Selective cyclooxygenase-1 (COX-1) inhibition has got into the spotlight with the discovery of COX-1 upregulation in various cancers and the cardioprotective role of COX-1 in control of thrombocyte aggregation. Yet, COX-1-selective inhibitors are poorly explored. Thus, three series of quinazoline derivatives were prepared and tested for their potential inhibitory activity toward COX-1 and COX-2. Of the prepared compounds, 11 exhibited interesting COX-1 selectivity, with 8 compounds being totally COX-1-selective. The IC50 value of the best quinazoline inhibitor was 64 nM. The structural features ensuring COX-1 selectivity were elucidated using in silico modeling.

Department of Pharmaceutical and Medicinal Chemistry Paracelsus Medical University of Salzburg Strubergasse 21 5020 Salzburg Austria

Laboratory of Plant Biotechnologies Czech Academy of Sciences Institute of Experimental Botany Rozvojova 263 165 02 Prague 6 Lysolaje Czech Republic

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Lu G.; Tsai A. L.; Van Wart H. E.; Kulmacz R. J. Comparison of the Peroxidase Reaction Kinetics of Prostaglandin H Synthase-1 and −2. J. Biol. Chem. 1999, 274, 16162–16167. 10.1074/jbc.274.23.16162. PubMed DOI

Cingolani G.; Panella A.; Perrone M. G.; Vitale P.; Di Mauro G.; Fortuna C. G.; Armen R. S.; Ferorelli S.; Smith W. L.; Scilimati A. Structural Basis for Selective Inhibition of Cyclooxygenase-1 (COX-1) by Diarylisoxazoles Mofezolac and 3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6). Eur. J. Med. Chem. 2017, 138, 661–668. 10.1016/j.ejmech.2017.06.045. PubMed DOI PMC

Desai S. J.; Prickril B.; Rasooly A. Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer. Nutr. Cancer 2018, 70 (3), 350–375. 10.1080/01635581.2018.1446091. PubMed DOI PMC

Perrone M. G.; Scilimati A.; Simone L.; Vitale P. Selective COX-1 inhibition: A Therapeutic Target to Be Reconsidered. Curr. Med. Chem. 2010, 17, 3769–3805. 10.2174/092986710793205408. PubMed DOI

Perrone M. G.; Lofrumento D. D.; Vitale P.; De Nuccio F.; La Pesa V.; Panella A.; Calvello R.; Cianciulli A.; Panaro M. A.; Scilimati A. Selective Cyclooxygenase-1 Inhibition by P6 and Gastrotoxicity: Preliminary Investigation. Pharmacology 2015, 95, 22–28. 10.1159/000369826. PubMed DOI

Ornelas A.; Zacharias-Millward N.; Menter D. G.; Davis J. S.; Lichtenberger L.; Hawke D.; Hawk E.; Vilar E.; Bhattacharya P.; Millward S. Beyond COX-1: The Effects of Aspirin on Platelet Biology and Potential Mechanisms of Chemoprevention. Cancer Metastasis Rev. 2017, 36, 289–303. 10.1007/s10555-017-9675-z. PubMed DOI PMC

Choi S. H.; Aid S.; Choi U.; Bosetti F. Cyclooxygenases-1 and −2 Differentially Modulate Leukocyte Recruitment into the Inflamed Brain. Pharmacogenomics J. 2010, 10, 448–457. 10.1038/tpj.2009.68. PubMed DOI PMC

Khan A. A.; Iadarola M.; Yang H. Y.; Dionne R. A. Expression of COX-1 and COX-2 in a Clinical Model of Acute Inflammation. J. Pain 2007, 8, 349–354. 10.1016/j.jpain.2006.10.004. PubMed DOI PMC

Li X.; Mazaleuskaya L. L.; Ballantyne L. L.; Meng H.; FitzGerald G. A.; Funk C. D. Genomic and Lipidomic Analyses Differentiate the Compensatory Roles of Two COX Isoforms During Systemic Inflammation in Mice. J. Lipid Res. 2018, 59, 102–112. 10.1194/jlr.M080028. PubMed DOI PMC

Pannunzio A.; Coluccia M. Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature. Pharmaceuticals 2018, 11, 101.10.3390/ph11040101. PubMed DOI PMC

