Synthesis and Biological Evaluation of Benzodioxol Derivatives as Cyclooxygenase Inhibitors

Nidal       Jaradat; Mohammed       Hawash; Murad       Abualhasan

Abstract

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutics; they are competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the conversion of arachidonic acid to inflammatory prostaglandins.

Objective: In this study, new benzodioxol derivatives with different core cycles and functional groups (i.e., aryl acetate, aryl acetic acid and diazepine) were designed, synthesized, identified and evaluated for their analgesic and anti-inflammatory activity, as a preliminary screening study to identify the most potent and more selective groups.

Methods: The synthesized compounds were identified using FTIR, HRMS, 1H-NMR and 13C-NMR, and evaluated for their inhibitory activity against ovine COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay kit.

Results and Discussion: Six compounds were synthesized as a preliminary screening study to identify which was the most potent and more selective group towards COX-2 versus COX-1, compared to ketoprofen as non-selective NSAIDs. The compounds have three different groups: aryl acetate, aryl acetic acid and diazepine. The results showed that the most potent compound against the COX- 1 enzyme was 4b (which has diazepine and 2-chlorophenyl) with IC50 = 0.363 μM, and the selectivity ratio of 4b was found to be better than ketoprofen. In contrast, compound 4a (which has diazepine and 3-chlorophenyl) was the most selective with a COX-1/COX-2 ratio value of 0.85 in comparison with a ketoprofen ratio value of 0.20.

Conclusion: In general, the synthesized library has moderate activity against both enzymes (i.e., COX-1 and COX-2). Moreover, all six compounds have better COX-2 inhibition selectivity compared to the commercial drug ketoprofen.

Keywords: NSAIDs, cyclooxygenase, benzodioxole, ketoprofen, diazepine, FTIR.

