ABSTRACT
2,3-Dihydroindoles are promising agents for the synthesis of new compounds with neuroprotective and antioxidant properties. Usually, these compounds are obtained by direct reduction of the corresponding indoles containing acceptor groups in the indole ring for its activation. In this work, we propose a synthetic strategy to obtain new 2,3-dihydroindole derivatives from the corresponding polyfunctional 2-oxindoles. Three methods were proposed for reduction of functional groups in the 2-oxindole and 2-chloroindole molecules using various boron hydrides. The possibility of chemoselective reduction of the nitrile group in the presence of an amide was shown. The proposed synthetic strategy can be used, for example, for the synthesis of new analogs of the endogenous hormone melatonin and other compounds with neuroprotective properties.
Subject(s)
Melatonin , Receptors, Melatonin , Structure-Activity Relationship , Melatonin/chemistry , Antioxidants/chemistry , Protein BindingABSTRACT
The study represents the new findings at the crossroads of chemistry and medicine, particularly between medicinal and organic chemistry and ophthalmology. In this work we describe how the chemical reactivity of indolinone scaffold may be used to create small molecule ligands with strong biological response comparable with and larger than that of endogenous hormone. The synthesis of oxindole-based melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) analogues was proposed and their ability to influence intraocular pressure (IOP) was studied in vivo. Time-dependent study revealed the prolonged effect (more than 6h) of the lead-compound. This effect in combination with high IOP reducing effect (41±6%) in low concentrations of the active compound (0.1wt%) and with high water solubility represents a great potential of low-cost oxindole derivatives as potent antiglaucoma agents.
Subject(s)
Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Intraocular Pressure/drug effects , Quinone Reductases/antagonists & inhibitors , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Ligands , Models, Molecular , Molecular Structure , Oxindoles , Quinone Reductases/metabolism , Structure-Activity Relationship , Time FactorsABSTRACT
New 5-acetamido-substituted melatonin derivatives were efficiently synthesized in excellent yields via Knoevenagel condensation. The relative binding affinity of new synthesized compounds to MT3 receptor was tested via enzymatic assays and the X-ray structures of the most potent compounds were determined in complex with MT3.
