Development of Novel Isoindolone-Based Compounds against Trypanosoma brucei rhodesiense

Autor(es)

Silva, Daniel G. ^{[1, 2]} ; Feijens, Pim-Bart ^[3] ; Hendrickx, Rik ^[3] ; Matheeussen, An ^[3] ; Grey, Lucie ^[4] ; Caljon, Guy ^[3] ; Maes, Louis ^[3] ; Emery, Flavio S. ^[1] ; Junker, Anna ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, QHeteM Lab Quim Heterocicl Med, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Westphalian Wilhelms Univ Munster, European Inst Mol Imaging EIMI, D-48149 Munster - Germany

^[3] Univ Antwerp, Lab Microbiol Parasitol & Hyg LMPH, Univ Pl 1, B-2610 Antwerp - Belgium

^[4] Westphalian Wilhelms Univ Munster, Inst Pharmaceut & Med Chem, D-48149 Munster - Germany

• Tipo de documento: Artigo Científico
• Fonte: CHEMISTRYOPEN; v. 10, n. 9, p. 922-927, SEP 2021.
• Citações Web of Science: 1

Resumo

This study identified the isoindolone ring as a scaffold for novel agents against Trypanosoma brucei rhodesiense and explored the structure-activity relationships of various aromatic ring substitutions. The compounds were evaluated in an integrated in vitro screen. Eight compounds exhibited selective activity against T. b. rhodesiense (IC(50)m) with no detectable side activity against T. cruzi and Leishmania infantum. Compound 20 showed low nanomolar potency against T. b. rhodesiense (IC50=40 nm) and no toxicity against MRC-5 and PMM cell lines and may be regarded as a new lead template for agents against T. b. rhodesiense. The isoindolone-based compounds have the potential to progress into lead optimization in view of their highly selective in vitro potency, absence of cytotoxicity and acceptable metabolic stability. However, the solubility of the compounds represents a limiting factor that should be addressed to improve the physicochemical properties that are required to proceed further in the development of in vivo-active derivatives. (AU)

• Processo FAPESP: 17/22001-0 - Síntese e avaliação de novos compostos heterociclos como potenciais agentes tripanossomicidas
• Beneficiário: Daniel Gedder Silva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/21146-4 - Explorando a química heterocíclica e a epigenética para o desenvolvimento de compostos de interesse químico medicinal
• Beneficiário: Flavio da Silva Emery
• Modalidade de apoio: Auxílio à Pesquisa - Regular