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[1] 
Fiorucci, S.; Meli, R.; Bucci, M.; Cirino, G. Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy? Biochem. Pharmacol.,  2001, 62(11), 1433-1438.
[http://dx.doi.org/10.1016/S0006-2952(01)00747-X ] [PMID:  11728379] 
[2] 
Zarghi, A.; Arfaei, S. Selective COX-2 inhibitors: A review of their structure-activity relationships. Iran. J. Pharm. Res.,  2011, 10(4), 655-683.
[PMID:  24250402] 
[3] 
Vane, J.R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat. New Biol.,  1971, 231(25), 232-235.
[http://dx.doi.org/10.1038/newbio231232a0 ] [PMID:  5284360] 
[4] 
El-Sayed, M.A.; Abdel-Aziz, N.I.; Abdel-Aziz, A.A.; El-Azab, A.S.; Asiri, Y.A.; Eltahir, K.E. Design, synthesis, and biological evaluation of substituted hydrazone and pyrazole derivatives as selective COX-2 inhibitors: Molecular docking study. Bioorg. Med. Chem.,  2011, 19(11), 3416-3424.
[http://dx.doi.org/10.1016/j.bmc.2011.04.027 ] [PMID:  21570309] 
[5] 
Frank, M.M.; Fries, L.F. The role of complement in inflammation and phagocytosis. Immunol. Today,  1991, 12(9), 322-326.
[http://dx.doi.org/10.1016/0167-5699(91)90009-I ] [PMID:  1755943] 
[6] 
Collier, H.O. Prostaglandins and aspirin. Nature,  1971, 232(5305), 17-19.
[http://dx.doi.org/10.1038/232017a0 ] [PMID:  4997426] 
[7] 
Cryer, B.; Feldman, M. Effects of nonsteroidal anti-inflammatory drugs on endogenous gastrointestinal prostaglandins and therapeutic strategies for prevention and treatment of nonsteroidal anti-inflammatory drug-induced damage. Arch. Intern. Med.,  1992, 152(6), 1145-1155.
[http://dx.doi.org/10.1001/archinte.1992.00400180017003 ] [PMID:  1599341] 
[8] 
Konturek, P.C.; Kania, J.; Burnat, G.; Hahn, E.G.; Konturek, S.J. Prostaglandins as mediators of COX-2 derived carcinogenesis in gastrointestinal tract. J. Physiol. Pharmacol.,  2005, 56(Suppl. 5), 57-73.
[PMID:  16247189] 
[9] 
Dannhardt, G.; Kiefer, W. Cyclooxygenase inhibitors--current status and future prospects. Eur. J. Med. Chem.,  2001, 36(2), 109-126.
[http://dx.doi.org/10.1016/S0223-5234(01)01197-7 ] [PMID:  11311743] 
[10] 
Dannhardt, G.; Kiefer, W.; Krämer, G.; Maehrlein, S.; Nowe, U.; Fiebich, B. The pyrrole moiety as a template for COX-1/COX-2 inhibitors. Eur. J. Med. Chem.,  2000, 35(5), 499-510.
[http://dx.doi.org/10.1016/S0223-5234(00)00150-1 ] [PMID:  10889329] 
[11] 
Bayly, C.I.; Black, W.C.; Léger, S.; Ouimet, N.; Ouellet, M.; Percival, M.D. Structure-based design of COX-2 selectivity into flurbiprofen. Bioorg. Med. Chem. Lett.,  1999, 9(3), 307-312.
[http://dx.doi.org/10.1016/S0960-894X(98)00717-3 ] [PMID:  10091674] 
[12] 
Lehmann, F.S.; Beglinger, C. Impact of COX-2 inhibitors in common clinical practice a gastroenterologist’s perspective. Curr. Top. Med. Chem.,  2005, 5(5), 449-464.
[http://dx.doi.org/10.2174/1568026054201703 ] [PMID:  15974940] 
[13] 
Botting, R.M. Inhibitors of cyclooxygenases: mechanisms, selectivity and uses. J. Physiol. Pharmacol.,  2006, 57(Suppl. 5), 113-124.
[PMID:  17218763] 
[14] 
McGettigan, P.; Henry, D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA,  2006, 296(13), 1633-1644.
[http://dx.doi.org/10.1001/jama.296.13.jrv60011 ] [PMID:  16968831] 
[15] 
Hawash, M.M.; Baytas, S.N. Antiproliferative activities of some biologically important scaffold. FABAD J. Pharm. Sci.,  2017, 43, 59.
[16] 
Hawash, M.M.; Kahraman, D.C.; Eren, F.; Cetin Atalay, R.; Baytas, S.N. Synthesis and biological evaluation of novel pyrazolic chalcone derivatives as novel hepatocellular carcinoma therapeutics. Eur. J. Med. Chem.,  2017, 129, 12-26.
[http://dx.doi.org/10.1016/j.ejmech.2017.02.002 ] [PMID:  28219046] 
[17] 
