A): a novel small molecule with efficacy in murine models of colitis. J. Med. Chem., 2012, 55(11), 5497-5505.
[http://dx.doi.org/10.1021/jm300390f] [PMID: 22663546]
[13]
Frankish, N.; Farrell, R.; Sheridan, H. Investigation into the mast cell stabilizing activity of nature-identical and synthetic indanones. J. Pharm. Pharmacol., 2004, 56(11), 1423-1427.
[http://dx.doi.org/10.1211/0022357044661] [PMID: 15525449]
[14]
Jelic, V.; Darreh-Shori, T. Donepezil: A Review of Pharmacological Characteristics and Role in the Management of Alzheimer Disease. Clin. Med. Insights Ther., 2010, 2, 771-788.
[http://dx.doi.org/10.4137/CMT.S5410]
[15]
Oldfield, V.; Keating, G.M.; Perry, C.M. Rasagiline: a review of its use in the management of Parkinson’s disease. Drugs, 2007, 67(12), 1725-1747.
[http://dx.doi.org/10.2165/00003495-200767120-00006] [PMID: 17683172]
[16]
Rodrigues, C.R.; Veloso, M.P.; Verli, H.; Fraga, C.A.M.; Miranda, A.L.P.; Barreiro, E.J. Selective PGHS-2 inhibitors: a rational approach for treatment of the inflammation. Curr. Med. Chem., 2002, 9(8), 849-867.
[http://dx.doi.org/10.2174/0929867024606786] [PMID: 11966448]
[17]
Vinegar, R.; Schreiber, W.; Hugo, R. Biphasic development of carrageenin edema in rats. J. Pharmacol. Exp. Ther., 1969, 166(1), 96-103.
[PMID: 5776026]
[18]
Vilela, F.C.; de Mesquita Padilha, M. Dos Santos-E-Silva, L.; Alves-da-Silva, G.; Giusti-Paiva, A. Evaluation of the antinociceptive activity of extracts of Sonchus oleraceus L. in mice. J. Ethnopharmacol., 2009, 124(2), 306-310.
[http://dx.doi.org/10.1016/j.jep.2009.04.037] [PMID: 19397974]
[19]
Muko, K.N.; Ohiri, F.C. A preliminary study on the anti-inflammatory properties of Emilia sonchifolia leaf extracts. Fitoterapia, 2000, 71(1), 65-68.
[http://dx.doi.org/10.1016/S0367-326X(99)00123-9] [PMID: 11449473]
[20]
Chowdhury, M.A.; Dong, Y.; Chen, Q.H.; Abdellatif, K.R.; Knaus, E.E. Synthesis and cyclooxygenase inhibitory activities of linear 1-(methanesulfonylphenyl or benzenesulfonamido)-2-(pyridyl)acetylene regioisomers. Bioorg. Med. Chem., 2008, 16(4), 1948-1956.
[http://dx.doi.org/10.1016/j.bmc.2007.11.003] [PMID: 18023187]
[21]
Sidhu, R.S.; Lee, J.Y.; Yuan, C.; Smith, W.L. Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers. Biochemistry, 2010, 49(33), 7069-7079.
[http://dx.doi.org/10.1021/bi1003298] [PMID: 20669977]
[22]
Eldridge, M.D.; Murray, C.W.; Auton, T.R.; Paolini, G.V.; Mee, R.P. Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J. Comput. Aided Mol. Des., 1997, 11(5), 425-445.
[http://dx.doi.org/10.1023/A:1007996124545] [PMID: 9385547]
[23]
Dewar, M.J.S.; Zoebisch, E.G.; Healy, E.F.; Stewart, J.J.P. Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model. J. Am. Chem. Soc., 1985, 107, 3902-3909.
[http://dx.doi.org/10.1021/ja00299a024]
[24]
Bezerra-Netto, H.J.; Lacerda, D.I.; Miranda, A.L.P.; Alves, H.M.; Barreiro, E.J.; Fraga, C.A.M. Design and synthesis of 3,4-methylenedioxy-6-nitrophenoxyacetylhydrazone derivatives obtained from natural safrole: new lead-agents with analgesic and antipyretic properties. Bioorg. Med. Chem., 2006, 14(23), 7924-7935.
[http://dx.doi.org/10.1016/j.bmc.2006.07.046] [PMID: 16904329]
[25]
Barreiro, E.J.; Lima, M.E.F. The synthesis and anti-inflammatory properties of a new sulindac analogue synthesized from natural safrole. J. Pharm. Sci., 1992, 81(12), 1219-1222.
[http://dx.doi.org/10.1002/jps.2600811219] [PMID: 1491344]
[26]
Ranu, B.C.; Jana, U.A. A new redundant rearrangement of aromatic ring fused cyclic α-hydroxydithiane derivatives. synthesis of aromatic ring fused cyclic 1,2-diketones with one-carbon ring expansion. J. Org. Chem., 1999, 64, 6380-6386.
[http://dx.doi.org/10.1021/jo990634s]
[27]
Gopalsamy, A.; Yang, H.; Ellingboe, J.W.; McKew, J.C.; Tam, S.; Joseph-McCarthy, D.; Zhang, W.; Shen, M.; Clark, J.D. 1,2,4-Oxadiazolidin-3,5-diones and 1,3,5-triazin-2,4,6-triones as cytosolic phospholipase A2alpha inhibitors. Bioorg. Med. Chem. Lett., 2006, 16(11), 2978-2981.
