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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.)

Improving the drug-likeness of inspiring natural products - evaluation of the antiparasitic activity against Trypanosoma cruzi through semi-synthetic and simplified analogues of licarin A

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Morais, Thiago R. [1] ; Alves Conserva, Geanne A. [2] ; Varela, Marina T. [1] ; Costa-Silva, Thais A. [2] ; Thevenard, Fernanda [2] ; Ponci, Vitor [1] ; Fortuna, Ana [3, 4] ; Falcao, Amilcar C. [3, 4] ; Tempone, Andre G. [5] ; Fernandes, Joao Paulo S. [1] ; Lago, Joao Henrique G. [2]
Total Authors: 11
[1] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Sao Paulo - Brazil
[2] Univ Fed ABC, Ctr Nat Sci & Humanities, BR-09210580 Sao Paulo - Brazil
[3] Univ Coimbra, Lab Pharmacol, Fac Pharm, P-3000370 Coimbra - Portugal
[4] Univ Coimbra, CIBIT ICNAS Coimbra Inst Biomed Imaging & Transla, P-3000370 Coimbra - Portugal
[5] Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246000 Sao Paulo - Brazil
Total Affiliations: 5
Document type: Journal article
Source: SCIENTIFIC REPORTS; v. 10, n. 1 MAR 25 2020.
Web of Science Citations: 2

Neolignan licarin A (1) was isolated from leaves of Nectandra oppositifolia (Lauraceae) and displayed activity against trypomastigote forms of the etiologic agent of American trypanosomiasis, Trypanosoma cruzi. Aiming for the establishment of SAR, five different compounds (1a - 1e) were prepared and tested against T. cruzi. The 2-allyl derivative of licarin A (1d) exhibited higher activity against trypomastigotes of T. cruzi (IC50=5.0 mu M and SI=9.0), while its heterocyclic derivative 1e displayed IC50 of 10.5 mu M and reduced toxicity against NCTC cells (SI>19.0). However, these compounds presented limited oral bioavailability estimation (<85%, Papp <1.0x10(-6)cm/s) in parallel artificial membrane permeability assays (PAMPA) due to excessive lipophilicity. Based on these results, different simplified structures of licarin A were designed: vanillin (2), vanillyl alcohol (3), isoeugenol (4), and eugenol (5), as well as its corresponding methyl (a), acetyl (b), O-allyl (c), and C-allyl (d) analogues. Vanillin (2) and its acetyl derivative (2b) displayed expressive activity against intracellular amastigotes of T. cruzi with IC50 values of 5.5 and 5.6 mu M, respectively, and reduced toxicity against NCTC cells (CC50>200 mu M). In addition, these simplified analogues showed a better permeability profile (Papp>1.0x10(-6)cm/s) on PAMPA models, resulting in improved drug-likeness. Vanillyl alcohol acetyl derivative (3b) and isoeugenol methyl derivative (4a) displayed activity against the extracellular forms of T. cruzi (trypomastigotes) with IC50 values of 5.1 and 8.8 mu M respectively. Based on these results, compounds with higher selectivity index against extracellular forms of the parasite (1d, 1e, 3d, and 4a) were selected for a mechanism of action study. After a short incubation period (1h) all compounds increased the reactive oxygen species (ROS) levels of trypomastigotes, suggesting cellular oxidative stress. The ATP levels were increased after two hours of incubation, possibly involving a high energy expenditure of the parasite to control the homeostasis. Except for compound 4a, all compounds induced hyperpolarization of mitochondrial membrane potential, demonstrating a mitochondrial imbalance. Considering the unique mitochondria apparatus of T. cruzi and the lethal alterations induced by structurally based on licarin A, these compounds are interesting hits for future drug discovery studies in Chagas disease. (AU)

FAPESP's process: 16/20633-6 - Bioactive metabolites from Nectandra oppositifolia Nees & Mart. (Lauraceae): molecular characterization, in vitro and in vivo antiparasitic potential evaluation and determination of mechanism of action
Grantee:Geanne Alexsandra Alves Conserva
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: 18/10279-6 - Selection and Optimization of New Drug Candidates for Leishmaniasis and Chagas Disease
Grantee:André Gustavo Tempone Cardoso
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