Bandgar, B.P.; Totre, J.V.; Gawande, S.S.; Khobragade, C.N.; Warangkar, S.C.; Kadam, P.D. Synthesis of novel 3,5-diaryl pyrazole derivatives using combinatorial chemistry as inhibitors of tyrosinase as well as potent anticancer, anti-inflammatory agents. Bioorg. Med. Chem.,  2010, 18(16), 6149-6155.
[http://dx.doi.org/10.1016/j.bmc.2010.06.046 ] [PMID:  20638287] 
[18] 
Abdellatif, K.R.; Lamie, P.F.; Omar, H.A. 3-methyl-2-phenyl-1-substituted-indole derivatives as indomethacin analogs: Design, synthesis and biological evaluation as potential anti-inflammatory and analgesic agents. J. Enzyme Inhib. Med. Chem.,  2016, 31(2), 318-324.
[http://dx.doi.org/10.3109/14756366.2015.1022174 ] [PMID:  25798690] 
[19] 
Abu-Hashem, A.A.; El-Shehry, M.F.; Badria, F.A. Design and synthesis of novel thiophenecarbohydrazide, thienopyrazole and thienopyrimidine derivatives as antioxidant and antitumor agents. Acta Pharm.,  2010, 60(3), 311-323.
[http://dx.doi.org/10.2478/v10007-010-0027-6 ] [PMID:  21134865] 
[20] 
Cihan-Üstündağ, G.; Gürsoy, E.; Naesens, L.; Ulusoy-Güzeldemirci, N.; Çapan, G. Synthesis and antiviral properties of novel indole-based thiosemicarbazides and 4-thiazolidinones. Bioorg. Med. Chem.,  2016, 24(2), 240-246.
[http://dx.doi.org/10.1016/j.bmc.2015.12.008 ] [PMID:  26707844] 
[21] 
Qneibi, M.; Jaradat, N.; Hawash, M.; Zaid, A.N.; Natsheh, A-R.; Yousef, R.; AbuHasan, Q. The neuroprotective role of Origanum syriacum L. and Lavandula dentata L. Essential oils through their effects on AMPA receptors. BioMed Res. Int.,  2019, 2019 5640173
[http://dx.doi.org/10.1155/2019/5640173 ] [PMID:  31275977] 
[22] 
Hsiao, G.; Shen, M-Y.; Chou, D-S.; Chang, Y.; Lee, L-W.; Lin, C-H.; Sheu, J-R. Mechanisms of antiplatelet and antithrombotic activity of midazolam in in vitro and in vivo studies. Eur. J. Pharmacol.,  2004, 487(1-3), 159-166.
[http://dx.doi.org/10.1016/j.ejphar.2004.01.026 ] [PMID:  15033388] 
[23] 
Grossi, G.; Di Braccio, M.; Roma, G.; Ballabeni, V.; Tognolini, M.; Calcina, F.; Barocelli, E. 1,5-benzodiazepines. Part XIII. Substituted 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines and 4H-imidazo[1,2-a][1,5]benzodiazepin-5-amines as analgesic, anti-inflammatory and/or antipyretic agents with low acute toxicity. Eur. J. Med. Chem.,  2002, 37(12), 933-944.
[http://dx.doi.org/10.1016/S0223-5234(02)01400-9 ] [PMID:  12660018] 
[24] 
Chadha, S.; Paul, S.; Kapoor, K. Synthesis and biological screening of 4-(5-alkyl-2-isoxazolin-3-yl)-2-aryl-2, 3-dihydro-1H-1, 5-benzodiazepines. J. Chem. Pharm. Res.,  2011, 3, 331.
[25] 
Dourlat, J.; Liu, W-Q.; Gresh, N.; Garbay, C. Novel 1,4-benzodiazepine derivatives with antiproliferative properties on tumor cell lines. Bioorg. Med. Chem. Lett.,  2007, 17(9), 2527-2530.
[http://dx.doi.org/10.1016/j.bmcl.2007.02.016 ] [PMID:  17317183] 
[26] 
Deshpande, S.R.; Nagrale, S.N.; Patil, M.V.; Chavan, P.S. Novel 3,4-methylenedioxybenzene scaffold incorporated 1,3,5-trisubstituted-2-pyrazolines: Synthesis, characterization and evaluation for chemotherapeutic activity. Indian J. Pharm. Sci.,  2015, 77(1), 24-33.
[http://dx.doi.org/10.4103/0250-474X.151588 ] [PMID:  25767315] 
[27] 
Rollas, S.; Küçükgüzel, S.G. Biological activities of hydrazone derivatives. Molecules,  2007, 12(8), 1910-1939.
[http://dx.doi.org/10.3390/12081910 ] [PMID:  17960096] 
[28] 
Miller, E.C.; Swanson, A.B.; Phillips, D.H.; Fletcher, T.L.; Liem, A.; Miller, J.A. Structure-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenylbenzene derivatives related to safrole and estragole. Cancer Res.,  1983, 43(3), 1124-1134.
[PMID:  6825084] 
[29] 
Lima, P.C.; Lima, L.M.; da Silva, K.C.; Léda, P.H.O.; de Miranda, A.L.; Fraga, C.A.M.; Barreiro, E.J. Synthesis and analgesic activity of novel N-acylarylhydrazones and isosters, derived from natural safrole. Eur. J. Med. Chem.,  2000, 35(2), 187-203.