[http://dx.doi.org/10.1016/j.bmcl.2006.02.067] [PMID: 16545564]
[28]
Karabatsos, G.J.; Hsi, N. Structural studies by nuclear magnetic resonance—XI: Conformations and configurations of oxime o-methyl ethers. Tetrahedron, 1967, 23, 1079-1095.
[http://dx.doi.org/10.1016/0040-4020(67)85058-0]
[29]
Li, C.B.; Cui, Y.; Zhang, W.Q.; Li, J.L.; Zhang, S.M.; Choi, M.C.K.; Chan, S.C. A convenient and efficient procedure for oxime ethers. Chin. Chem. Lett., 2002, 13, 95-96.
[30]
Janusz, J.M.; Young, P.A.; Ridgeway, J.M.; Scherz, M.W.; Enzweiler, K.; Wu, L.I.; Gan, L.; Darolia, R.; Matthews, R.S.; Hennes, D.; Kellstein, D.E.; Green, S.A.; Tulich, J.L.; Rosario-Jansen, T.; Magrisso, I.J.; Wehmeyer, K.R.; Kuhlenbeck, D.L.; Eichhold, T.H.; Dobson, R.L.; Sirko, S.P.; Farmer, R.W. New cyclooxygenase-2/5-lipoxygenase inhibitors. 1. 7-tert-buty1-2,3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: discovery and variation of the 5-keto substituent. J. Med. Chem., 1998, 41(7), 1112-1123.
[http://dx.doi.org/10.1021/jm970679q] [PMID: 9544211]
[31]
Hunskaar, S.; Hole, K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain, 1987, 30(1), 103-114.
[http://dx.doi.org/10.1016/0304-3959(87)90088-1] [PMID: 3614974]
[32]
Dubuisson, D.; Dennis, S.G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain, 1977, 4(2), 161-174.
[http://dx.doi.org/10.1016/0304-3959(77)90130-0] [PMID: 564014]
[33]
Abram, S.E.; Olson, E.E. Systemic opioids do not suppress spinal sensitization after subcutaneous formalin in rats. Anesthesiology, 1994, 80(5), 1114-1119.
[http://dx.doi.org/10.1097/00000542-199405000-00020] [PMID: 8017649]
[34]
Manning, B.H. A lateralized deficit in morphine antinociception after unilateral inactivation of the central amygdala. J. Neurosci., 1998, 18(22), 9453-9470.
[http://dx.doi.org/10.1523/JNEUROSCI.18-22-09453.1998] [PMID: 9801383]
[35]
Rosland, J.H.; Tjølsen, A.; Maehle, B.; Hole, K. The formalin test in mice: effect of formalin concentration. Pain, 1990, 42(2), 235-242.
[http://dx.doi.org/10.1016/0304-3959(90)91167-H] [PMID: 2247320]
[36]
Yamamoto, T.; Nozaki-Taguchi, N. The role of cyclooxygenase-1 and -2 in the rat formalin test. Anesth. Analg., 2002, 94(4), 962-967.
[http://dx.doi.org/10.1097/00000539-200204000-00035] [PMID: 11916805]
[37]
Yamamoto, T.; Nozaki-Taguchi, N.; Chiba, T. Analgesic effect of intrathecally administered orexin-A in the rat formalin test and in the rat hot plate test. Br. J. Pharmacol., 2002, 137(2), 170-176.
[http://dx.doi.org/10.1038/sj.bjp.0704851] [PMID: 12208773]
[38]
Santos, A.R.S.; Calixto, J.B. Further evidence for the involvement of tachykinin receptor subtypes in formalin and capsaicin models of pain in mice. Neuropeptides, 1997, 31(4), 381-389.
[http://dx.doi.org/10.1016/S0143-4179(97)90075-5] [PMID: 9308027]
[39]
Henriques, M.G.; Silva, P.M.; Martins, M.A.; Flores, C.A.; Cunha, F.Q.; Assreuy-Filho, J.; Cordeiro, R.S. Mouse paw edema. A new model for inflammation? Braz. J. Med. Biol. Res., 1987, 20(2), 243-249.
[PMID: 3690058]
[40]
Kurumbail, R.G.; Stevens, A.M.; Gierse, J.K.; McDonald, J.J.; Stegeman, R.A.; Pak, J.Y.; Gildehaus, D.; Miyashiro, J.M.; Penning, T.D.; Seibert, K.; Isakson, P.C.; Stallings, W.C. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature, 1996, 384(6610), 644-648.
[http://dx.doi.org/10.1038/384644a0] [PMID: 8967954]
[41]
Jones, G.; Willett, P.; Glen, R.C.; Leach, A.R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol., 1997, 267(3), 727-748.
[http://dx.doi.org/10.1006/jmbi.1996.0897] [PMID: 9126849]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 10
Year: 2019
Page: [1157 - 1166]
Pages: 10
DOI: 10.2174/1570180815666180620145609
Price: $65

Article Metrics

PDF: 31
HTML: 2

Special-new-year-discount