ABSTRACT
A series of isoindoline derivatives were designed, synthesized, and evaluated for their double inhibitory activities. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Preliminary in vitro pharmacological tests showed that all compounds exhibited 5-HT or NE reuptake inhibition activity. Among the tested compounds, compound I-3 exhibited potent inhibitory activity against 5-HT and NE reuptake in vitro, and exhibited potent antidepressant activity in vivo. These compounds designed can be further optimized for finding more potent 5-HT/NE dual reuptake inhibitors and antidepressant candidates as well.
Subject(s)
Antidepressive Agents , Chemistry , Biological Transport , Drug Design , Isoindoles , Chemistry , Selective Serotonin Reuptake Inhibitors , Chemistry , Structure-Activity RelationshipABSTRACT
To explore novel histone deacetylase (HDAC) inhibitors with anti-tumor activity, twelve target compounds were synthesized, and their structures were confirmed by 1H NMR, MS and elemental analyses. Evaluation results in vitro showed that compound Ia exhibited potent inhibition against HDAC and is worth for further investigation. And compounds IIa, IIb, IIIa-IIIi possessed moderate HDAC inhibitory activity.
Subject(s)
Animals , Mice , Antineoplastic Agents , Chemistry , Pharmacology , Biphenyl Compounds , Chemistry , Pharmacology , Histone Deacetylase Inhibitors , Chemistry , Pharmacology , Histone Deacetylases , Metabolism , Molecular Structure , Phenylpropionates , Chemistry , PharmacologyABSTRACT
Drugs designed to act on individual molecular targets usually can not combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes. Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand. The multi-target drugs which impact multiple targets simultaneously are better at controlling complex disease systems and are less prone to drug resistance. Here, we compare the disadvantage of the selective ligands and the predominance of multi-targets drugs in detail and introduce the approaches of designing multiple ligands and the procedure of optimization particularly. A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. On this point, the multi-target approach represents a new challenge for medicinal chemists, pharmacologists, toxicologists, and biochemists.
Subject(s)
Humans , Chemistry, Pharmaceutical , Methods , Drug Combinations , Drug Delivery Systems , Methods , Drug Design , Ligands , PharmacokineticsABSTRACT
Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.
Subject(s)
Adrenergic alpha-1 Receptor Antagonists , Dopamine D2 Receptor Antagonists , Drug Delivery Systems , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels , Chemistry , Molecular Conformation , Molecular Structure , Receptor, Serotonin, 5-HT2A , Chemistry , Receptors, Adrenergic, alpha-1 , Chemistry , Receptors, Dopamine D2 , Chemistry , Serotonin 5-HT2 Receptor Antagonists , Structure-Activity RelationshipABSTRACT
A novel inhibitor series for matrix metalloproteinases (MMPs) were designed and synthesized. Using succinate and malonate as zinc binding groups and long hydrophobic substituents to bind with S1' pockets, the compounds showed micromolar inhibition and selectivity for MMP-2 over others. And we found a better activity compound. It is a chance to find a better precursor of MMP-2 inhibitors with activity and bioavailability by further optimization of compounds.
Subject(s)
Drug Design , Enzyme Inhibitors , Chemistry , Matrix Metalloproteinase Inhibitors , Matrix Metalloproteinases , Chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
<p><b>OBJECTIVE</b>To build 3D-pharmacophore model of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors using distance comparisons method and design novel EGFR inhibitors.</p><p><b>METHODS</b>Thirteen typical EGFR inhibitors were selected, and their biologically active conformations were obtained by using DOCK5.0 program, then 3D-pharmacophore model of EGFR inhibitors was built using distance comparisons method.</p><p><b>RESULTS</b>Validation of the 3D-pharmacophore model was carried out and novel structures with potential inhibitory activity were selected by means of 3D-searching and docking method.</p><p><b>CONCLUSION</b>This method can improve hit rate of lead compounds discovery and can be used to design novel EGFR inhibitors.</p>