Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC50 values in the nanomolar range (9-252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.

Department of Pharmacy Pharmacognosy and Center of Molecular Biosciences University of Innsbruck Innsbruck Austria

Faculty of Pharmacy in Hradec Kralové Charles University Hradec Kralové Czech Republic

Laboratory of Plant Biotechnologies Institute of Experimental Botany of the Czech Academy of Sciences Prague Czech Republic

Zobrazit více v PubMed

World Health Organization, Cardiovascular diseases, https://www.who.int/health-topics/cardiovascular-diseases#tab=tab_1, 2022 (accessed: June 2022).

E. Ricciotti, G. A. FitzGerald, Annu. Rev. Med. 2021, 72, 473. https://doi.org/10.1146/annurev-med-051019-102940

A. J. J. Wood, C. Patrono, N. Engl. J. Med. 1994, 330, 1287. https://doi.org/10.1056/NEJM199405053301808

I. G. E. Zarraga, E. R. Schwarz, J. Am. Coll. Cardiol. 2007, 49, 1. https://doi.org/10.1016/j.jacc.2006.10.003

J. A. Mitchell, T. D. Warner, Nat. Rev. Drug Discov. 2006, 5, 75. https://doi.org/10.1038/nrd1929

M. G. Perrone, A. Scilimati, L. Simone, P. Vitale, Curr. Med. Chem. 2010, 17, 3769. https://doi.org/10.2174/092986710793205408

C. C. Chang, W. S. Lee, H. G. Hsieh, C. L. Chuang, H. C. Huang, F. Y. Lee, S. D. Lee, PLoS One 2017, 12, e0179809. https://doi.org/10.1371/journal.pone.0179809

E. W. Griffin, D. T. Skelly, C. L. Murray, C. Cunningham, J. Neurosci. 2013, 33, 15248. https://doi.org/10.1523/JNEUROSCI.6361-11.2013

M. Toriyabe, K. Omote, T. Kawamata, A. Namiki, Anesthesiology 2004, 101, 983. https://doi.org/10.1097/00000542-200410000-00025

R. Calvello, D. D. Lofrumento, M. G. Perrone, A. Cianciulli, R. Salvatore, P. Vitale, F. De Nuccio, L. Giannotti, G. Nicolardi, M. A. Panaro, A. Scilimati, Front. Neurol. 2017, 8, 251. https://doi.org/10.3389/fneur.2017.00251

G. A. FitzGerald, C. Patrono, N. Engl. J. Med. 2001, 345, 433. https://doi.org/10.1056/NEJM200108093450607

A. Pannunzio, M. Coluccia, Pharmaceuticals 2018, 11, 101. https://doi.org/10.3390/ph11040101

M. Dvorakova, L. Langhansova, V. Temml, A. Pavicic, T. Vanek, P. Landa, ACS Med. Chem. Lett. 2021, 12, 610. https://doi.org/10.1021/acsmedchemlett.1c00004

M. G. Perrone, M. Miciaccia, P. Vitale, S. Ferorelli, C. C. B. Araújo, G. S. de Almeida, T. F. Souza Domingos, L. C. R. P. da Silva, M. de Pádula, L. M. Cabral, P. C. Sathler, C. Bonaccorso, C. G. Fortuna, A. Scilimati, Eur. J. Med. Chem. 2021, 209, 112919. https://doi.org/10.1016/j.ejmech.2020.112919

S. H. Yoon, D. Y. Cho, S. Choi, J. Lee, D. K. Choi, E. Kim, J. Y. Park, Biol. Pharm. Bull. 2021, 44, 1230. https://doi.org/10.1248/bpb.b20-00991

M. L. Pati, P. Vitale, S. Ferorelli, M. Iaselli, M. Miciaccia, A. Boccarelli, G. D. Di Mauro, C. G. Fortuna, T. F. Souza Domingos, L. C. Rodrigues Pereira da Silva, M. de Pádula, L. M. Cabral, P. C. Sathler, A. Vacca, A. Scilimati, M. G. Perrone, Eur. J. Med. Chem. 2019, 164, 59. https://doi.org/10.1016/j.ejmech.2018.12.029

A. H. Abdelazeem, M. T. El-Saadi, A. G. Safi El-Din, H. A. Omar, S. M. El-Moghazy, Bioorg. Med. Chem. 2017, 25, 665. https://doi.org/10.1016/j.bmc.2016.11.037

P. Vitale, M. G. Perrone, P. Malerba, A. Lavecchia, A. Scilimati, Eur. J. Med. Chem. 2014, 74, 606. https://doi.org/10.1016/j.ejmech.2013.12.023

P. Vitale, S. Tacconelli, M. G. Perrone, P. Malerba, L. Simone, A. Scilimati, A. Lavecchia, M. Dovizio, E. Marcantoni, A. Bruno, P. Patrignani, J. Med. Chem. 2013, 56, 4277. https://doi.org/10.1021/jm301905a

L. Wu, Y. Chen, M. Tang, X. Song, G. Chen, X. Song, Q. Lin, Synlett 2012, 23, 1529. https://doi.org/10.1055/s-0031-12911042

N. T. Pokhodylo, V. S. Matiychuk, M. D. Obushak, Chem. Heterocycl. Compds. 2009, 45, 1469. https://doi.org/10.1007/s10593-010-0452-y

R. Joncour, N. Susperregui, N. Pinaud, K. Miqueu, E. Fouquet, J. M. Sotiropoulos, F. X. Felpin, Chem. Eur. J. 2013, 19, 9291. https://doi.org/10.1002/chem.201300858

N. Chandrasekharan, D. L. Simmons, Genome Biol. 2004, 5, 241. https://doi.org/10.1186/gb-2004-5-9-241

X. W. Teng, A. K. Abu-Mellal, N. M. Davies, J. Pharm. Pharm. Sci. 2003, 6, 205.

L. Pelligand, N. Suemanotham, J. N. King, W. Seewald, H. Syme, K. Smith, P. Lees, J. Elliott, BMC Vet. Res. 2015, 11, 296. https://doi.org/10.1186/s12917-015-0598-z

V. D'Agati, Am. J. Kidney Dis. 1996, 28, S24. https://doi.org/10.1016/s0272-6386(96)90565-x

L. Applova, E. Veljovic, S. Muratovic, J. Karlickova, K. Macakova, D. Zavrsnik, L. Saso, K. Duric, P. Mladenka, Med. Chem. 2018, 14, 200. https://doi.org/10.2174/1573406413666171010102535

L. Applová, J. Karlíčková, P. Warncke, K. Macáková, M. Hrubša, M. Macháček, V. Tvrdý, D. Fischer, P. Mladěnka, Mol. Nutr. Food Res. 2019, 63, 1900261. https://doi.org/10.1002/mnfr.201900261

L. Friedrich, G. Cingolani, Y.-H. Ko, M. Iaselli, M. Miciaccia, M. G. Perrone, K. Neukirch, V. Bobinger, D. Merk, R. K. Hofstetter, O. Werz, A. Koeberle, A. Scilimati, G. Schneider, Adv. Sci. 2021, 8, 2100832. https://doi.org/10.1002/advs.202100832