Navegando por Palavras-chave "Synthesis Of Bioactive Compounds"

Agora exibindo 1 - 2 de 2
  • Imagem de Miniatura
    Item
    Acesso aberto (Open Access)
    Arilalquilpiperazinas como agentes multialvo moduladores de receptores histaminérgicos, dopaminérgicos e da acetilcolinesterase
    (Universidade Federal de São Paulo (UNIFESP), 2021) Aranha, Cecilia Maria Simoes De Queiroz [UNIFESP]; Fernandes, João Paulo dos Santos [UNIFESP]; Universidade Federal de São Paulo
    Several neurological disorders can be associated with cognitive decline, and the mechanisms responsible for controlling these disorders are complex and diverse. The role of cholinergic, histaminergic and dopaminergic neurotransmission has considerable relevance for the development of these difunctions, and the heterogeneous nature indicates that multi-target strategies, considering targets associated to these systems, may be more appropriate in the treatment of these disfunctions. In this scenario, this work presents a series of 24 arylalkylpiperazines, with different aromatic nuclei (naphthyl, benzofuranyl and quinolinyl), linkers (ethylene and propylene) and substituents in the piperazine terminal nitrogen (methyl, phenyl and pyridyl), synthesized from classic organic reactions, which led to yields varying from 21 to 97%. Out of these, 12 compounds were evaluated at histamine H3 (H3R) and H4 (H4R) and dopamine D2 (D2R) and D3 (D3R) receptors through binding assays, while 21 compounds were evaluated for acetylcholinesterase (AChE) inhibition using a modified Ellman’s method. Seven compounds showed good affinity for H3R, with compound LINS05014 showing the best affinity (1,1 µM), and most showed good selectivity over H4R. Four compounds showed good affinity for D3R, with compound LINS05006 showing the best affinity (0,7 µM), and also showed good selectivity over D2R. The compounds showed low affinity for AChE, with compound LINS05030 showing the best affinity (72,7 µM). As for multitargeting approach, two compounds showed to be promising in the three selected targets (LINS05006 = Ki: H3R = 2.8 µM; D3R = 0.7 µM; IC50: AChE = 107.1 µM; LINS05020 = Ki: H3R = 1.7 µM; D3R = 1.4 µM; IC50: AChE = 114.7µM) and can be used as a prototype, together with overall results, to improve the development of better multitargeting ligands.
  • Imagem de Miniatura
    Item
    Acesso aberto (Open Access)
    Novas aril-metil-piperazinas da série LINS01 como ligantes de receptores de histamina H3R/H4R
    (Universidade Federal de São Paulo (UNIFESP), 2019-05-31) Nascimento, Lillian Ferreira Dos Santos [UNIFESP]; Fernandes, João Paulo dos Santos [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Histamine is an important biogenic amine distributed widely in all tissues. It plays an important role in the physiology and homeostasis of the organism, as well as in allergic and inflammatory processes. Its effects are observed through interaction with four histaminergic receptors G protein-coupled histaminergic receptors called H1, H2, H3 and H4, and the cell signaling that activates each receptor is distinct. The four histaminergic receptors are important targets for the treatment of various diseases. The first two receptors identified were already intensively researched and already have definite application in therapy. The H3 receptor has been characterized as auto and hetero-receptor and is found mostly in the central nervous system (CNS). It has thus become a promising target for the treatment of CNS disorders. Because it has been characterized later, the H4 receptor, present mainly in cells of hematopoietic origin, has been studied by several research groups as a target for the treatment of immunological and inflammatory diseases. Due to the homology between the H3 and H4 receptors many ligands may have affinity for both receptors. Thus, molecules with antagonistic or inverse agonist activity towards the H3 and/or H4 receptors demonstrate relevance in the treatment of several diseases involving alone or in combination these receptors. Therefore, the purpose of this work was to synthesize molecules based on the LINS 01 series with the highest yield and purity possible, to evaluate the affinity of these receptors for H3 and / or H4 receptors and to verify their activity as antagonist or agonist. Synthesis of the ligands involved steps such as allylation, Claisen rearrangement and reductive amination, resulting in intermediates which had crude yields of ~ 1 to 93%. The compounds designed in this work were not obtained due to the failure of chemical steps (low yield and / or no yield of the desired product) and purification. Thus, some intermediates obtained were tested through the binding test, but showed very low affinity in both receptors and thus it was not possible to evaluate their activities as antagonists or agonists in H3 and H4 receptors.