Discovery two potent and new inhibitors of 15-lipoxygenase: (E)-3-((3,4-dihydroxybenzylidene) amino)-7-hydroxy-2H-chromen-2-one and (E)-O-(4-(((7-hydroxy-2-oxo-2H-chromen-3-yl) imino)methine) phenyl)dimethylcarbamothioate
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The mechanisms of action and structural determinants of lipoxygenases inhibitors have been explored on several occasions, but many questions remain unanswered, especially about the differences of the inhibition mechanisms and their effect on the selectivity of lipoxygenases isoenzymes. Thus, REDOX mechanism has been proposed in this research to clarify the lipoxygenases inhibition by coumarins derivates on 15-sLOX. A series of fifteen coumarin derivatives were synthetized and evaluated as 15-lipoxygenase inhibitors. The results showed that some molecules had submicromolar activities and compete with the substrate as we observed by kinetic studies. The most relevant and interesting result was found for compound 6 who showed an inhibitory activity comparable to nordihydroguaiaretic acid a potent and REDOX inhibitor of lipoxygenases (0.17 and 0.29 μM, respectively). Finally, the docking and molecular dynamics studies showed that the better ligands were accommodated into the binding site being related with those obtained biological data. In addition, our findings contribute at the understanding of inhibitor structural requirements and elucidate the inhibition mechanism of cumarin derivatives on 15-sLOX. Thus, we point to new parameters for the future design of new ligands with potential therapeutic utility where are involved the lipoxygenases enzymes.
Keywords15-Lipoxygenase Coumarin derivatives Kinetic assay Pseudoperoxidase SAR study
Financial support from DICYT 021641MC; Fondecyt 1120379, Fondecyt 1161375 and the Millennium Scientific Initiative (Grant P05-001-F).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Chauhan BF, Ducharme FM (2012) Anti‐leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. The Cochrane LibraryGoogle Scholar
- Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Jr., Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian ‘09, Revision A.1. ’09. Wallingford, CTGoogle Scholar
- García-Beltrán O, Rodríguez A, Trujillo A, Cañete A, Aguirre P, Gallego-Quintero S, Aliaga ME (2015a) Synthesis and characterization of a novel fluorescent and colorimetric probe for the detection of mercury (II) even in the presence of relevant biothiols. Tetrahedron Lett 56:5761–5766CrossRefGoogle Scholar
- García-Beltrán O, Rodríguez A, Trujillo A, Cañete A, Aguirre P, Gallego-Quintero S, Aliaga ME (2015b) Synthesis and characterization of a novel fluorescent and colorimetric probe for the detection of mercury (II) even in the presence of relevant biothiols. Tetrahedron Lett 56:5761–5766CrossRefGoogle Scholar
- Dennington R, Keith T, Millam J (2009) GaussView, Version 5 Semichem Inc., Shawnee Mission, KS,Google Scholar
- GraphPad Software, La Jolla California USA, www.graphpad.com
- Huff JB, Merchant BT, Mullen CR, Venkata SRT (1999) U.S. Patent No. 5,998,593. Washington, DC: U.S. Patent and Trademark OfficeGoogle Scholar
- Singh D, Pathak DP (2016) Coumarins: an overview of medicinal chemistry. Potential for new drug molecules. Int J Pharm Sci Rev Res 7:482Google Scholar
- Tresaugues L, Moche M, Arrowsmith CH, Berglund H, Busam RD, Collins R, Graslund, S (2008) Crystal structure of the lipoxygenase domain of human Arachidonate 12-lipoxygenase, 12S-type. Submitted. PDB entry 3D3LGoogle Scholar