ABSTRACT
A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed.
Subject(s)
Antineoplastic Agents/pharmacology , Aurora Kinase B/antagonists & inhibitors , Drug Discovery , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Urea/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aurora Kinase B/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
A series of 19 huprines has been evaluated for their activity against cultured bloodstream forms of Trypanosoma brucei and Plasmodium falciparum. Moreover, cytotoxicity against rat myoblast L6 cells was assessed for selected huprines. All the tested huprines are moderately potent and selective trypanocidal agents, exhibiting IC(50) values against T. brucei in the submicromolar to low micromolar range and selectivity indices for T. brucei over L6 cells of approximately 15, thus constituting interesting trypanocidal lead compounds. Two of these huprines were also found to be active against a chloroquine-resistant strain of P. falciparum, thus emerging as interesting trypanocidal-antiplasmodial dual acting compounds, but they exhibited little selectivity for P. falciparum over L6 cells.
Subject(s)
Aminoquinolines/chemical synthesis , Antimalarials/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Plasmodium falciparum/drug effects , Trypanocidal Agents/chemical synthesis , Trypanosoma brucei brucei/drug effects , Aminoquinolines/chemistry , Aminoquinolines/classification , Aminoquinolines/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Cells, Cultured , Heterocyclic Compounds, 4 or More Rings/classification , Heterocyclic Compounds, 4 or More Rings/pharmacology , Molecular Structure , Rats , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacologyABSTRACT
As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC50 values of 13 and 107â nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.