implified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidate

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: CHEMISTRY & BIODIVERSITY; v. 18, n. 10 SEP 2021.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 19/13906-4 - Busca de novos protótipos frente a Doença de Chagas a partir de moléculas bioativas de plantas brasileiras
• Beneficiário: João Henrique Ghilardi Lago
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/02789-7 - Busca de metabólitos bioativos com ação antiparasitária em espécies vegetais de regiões de Mata Atlântica e Cerrado - uma abordagem química, fenotípica e metabolômica
• Beneficiário: João Henrique Ghilardi Lago
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Regular
• Processo FAPESP: 21/04464-8 - Protótipos microbianos e vegetais como candidatos a fármacos para protozooses negligenciadas e bactérias multirresistentes
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular