ABSTRACT
A series of new ureidoindolin-2-one derivatives were synthesized and evaluated as inhibitors of receptor tyrosine kinases. Investigation of structure-activity relationships at positions 5, 6, and 7 of the oxindole skeleton led to the identification of 6-ureido-substituted 3-pyrrolemethylidene-2-oxindole derivatives that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) families of receptor tyrosine kinases. Several derivatives showed potency against the PDGFR inhibiting both its enzymatic and cellular functions in the single-digit nanomolar range. Among them, compound 35 was a potent inhibitor against tyrosine kinases, including VEGFR and PDGFR families, as well as Aurora kinases. Inhibitor 36 (non-substituted on the pyrrole or phenyl ring) had a moderate pharmacokinetic profile and completely inhibited tumor growth initiated with the myeloid leukemia cell line, MV4-11, in a subcutaneous xenograft model in BALB/c nude mice.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Indoles/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrroles/chemistry , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Urea/analogs & derivatives , Animals , Aurora Kinases , Binding Sites , Cell Line, Tumor , Computer Simulation , Drug Screening Assays, Antitumor , ErbB Receptors/metabolism , Humans , Indoles/therapeutic use , Indoles/toxicity , Leukemia, Myeloid/drug therapy , Mice , Oxindoles , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/toxicity , Protein Serine-Threonine Kinases/metabolism , Pyrroles/therapeutic use , Pyrroles/toxicity , Receptors, Platelet-Derived Growth Factor/metabolism , Structure-Activity Relationship , Transplantation, Heterologous , Urea/chemistry , Urea/therapeutic use , Urea/toxicityABSTRACT
Spiro derivatives of oxindole and isoxazole-5-one were synthesized by using Michael addition reaction, highlighting the regioselective approach towards the synthesis of Michael diadduct followed by condensation of Michael diadduct. The spiro compound 4 showed antitubercular activity against Mycobacterium tuberculosis H37Rv whereas spiro compound 9 possesses pronounced anticancer and antibacterial profile.