Perrone M. G.; Luisi O.; De Grassi A.; Ferorelli S.; Cormio G.; Scilimati A. Translational Theragnosis of Ovarian Cancer: Where Do We Stand?. Curr. Med. Chem. 2020, 27, 5675–5715. 10.2174/0929867326666190816232330. PubMed DOI

Vitale P.; Panella A.; Scilimati A.; Perrone M. G. COX-1 Inhibitors: Beyond Structure Toward Therapy. Med. Res. Rev. 2016, 36, 641–671. 10.1002/med.21389. PubMed DOI

Belton O.; Fitzgerald D. J. Cyclooxygenase Isoforms and Atherosclerosis. Expert. Rev. Mol. Med. 2003, 5, 1–18. PubMed

Loftin C. D.; Trivedi D. B.; Langenbach R. Cyclooxygenase-1-selective Inhibition Prolongs Gestation in Mice without Adverse Effects on the Ductus Arteriosus. J. Clin. Invest. 2002, 110, 549–557. 10.1172/JCI0214924. PubMed DOI PMC

Calvello R.; Lofrumento D. D.; Perrone M. G.; Cianciulli A.; Salvatore R.; Vitale P.; De Nuccio F.; Giannotti L.; Nicolardi G.; Panaro M. A.; Scilimati A. Highly Selective Cyclooxygenase-1 Inhibitors P6 and Mofezolac Counteract Inflammatory State both in vitro and in vivo Models of Neuroinflammation. Front. Neurol. 2017, 8, 00251.10.3389/fneur.2017.00251. PubMed DOI PMC

Calvello R.; Panaro M. A.; Carbone M. L.; Cianciulli A.; Perrone M. G.; Vitale P.; Malerba P.; Scilimati A. Novel Selective COX-1 Inhibitors Suppress Neuroinflammatory Mediators in LPS-stimulated N13 Microglial Cells. Pharmacol. Res. 2012, 65, 137–148. 10.1016/j.phrs.2011.09.009. PubMed DOI

Meek I. L.; Vonkeman H. E.; Kasemier J.; Movig K. L.; van de Laar M. A. Interference of NSAIDs with the Thrombocyte Inhibitory Effect of Aspirin: A Placebo-Controlled, ex vivo, Serial Placebo-Controlled Serial Crossover Study. Eur. J. Clin. Pharmacol. 2013, 69, 365–371. 10.1007/s00228-012-1370-y. PubMed DOI

Mitchell J. A.; Shala F.; Elghazouli Y.; Warner T. D.; Gaston-Massuet C.; Crescente M.; Armstrong P. C.; Herschman H. R.; Kirkby N. S. Cell-Specific Gene Deletion Reveals the Antithrombotic Function of COX1 and Explains the Vascular COX1/Prostacyclin Paradox. Circ. Res. 2019, 125, 847–854. 10.1161/CIRCRESAHA.119.314927. PubMed DOI PMC

Roodhart J. M.; Daenen L. G.; Stigter E. C.; Prins H. J.; Gerrits J.; Houthuijzen J. M.; Gerritsen M. G.; Schipper H. S.; Backer M. J.; van Amersfoeort M.; Vermaat J. S. P.; Moerer P.; Ishihara K.; Kalkhoven E.; Beijnen J. H.; Derksen P. W. B.; Medema R. H.; Martens A. C.; Brenkman A. B.; Voest E. E. Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids. Cancer Cell 2011, 20, 370–383. 10.1016/j.ccr.2011.08.010. PubMed DOI

Chandrika P. M.; Yakaiah T.; Rao A. R.; Narsaiah B.; Reddy N. C.; Sridhar V.; Rao J. V. Synthesis of Novel 4,6-Disubstituted Quinazoline Derivatives, Their Anti-Inflammatory and Anti-Cancer Activity (Cytotoxic) Against U937 Leukemia Cell Lines. Eur. J. Med. Chem. 2008, 43, 846–852. 10.1016/j.ejmech.2007.06.010. PubMed DOI

