Fig 1.
The structures of representative HDAC inhibitors.
Fig 2.
The design strategy of new 3-phenylisoxazole HDAC1 inhibitors.
(A-B) The predicted binding modes of hit 7 (white) with HDAC1 (PDB: 5ICN). (C) The design scheme of new 3-phenylisoxazole HDAC1 inhibitors.
Fig 3.
The Synthetic route of 3-phenylisoxazole derivatives.
Reagents and conditions: (a) Hydroxylamine, EtOH, 60°C, 2 h; (b) N-Chlorosuccinimide, DMF, 40°C, 2 h; (c) Methyl 3-cyclopropyl-3-oxopropionate, triethylamine, EtOH, 0°C-re, 5-6 h; (d) NaOH, H2O, 80°C, re, 1 h; (e) Suitable amine compounds, DIPEA, EDCI, rt, 2 h; (f) Hydroxylamine, NaOH, H2O, rt, 1 h.
Table 1.
The HDAC1 inhibitory activity of 3-phenylisoxazole derivatives 6-20.
Fig 4.
The summary for SAR studies of 3-phenylisoxazole derivatives.
Table 2.
The predicted drug-like parameters of representative compounds.
Fig 5.
The drug-like analysis diagrams of the compounds 10, 17 and 22.
Table 3.
The anti-proliferative activity of representative 3-phenylisoxazole derivatives.
Fig 6.
The binding modes of compound 17 with HDAC1.
(A) Interactions between 17 (pink) and residues of HDAC1. (B) The binding pocket surface of HDAC1 and 17 (PDB: 5ICN).