- Study of the Effect of Substituents of ortho-Phenylenediamines in the Opening of Lactones and Lactams for Access to Benzimidazol-2-yl Alkanols and Benzimidazol-2-yl Alkylamines
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Benzimidazoles represent common chemical moieties in bioactive compounds. The synthesis of this heterocycle often involves a condensation of an ortho-phenylenediamine with a carboxylic acid derivative. The observed dialkylation of the starting ortho-phenylenediamine is avoided by opening of lactones or lactams. This strategy can directly yield 1 H-benzimidazoles substituted at the 2-position by a functionalized chain. We present herein a study of the effect of different electron-withdrawing or electron-donating groups at the 4-position of ortho-phenylenediamines on the opening of lactones or lactams to synthesize benzimidazol-2-yl alkanols and benzimidazol-2-yl alkylamines.
- Arimondo, Paola B.,Balleé, Alexia,Beaurain, Florian,Castillo-Aguilera, Omar,Depreux, Patrick,Goossens, Laurence
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p. 1216 - 1220
(2020/07/30)
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- Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives
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In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.
- Czopek, Anna,Partyka, Anna,Bucki, Adam,Paw?owski, Maciej,Ko?aczkowski, Marcin,Siwek, Agata,G?uch-Lutwin, Monika,Koczurkiewicz, Paulina,P?kala, El?bieta,Jaromin, Anna,Tyliszczak, Bo?ena,Weso?owska, Anna,Zagórska, Agnieszka
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- A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N -[3-[(Benzimidazol-2-yl)amino]propyl]amides
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Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group. (Graph Presented).
- Keurulainen, Leena,Vahermo, Mikko,Puente-Felipe, Margarita,Sandoval-Izquierdo, Elena,Crespo-Fernández, Benigno,Guijarro-López, Laura,Huertas-Valentín, Leticia,De Las Heras-Due?a, Laura,Leino, Teppo O.,Siiskonen, Antti,Ballell-Pages, Lluís,Sanz, Laura M.,Casta?eda-Casado, Pablo,Jiménez-Díaz, M. Belén,Martínez-Martínez, María S.,Viera, Sara,Kiuru, Paula,Calderón, Félix,Yli-Kauhaluoma, Jari
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supporting information
p. 4573 - 4580
(2015/06/25)
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