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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.)

implified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidate

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Souza, Dalete Christine S. [1] ; Costa-Silva, Thais A. [2] ; Morais, Thiago R. [3] ; Brito, Juliana R. [1] ; Ferreira, Edgard A. [4] ; Antar, Guilherme M. [5] ; Sartorelli, Patricia [1] ; Tempone, Andre G. [6] ; Lago, Joao Henrique G. [2]
Total Authors: 9
[1] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09913030 Diadema, SP - Brazil
[2] Fed Univ ABC, Ctr Nat & Human Sci, BR-09210580 Santo Andre, SP - Brazil
[3] Univ Guarulhos, Neglected Dis Res Ctr, BR-07023070 Guarulhos, SP - Brazil
[4] Univ Prebiteriana Mackenzie, Sch Engn, BR-01302907 Sao Paulo, SP - Brazil
[5] Univ Sao Paulo, Inst Biosci, BR-05508090 Sao Paulo, SP - Brazil
[6] Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246902 Sao Paulo, SP - Brazil
Total Affiliations: 6
Document type: Journal article
Source: CHEMISTRY & BIODIVERSITY; v. 18, n. 10 SEP 2021.
Web of Science Citations: 0

The search for the pharmacophore of a bioactive compound, crucial for drug discovery studies, involves the adequate arrangement of different atoms in the molecule. As part of a continuous work aiming discovery of new drug candidates against the protozoan parasite Trypanosoma cruzi, the hexane extract of Hydrocotyle bonariensis was subjected to a bioactivity-guided fractionation to afford two chemically related dibenzylbutyrolactone lignans - hinokinin (1) and hibalactone (2). Compounds 1 and 2 showed activity against trypomastigote with EC50 values of 17.0 and 69.4 mu M, respectively. Compound 1 was also active against the clinically relevant form of the parasite, amastigotes, displaying an EC50 value of 34.4 mu M. The structure-activity relationship (SAR) indicated that the absence of the double bond at C-7 is a crucial feature for the increment of the antiparasitic activity. The lethal action of the most potent compound 1 was investigated in the trypomastigotes. The fluorescent-based assay with SYTOX Green demonstrated a significant alteration of the plasma membrane permeability of the parasite. Additionally, compound 1 demonstrated no significant hemolytic activity in mice erythrocytes at 200 mu M. To search the pharmacophore, three different simplified compounds - 3,4-methylenedioxydihydrocinnamic acid (3), 3,4-methylenedioxydihydrocinnamic alcohol (4) and 3,4-methylenedioxycinnamic acid (5) - were prepared and tested against T. cruzi. These derivatives displayed EC50 values of 37.2 (3), 25.8 (4) and 73.5 (5) mu M against trypomastigotes, and 41.3 (3) and 48.2 (4) mu M against amastigotes, whereas compound 5 was inactive. Except for compound 2, which resulted in a CC50 value of 114.5 mu M, all compounds showed no mammalian cytotoxicity at 200 mu M. An in silico ADMET study was performed and predicted values demonstrated an acceptable drug-likeness profile for compounds 1-5. Despite the minor reduction in the potency, the simplified derivatives retained the antitrypanosomal activity against the intracellular amastigotes, even with 95 % reduction of their molecular weight. Additionally, in silico studies suggested them as more soluble compounds, making these simplified structures promising scaffolds for optimization studies in Chagas disease. (AU)

FAPESP's process: 19/13906-4 - Discovering new drug leads against Chagas Disease Based on Brazilian bioactive plant molecules
Grantee:João Henrique Ghilardi Lago
Support type: Regular Research Grants
FAPESP's process: 21/02789-7 - Search for bioactive metabolites with antiparasitic action in plant species from Atlantic Forest and Cerrado regions - a chemical, phenotypical, and metabolomic approach
Grantee:João Henrique Ghilardi Lago
Support type: BIOTA-FAPESP Program - Regular Research Grants
FAPESP's process: 21/04464-8 - Microbial and plant prototypes as drug candidates for protozoan neglected diseases and multidrug-resistant bacteria
Grantee:André Gustavo Tempone Cardoso
Support type: Regular Research Grants