Discovery of novel pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione (PBD) derivatives as selective HDAC6 inhibitors for the efficient treatment of idiopathic pulmonary fibrosis (IPF) in vitro and in vivo.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive fibrotic phenotype. Immunohistochemical studies on HDAC6 overexpression in IPF lung tissues confirmed that IPF is associated with aberrant HDAC6 activity. We herein developed a series of novel HDAC6 inhibitors that can be used as potential pharmacological tools for IPF treatment.

Discovery of novel tryptamine derivatives as GluN2B subunit-containing NMDA receptor antagonists via pharmacophore-merging strategy with orally available therapeutic effect of cerebral ischemia.

A series of tryptamine derivatives has been designed and synthesized as novel GluN2B subunit-containing NMDA receptor (GluN2B-NMDAR) antagonists, which could simultaneously manifest the receptor-ligand interactions of representative GluN2B-NMDAR antagonists ifenprodil (1) and EVT-101 (3). In the present study, the neuroprotective potential of these compounds was explored through chemical synthesis and pharmacological characterization. Compound Z25 with significantly better neuroprotective activity than the positive control drug (percentage of protection: 55.

Novel pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione (PBD) derivatives as selective HDAC6 inhibitors to suppress tumor metastasis and invasion in vitro and in vivo.

Selective inhibition of histone deacetylase 6 (HDAC6) has been emerged as a promising approach to cancer treatment. As a pivotal strategy for drug discovery,molecular hybridization was introduced in this study and a series of pyrrolo[2,1-c][1,4] benzodiazepine-3,11-diones (PBDs) based hydroxamic acids was rationally designed and synthesizedas novel selective HDAC6 inhibitors. Preliminary in vitro enzyme inhibition assay and structure-activity relationship (SAR) discussion confirmed our design strategy and met the expectation.

Repurposing of cefpodoxime proxetil as potent neuroprotective agent through computational prediction and in vitro validation.

In recent reports, NR2B-NMDA receptor antagonists showed more research value because of its strong targeting ability and less side effects potential. In 2016, EVT-101 was reported to bind in an almost entirely new binding region of this target. Whether strikingly different binding modes can improve targeting and reduce side effects is worth studying.

Discovery of specific HDAC6 inhibitor with anti-metastatic effects in pancreatic cancer cells through virtual screening and biological evaluation.

Histone deacetylase 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, and HDAC6 inhibition is therefore considered as a promising epigenetic strategy for cancer treatment. At present, only a minority of compounds have been reported as HDAC6 inhibitors, so specific HDAC6 inhibitors with safety profile need to be discovered urgently. In this paper, HDAC6 inhibitors with diverse structures were used to generate the pharmacophore model by ligand-based method, which contained two hydrogen bond acceptors and two hydrophobic groups.

Design, synthesis and biological evaluation of 1-benzyl-5-oxopyrrolidine-2-carboximidamide derivatives as novel neuroprotective agents.

A series of 1-benzyl-5-oxopyrrolidine-2-carboximidamide derivatives were designed and synthesized. Their protective activities against N-methyl-d-aspartic acid (NMDA)-induced cytotoxicity were investigated in vitro. All of the compounds exhibited neuroprotective activities, especially 12k, which showed higher potency than reference compound 1 (ifenprodil).