Antiparasitic activity of new gibbilimbol analogues and SAR analysis through efficiency and statistical methods

Autor(es)

Varela, Marina T. ^[1] ; Romaneli, Maiara M. ^[2] ; Lima, Marta L. ^{[2, 3]} ; Borborema, Samanta E. T. ^[2] ; Tempone, Andre G. ^[2] ; Fernandes, Joao P. 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] Adolfo Lutz Inst, Ctr Parasitol & Micol, Av Dr Arnaldo 355, BR-01246000 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Inst Med Trop Sao Paulo, Av Dr Eneas Carvalho de Aguiar 470, BR-05403000 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmaceutical Sciences; v. 122, p. 31-41, SEP 15 2018.
• Citações Web of Science: 4

Resumo

Chagas' disease and leishmaniasis are parasitic infections enrolled among the neglected tropical diseases, which urge for new treatments. In the search for new chemical entities as prototypes, gibbilimbols A/B have shown antiparasitic activity against Trypanosoma cruzi and Leishmania infantum, and then a set of analogues (LINS03 series) of this natural product were synthesized and evaluated in vitro against the parasites. In the present paper we reported five new compounds with activity against these protozoan parasites, and quite low cytotoxicity. Moreover, the interference of plasma membrane permeability of these analogues were also evaluated. We found that {[}(4-methoxyphenyl) methyl] octylamine (4) was noteworthy due to its high activity against the amastigote form of both parasites (IC50 1.3-5.8 mu M) and good selectivity index. In order to unveil the SAR for this chemotype, we also presented a group efficiency analysis and PCA and HCA study, which indicated that the methoxyl provides good activity with lower cytotoxicity to mammalian cells. The results from SAR analyses suggest different mechanisms of action between the neutral and basic compounds. In summary, the analogues represent important activity against these parasites and must be prototypes for further exploitation. (AU)

• 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: 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
• Processo FAPESP: 16/00195-4 - Síntese e avaliação da atividade de alquilfenóis substituídos em Trypanosoma cruzi
• Beneficiário: Marina Themoteo Varela
• Modalidade de apoio: Bolsas no Brasil - Mestrado