ABSTRACT
Novel azole compounds were prepared which demonstrated potent hCB2 binding activities with antioxidant activity for a selected compound. These compounds show good selectivity over the hCB1 receptor and are full agonists at the hCB2 receptor.
Subject(s)
Azoles/chemistry , Azoles/metabolism , Cannabinoid Receptor Agonists/chemistry , Cannabinoid Receptor Agonists/metabolism , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/metabolism , Animals , CHO Cells , Cannabinoids/chemistry , Cannabinoids/metabolism , Cricetinae , Cricetulus , HumansABSTRACT
A series of dipeptides with dual inhibitory activities on calpain and lipid peroxidation were prepared to target the intracellular calpain. This optimization program focused on the variations of the linker and the N-terminal amino acid of the peptidic core. Two compounds 6d-05 and 6d-08 exhibited potent intracellular calpain inhibition. The polar surface area and the number of rotors appeared to be critical descriptors to account for the behavior of these hybrid molecules in the cellular calpain assay.
Subject(s)
Antioxidants/pharmacology , Calpain/antagonists & inhibitors , Cell Death/drug effects , Dipeptides/pharmacology , Lipid Peroxidation/drug effects , Animals , Antioxidants/chemical synthesis , Brain/drug effects , Calpain/metabolism , Dipeptides/chemical synthesis , Glioma/drug therapy , Humans , Inhibitory Concentration 50 , Microsomes/drug effects , Rats , Structure-Activity RelationshipABSTRACT
A series of molecules with dual inhibitory activities on calpain and lipid peroxidation were synthesized. These hybrid compounds were built on the calpain pharmacophore 2-hydroxytetrahydrofuran linked to a set of antioxidants via a l-leucine linker. Compound 7, the most potent in cellular calpain and lipid peroxidation inhibitions, provided effective protection against glial cell death induced by maitotoxin.
Subject(s)
Antioxidants/chemical synthesis , Calpain/antagonists & inhibitors , Cell Death/drug effects , Lipid Peroxidation/drug effects , Lipoxygenase Inhibitors/chemical synthesis , Antioxidants/pharmacology , Calpain/metabolism , Furans/chemistry , Humans , Inhibitory Concentration 50 , Leucine/chemistry , Lipoxygenase Inhibitors/pharmacology , Neuroglia , Structure-Activity RelationshipABSTRACT
Novel phenolic thiazoles compounds were prepared which demonstrated potent antioxidant activity and potent in vivo neuroprotection in mitochondrial toxin models and also possess good oral bioavailability.
Subject(s)
Antioxidants/administration & dosage , Neuroprotective Agents/administration & dosage , Phenols/administration & dosage , Thiazoles/administration & dosage , Administration, Oral , Animals , Antioxidants/chemistry , Dose-Response Relationship, Drug , MPTP Poisoning/metabolism , MPTP Poisoning/prevention & control , Mice , Neuroprotective Agents/chemistry , Phenols/chemistry , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Thiazoles/chemistryABSTRACT
A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS selectivity (67.5). This shows that nNOS was able to accommodate very bulky groups such as di-tert-butyl or di-iso-propyl phenol in its active site.
Subject(s)
Antioxidants/chemical synthesis , Antioxidants/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Lipid Peroxidation/drug effects , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/pharmacology , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type III , Propofol/analogs & derivatives , Propofol/chemical synthesis , Propofol/pharmacology , Substrate SpecificityABSTRACT
The synthesis and biological activity of novel lipoic acid analogues are reported. Lipoic acid and structural homologues coupled to arylthiophene amidine via carboxamide linkers are metabolic antioxidants capable of protecting neuronal cells against glutamate cytotoxicity, preventing loss of intracellular glutathione, and inhibit nitric oxide synthase.