Abdel-Aziz A. A.; Abou-Zeid L. A.; ElTahir K. E. H.; Ayyad R. R.; El-Sayed M. A.; El-Azab A. S. Synthesis, Anti-Inflammatory, Analgesic, COX-1/2 Inhibitory Activities and Molecular Docking Studies of Substituted 2-Mercapto-4(3H)-Quinazolinones. Eur. J. Med. Chem. 2016, 121, 410–421. 10.1016/j.ejmech.2016.05.066. PubMed DOI

El-Feky S. A.; Imran M.; Nayeem N. Design, Synthesis, and Anti-Inflammatory Activity of Novel Quinazolines. Orient. J. Chem. 2017, 33, 707–716. 10.13005/ojc/330217. DOI

Aboraia A. S.; Hara M. A.; Abdelrahman M. H.; Amin M. M.; El-Sabbaghab O. I. Design, Synthesis and COX1/2 Inhibitory Activity of New Quinazoline-5-one Derivatives. J. Adv. Chem. 2017, 13, 5923–5931. 10.24297/jac.v13i12.6019. DOI

Kavitha K.; Srinivasan N.; Hari Babu Y.; Suresh R. Synthesis and Molecular Docking Study of Novel 2-Phenyl Quinazoline-4-(3H)-one Derivative as COX-2 Inhibitor. Indo Am. J. Pharm. Sci. 2019, 06, 4032–4037. 10.5281/zenodo.2566370. DOI

Kumar A.; Sharma S.; Archana; Bajaj K.; Sharma S.; Panwar H.; Singh T.; Srivastava V. K. Some New 2,3,6-Trisubstituted Quinazolinones as Potent Anti-Inflammatory, Analgesic and COX-II Inhibitors. Bioorg. Med. Chem. 2003, 11, 5293–5299. 10.1016/S0968-0896(03)00501-7. PubMed DOI

Sakr A.; Kothayer H.; Ibrahim S. M.; Baraka M. M.; Rezq S. 1,4-Dihydroquinazolin-3(2H)-yl Benzamide Derivatives as Anti-Inflammatory and Analgesic Agents with an Improved Gastric Profile: Design, Synthesis, COX-1/2 Inhibitory Activity and Molecular Docking Study. Bioorg. Chem. 2019, 84, 76–86. 10.1016/j.bioorg.2018.11.030. PubMed DOI

Dvorakova M.; Landa P. Anti-Inflammatory Activity of Natural Stilbenoids: A Review. Pharmacol. Res. 2017, 124, 126–145. 10.1016/j.phrs.2017.08.002. PubMed DOI

Okano M.; Mito J.; Maruyama Y.; Masuda H.; Niwa T.; Nakagawa S.; Nakamura Y.; Matsuura A. Discovery and Structure-Activity Relationships of 4-Aminoquinazoline Derivatives, A Novel Class of Opioid Receptor Like-1 (ORL1) Antagonists. Bioorg. Med. Chem. 2009, 17, 119–132. 10.1016/j.bmc.2008.11.012. PubMed DOI

Jiang Y.; Chen A. C.; Kuang G. T.; Wang S. K.; Ou T. M.; Tan J. H.; Li D.; Huang Z. S. Design, Synthesis and Biological Evaluation of 4-Anilinoquinazoline Derivatives as New c-Myc G-Quadruplex Ligands. Eur. J. Med. Chem. 2016, 122, 264–279. 10.1016/j.ejmech.2016.06.040. PubMed DOI

Miyaura N.; Suzuki A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. 10.1021/cr00039a007. DOI

Knights K. M.; Mangoni A. A.; Miners J. O. Defining the COX Inhibitor Selectivity of NSAIDs: Implications for Understanding Toxicity. Expert Rev. Clin. Pharmacol. 2010, 3, 769–776. 10.1586/ecp.10.120. PubMed DOI

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. 10.1021/bi1003298. PubMed DOI PMC

Kurumbail R. G.; Stevens A. M.; Gierse J. K.; McDonald J. J.; Stegeman R. A.; Pak J. Y.; Gildehaus D.; iyashiro 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, 644–648. 10.1038/384644a0. PubMed DOI

Unveiling the role of Ndrg1 gene on the oxidative stress induction behind the anticancer potential of styrylquinazoline derivatives