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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: European Journal of Pharmaceutical Sciences; v. 122, p. 31-41, SEP 15 2018.
• Web of Science Citations: 4

Abstract

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)

• FAPESP's process: 15/23403-9 - Rational Pre-Clinical Study of New Drug Candidates Against Neglected Protozoan Diseases Using Pharmacokinetic Approaches
• Grantee: André Gustavo Tempone Cardoso
• Support type: Regular Research Grants
• FAPESP's process: 16/00195-4 - Synthesis and evaluation of the activity of substituted alkylphenols in Trypanosoma cruzi
• Grantee: Marina Themoteo Varela
• Support type: Scholarships in Brazil - Master
• FAPESP's process: 16/25028-3 - Antihistamines H3R/H4R as procognitive agents: a multitarget approach
• Grantee: João Paulo dos Santos Fernandes
• Support type: Regular Research Grants