Evaluation of the antitrypanosoma activity and SAR study of novel LINS03 derivatives

Autor(es)

Varela, Marina T. ^[1] ; Costa-Silva, Thais A. ^[2] ; Lago, Joao Henrique G. ^[2] ; Tempone, Andre G. ^[3] ; Fernandes, Joao Paulo S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Ciencias Farmaceut, Rua Sao Nicolau 210, BR-09913030 Diadema, SP - Brazil

^[2] Univ Fed ABC, Ctr Ciencias Nat & Humanas, Av Estados 5001, BR-09210580 Santo Andre, SP - Brazil

^[3] Adolfo Lutz Inst, Ctr Parasitol & Mycol, Av Dr Amoldo 351, BR-01246000 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BIOORGANIC CHEMISTRY; v. 89, AUG 2019.
• Citações Web of Science: 0

Resumo

Chagas' disease is a parasitic infection caused by Trypanosoma cruzi that is still treated by old and toxic drugs. In the search for novel alternatives, natural sources are an important source for new drug prototypes against T. cruzi to further structural exploitation. A set of natural-based compounds (LINS03) was designed, showing promising antitrypanosoma activity and low cytotoxicity to host cells. In this paper, nine novel LINS03 derivatives were evaluated against T. cruzi trypomastigotes and amastigotes. The selectivity was assessed through cytotoxicity assays using NCTC mammalian cells and calculating the CC50/IC50 ratio. The results showed that compounds 2d and 4c are noteworthy, due their high activity against amastigotes (IC50 13.9 and 5.8 mu M) and low cytotoxicity (CC50 107.7 mu M and > 200 mu M, respectively). These compounds did not showed alteration on plasma membrane permeability in a Sytox green model. SAR analysis suggested an ideal balance between hydrosolubility and lipophilicity is necessary to improve the activity, and that insertion of a meta-substituent is detrimental to the activity of the amine derivatives but not to the neutral derivatives, suggesting different mechanisms of actions. The results presented herein are valuable for designing novel compounds with improved activity and selectivity to be applied in future studies. (AU)

• Processo FAPESP: 18/03918-2 - Avaliação da atividade antiparasitária e da citotoxicidade de derivados de produtos naturais em Trypanosoma cruzi: planejamento e síntese de análogos potencialmente superiores
• Beneficiário: Marina Themoteo Varela
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/25028-3 - Anti-histamínicos H3R/H4R como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: João Paulo dos Santos Fernandes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/07885-1 - Biomoléculas oriundas de espécies vegetais de áreas remanescentes da Mata Atlântica e do Cerrado para tratamento de doenças tropicais negligenciadas - aspectos químicos e farmacológicos
• Beneficiário: João Henrique Ghilardi Lago
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Regular
• Processo FAPESP: 15/23403-9 - Estudo Pré-Clínico Racional de Novos Candidatos a Fármacos em Protozooses Negligenciadas Utilizando Abordagens Farmacocinéticas
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular