Design and synthesis of novel 3,4-disubstituted pyrazoles for nanomedicine applications against malignant gliomas

A series of novel 3,4-disubstituted pyrazoles were synthesized. The cytotoxicity against U87MG glioma cell line have been investigated in vitro and three of these compounds showed promising inhibitory activity on cell growth with an IC(50) lower than 90 mu M. AutoDock molecular docking into type I TGF-beta receptor (TGF-beta-RI; PDB: 1py5) has been done for lead optimization of the mentioned compounds as potential TGF-beta-RI1 inhibitors. In particular, 3-aryl-4-amido pyrazole containing long omega-amino-aliphatic chain emerged as a good candidate for further optimization. Entrapment into targetable PEG-based micelles improved growth inhibition IC(50) values up to 100 nM and this could lead to a novel drug delivery strategy for treating glioblastoma. (C) 2010 Elsevier Masson SAS. All rights reserved.