| dc.description.abstract | Alzheimer's disease (AD) is a neurodegenerative pathogenesischaracterized by cognitive impairment in patients, such as short-term memory impairment, speech and language loss, impaired motor coordination, and patient learning ability. Galanthamine and donepezil are two important drugs used to treat AD. Its mechanism of action is involved with an inhibition of cholinesterase enzymes which increase in the level of acetylcholine in the synaptic cleft. These drugs are palliative, that is, they reduce the symptoms of the disease, without interfering in its progress. Galanthamine is the only one drug derived from natural sources, being extracted from the bulb of different species of the family Amaryllidaceae with a maximum efficiency of 0.5% (dry extract). There are several synthetic routes described for galanthamine, usually based on phenolic oxidative coupling reactions or the Heck reaction as a key step. However, even with the various routes of synthesis described, until now galanthamine is still obtained from natural sources. This work describes a synthetic route to obtain galanthamine, using the reaction of Friedel-Crafts as key step. In addition, since the drugs are palliative, having an effect in the early to moderate stages of the Alzheimer disease, the development of drugs that may slow the progress of AD is necessary. One strategy for the development of novel drugs for complex diseases such as AD is call multi-target direct ligands (MTDLs). This strategy is based on the hybridization of different pharmacophore groups of drugs that interact with differents targets of the disease. In this work,we synthesized two hybrids donepezil-lipoic acid, with ability to interact with cholinesterase enzymes and with antioxidant activity. The hybrids differ by connection between the pharmacophoric units, with one are directly connected and the other has a linker between the pharmacophoric units. These were synthesized in four steps with 42% and in six steps with 19% overall yield, respectively. Hybrid with linker showed moderate activity in inhibiting ChE enzymes. This lower activity than donepezil (reference drug) can be attributed to non-observation of the interaction with the amino acid Trp86A in CAS of the AChE in the docking studies. In relation to antioxidant activity, all compoundswere shown to be active by the DPPH assay, since hybrid with linker showed a superior ability to sequester DPPH radicals than lipoic acid (reference drug) and the other hybrid. | |
