Indole-like Trk receptor antagonists

Abstract

The virtual screening for new scaffolds for TrkA receptor antagonists resulted in potential low molecular weight drug candidates for the treatment of neuropathic pain and cancer. In particular, the compound (Z)-3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxindole and its derivatives were assessed for their inhibitory activity against Trk receptors. The IC50 values were computationally predicted in combination of molecular and fragment-based QSAR. Thereafter, based on the structure-activity relationships (SAR), a series of new compounds were designed and synthesized. Among the final selection of 13 compounds, (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-N-methyl-2-oxindole-5-sulfonamide showed the best TrkA inhibitory activity using both biochemical and cellular assays and (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-2-oxindole-5-sulfonamide was the most potent inhibitor of TrkB and TrkC.

Identification of Natural Compounds against Neurodegenerative Diseases Using In Silico Techniques

“…The two-dimensional molecular structures of the compounds obtained in Section 3.1 were converted into three-dimensional structures using Open Babel [ 40 ]. Conformational search was carried out by the CMol3D program of FQSARModel [ 41 , 42 ] for the dataset structures, where random conformations were constructed by means of the stochastic proximity embedding algorithm [ 43 ], followed by optimization based on MMFF94s force field [ 44 ] to improve their quality. Thereafter, all geometries were optimized as random vacuum conformer with the minimum potential energy using MOPAC 6.0 [ 45 ].…”

Design, synthesis and biological evaluation of 3-substituted-2-oxindole hybrid derivatives as novel anticancer agents

“…The 2-oxindole nucleus is a promising pharmacophore present in a wide series of compounds endowed of interesting biological properties as anticancer agents [1][2][3][4][5][6][7]. The fascinating properties of molecules bearing the 3-substituted-2-oxindole scaffold has attracted the attention of numerous researchers and 2-oxindole conjugates with heterocycles such as pyrrole and thiophene have been recognized as antineoplastic agents with a broad spectrum of activity against many cancer cell lines [8][9][10]. A wide number of 3-[(substituted-1H-pyrrol-2yl)methylidenyl]-2-oxindole derivatives, such as SU 5402 (1a), SU 5416 or Semaxinib (1b), SU 6668 (1c) and Sunitinib (1d) [11], have demonstrated promising antitumor activity and identified as receptor tyrosine kinase (RTK) inhibitors (Chart 1) [12].…”