Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates |
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Authors: | Dalete Christine S Souza Thais A Costa-Silva Thiago R Morais Juliana R Brito Edgard A Ferreira Guilherme M Antar Patricia Sartorelli Andre G Tempone João Henrique G Lago |
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Institution: | 1. Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, 09913-030 Diadema, SP, Brazil;2. Center for Natural and Human Sciences, Federal University of ABC, 09210-580 Santo Andre, SP, Brazil;3. Neglected Diseases Research Center, University of Guarulhos, 07023-070 Guarulhos, SP, Brazil;4. School of Engineering, Mackenzie Presbyterian University, 01302-907 Sao Paulo, SP, Brazil;5. Institute of Biosciences, University of São Paulo, 05508-090 São Paulo, SP, Brazil;6. Center for Parasitology and Mycology, Instituto Adolfo Lutz, 01246-902 São Paulo, SP, Brazil |
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Abstract: | 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 μM, respectively. Compound 1 was also active against the clinically relevant form of the parasite, amastigotes, displaying an EC50 value of 34.4 μM. 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 μM. 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 ) μM against trypomastigotes, and 41.3 ( 3 ) and 48.2 ( 4 ) μM against amastigotes, whereas compound 5 was inactive. Except for compound 2 , which resulted in a CC50 value of 114.5 μM, all compounds showed no mammalian cytotoxicity at 200 μM. 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. |
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Keywords: | hinokinin hibalactone simplified derivatives Trypanosoma cruzi membrane permeability |
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