RESUMO
Alzheimer's disease is a widespread type of neurodegenerative dementia that mainly affects the elderly. Currently, this disease can only be treated palliatively. Existing drugs can only improve patients' symptoms. The search for new drugs that can effectively treat this disease is an important field of research in medicinal chemistry. Here we report a structure-activity relationship study of tacrine and some of its analogues in relation to their inhibitory activities against Alzheimer's disease. All of the molecular descriptors were calculated at the M062X/6-311++G(d,p) level of theory. Principal component analysis of the molecular descriptors showed that the compounds could be categorized into active and inactive compounds using just two descriptors: the HOMO and LUMO energies. These results should help us to explain the activities of tacrine derivatives and to model new tacrine analogues that are active against Alzheimer's disease. Graphical abstract PCA score plot for tacrine and its analogues.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Relação Estrutura-Atividade , Tacrina/química , Doença de Alzheimer/patologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Modelos Moleculares , Análise de Componente Principal , Tacrina/análogos & derivados , Tacrina/uso terapêuticoRESUMO
Tacrine was the first drug approved by FDA for the treatment of Alzheimer's disease. However, its use was restricted in function of side effects observed in some patients. Investigations on the structural basis by which tacrine inhibits cholinesterases activity brought new perspectives for the design of more potent analogs with fewer side effects. This review discusses the recent advances on the development of tacrine-structure-based compounds capable to target multiple molecules involved in Alzheimer's disease. Detailed information on strategies of molecular modifications commonly used in medicinal chemistry, such as bioisosterism, hybridization, dimerization and simplification is presented as well.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Tacrina/uso terapêutico , Dimerização , Humanos , Tacrina/químicaRESUMO
Alzheimer's disease (AD) is the most common form of dementia in adults, which is characterized by senile plaquets and cholinergic deficit as the disease progresses. Improvement of cholinergic neurotransmission is the basis of some drugs currently used in the treatment of AD. It is achieved by acetylcholinesterase (AChE) inhibition, the enzyme responsible for acetylcholine hydrolysis. Molecular modeling techniques were of utmost importance to design a new pharmaceutical against Alzheimer's disease, with potential inhibitory activity over AChE, since the inhibition of human plasma butyrylcholinesterase (BChE) may cause side effects. Some of the drugs currently used in the treatment of AD are capable of increasing the cholinergic transmission through the AChE inhibition. In this work we proposed molecular hybrids of tacrine with donepezil (fusion of these structures), in order to suggest new proposals of AChE inhibitors for future treatment of AD. We have analyzed all the structures by docking, density functional studies and drug like properties.