[http://dx.doi.org/10.1016/S0223-5234(00)00120-3 ] [PMID:  10758281] 
[30] 
Khayyat, S.A. Photosynthesis of dimeric cinnamaldehyde, eugenol, and safrole as antimicrobial agents. J. Saudi Chem. Soc.,  2013, 17, 61.
[http://dx.doi.org/10.1016/j.jscs.2011.07.014] 
[31] 
Espahbodinia, M.; Ettari, R.; Wen, W.; Wu, A.; Shen, Y.C.; Niu, L.; Grasso, S.; Zappalà, M. Development of novel N-3-bromoisoxazolin-5-yl substituted 2,3-benzodiazepines as noncompetitive AMPAR antagonists. Bioorg. Med. Chem.,  2017, 25(14), 3631-3637.
[http://dx.doi.org/10.1016/j.bmc.2017.05.036 ] [PMID:  28571973] 
[32] 
Irannejad, H.; Kebriaieezadeh, A.; Zarghi, A.; Montazer-Sadegh, F.; Shafiee, A.; Assadieskandar, A.; Amini, M. Synthesis, docking simulation, biological evaluations and 3D-QSAR study of 5-Aryl-6-(4-methylsulfonyl)-3-(metylthio)-1,2,4-triazine as selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem.,  2014, 22(2), 865-873.
[http://dx.doi.org/10.1016/j.bmc.2013.12.002 ] [PMID:  24361187] 
[33] 
Zarghi, A.; Ghodsi, R. Design, synthesis, and biological evaluation of ketoprofen analogs as potent cyclooxygenase-2 inhibitors. Bioorg. Med. Chem.,  2010, 18(16), 5855-5860.
[http://dx.doi.org/10.1016/j.bmc.2010.06.094 ] [PMID:  20650641] 
[34] 
Bandyopadhyay, S.; Pal, B.C.; Parasuraman, J.; Roy, S.; Chakrabotry, J.B.; Mukherjee, C.; Mahato, K.; Konar, A.; Rakshit, S.; Mandal, L.; Ganguly, D.; Paul, K.; Manna, A.; Vinayagam, J.; Pal, C. InventorsInhibitors of phosphatidylinositol-3-kinase (PI3)
and inducers of nitric oxide (NO) ; United States. , 2016. 
[35] 
Zappalà, M.; Pellicanò, A.; Micale, N.; Menniti, F.S.; Ferreri, G.; De Sarro, G.; Grasso, S.; De Micheli, C. New 7,8-ethylenedioxy-2,3-benzodiazepines as noncompetitive AMPA receptor antagonists. Bioorg. Med. Chem. Lett.,  2006, 16(1), 167-170.
[http://dx.doi.org/10.1016/j.bmcl.2005.09.029 ] [PMID:  16216501] 
[36] 
Zappalà, M.; Postorino, G.; Micale, N.; Caccamese, S.; Parrinello, N.; Grazioso, G.; Roda, G.; Menniti, F.S.; De Sarro, G.; Grasso, S. Synthesis, chiral resolution, and enantiopharmacology of a potent 2,3-benzodiazepine derivative as noncompetitive AMPA receptor antagonist. J. Med. Chem.,  2006, 49(2), 575-581.
[http://dx.doi.org/10.1021/jm050552y ] [PMID:  16420043] 
[37] 
Micale, N.; Colleoni, S.; Postorino, G.; Pellicanò, A.; Zappalà, M.; Lazzaro, J.; Diana, V.; Cagnotto, A.; Mennini, T.; Grasso, S. Structure-activity study of 2,3-benzodiazepin-4-ones noncompetitive AMPAR antagonists: identification of the 1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one as neuroprotective agent. Bioorg. Med. Chem.,  2008, 16(5), 2200-2211.
[http://dx.doi.org/10.1016/j.bmc.2007.11.080 ] [PMID:  18083036] 
[38] 
Xia, H.; Cai, S.X.; Field, G.; Ana, S.; Lan, N.S.; Wang, Y. Inventors
Substituted 2,3-benzodiazepin-4-ones and the use thereof; United States. , 1999. 
[39] 
Jin, G.; Lee, S.; Choi, M.; Son, S.; Kim, G.W.; Oh, J.W.; Lee, C.; Lee, K. Chemical genetics-based discovery of indole derivatives as HCV NS5B polymerase inhibitors. Eur. J. Med. Chem.,  2014, 75, 413-425.
[http://dx.doi.org/10.1016/j.ejmech.2014.01.062 ] [PMID:  24561671] 
[40] 
Ergün, B.C.; Nuñez, M.T.; Labeaga, L.; Ledo, F.; Darlington, J.; Bain, G.; Cakir, B.; Banoglu, E. Synthesis of 1,5-diarylpyrazol-3-propanoic acids towards inhibition of cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4 formation. Arzneimittelforschung,  2010, 60(8), 497-505.
[PMID: 20863006] 

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DOI https://dx.doi.org/10.2174/1570180817999200420114402	Print ISSN 1570-1808
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Synthesis and Biological Evaluation of Benzodioxol Derivatives as Cyclooxygenase Inhibitors

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