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Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer's Disease

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Autor(es):
Fernandes, Thais B. [1] ; Cunha, Micael R. [1] ; Sakata, Renata P. [2] ; Candido, Thalita M. [1] ; Baby, Andre R. [1] ; Tavares, Mauricio T. [1] ; Barbosa, Euzebio G. [3] ; Almeida, Wanda P. [2] ; Parise-Filho, Roberto [1]
Número total de Autores: 9
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Av Prof Lineu Prestes Ave 580, Cidade Univ, BR-05508000 Sao Paulo, SP - Brazil
[2] Univ Estadual Campinas, Dept Pharm, Fac Pharmaceut Sci, Campinas, SP - Brazil
[3] Univ Fed Rio Grande do Norte, Dept Pharm, Hlth Sci Ctr, Natal, RN - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: ARCHIV DER PHARMAZIE; v. 350, n. 11 NOV 2017.
Citações Web of Science: 4
Resumo

Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC50 values of 0.64-51.09M. The preliminary structure-activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC50 (0.64M). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD. (AU)

Processo FAPESP: 13/19311-6 - Planejamento, síntese e avaliação do potencial antitumoral de compostos arilsulfonil-hidrazônicos
Beneficiário:Thais Batista Fernandes
Modalidade de apoio: Bolsas no Brasil - Mestrado