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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Varela, Marina T. [1] ; Costa-Silva, Thais A. [2] ; Lago, Joao Henrique G. [2] ; Tempone, Andre G. [3] ; Fernandes, Joao Paulo S. [1]
Total Authors: 5
[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
Total Affiliations: 3
Document type: Journal article
Source: BIOORGANIC CHEMISTRY; v. 89, AUG 2019.
Web of Science Citations: 0

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)

FAPESP's process: 18/03918-2 - Evaluation of the antiparasitic activity and cytotoxicity of natural products derivatives in Trypanosoma cruzi: design and synthesis of analogues potentially superior
Grantee:Marina Themoteo Varela
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 16/25028-3 - Antihistamines H3R/H4R as procognitive agents: a multitarget approach
Grantee:João Paulo dos Santos Fernandes
Support Opportunities: Regular Research Grants
FAPESP's process: 18/07885-1 - Biomolecules from plant species of remnant areas of the Atlantic Forest and Cerrado to treat neglected tropical diseases - chemical and pharmacological aspects
Grantee:João Henrique Ghilardi Lago
Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
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 Opportunities: Regular Research Grants