Abstract
Chagas disease (CD) affects more than 6 million people worldwide. The available treatment is far from ideal, creating a demand for new alternative therapies. Botanical diversity provides a wide range of novel potential therapeutic scaffolds. Presently, our aim was to evaluate the mammalian host toxicity and anti-Trypanosoma cruzi activity of botanic natural products including extracts, fractions and purified compounds obtained from Brazilian flora. In this study, 36 samples of extracts and fractions and eight pure compounds obtained from seven plant species were evaluated. The fraction dichloromethane from Aureliana fasciculata var. fasciculata (AFfPD) and the crude extract of Piper tectoniifolium (PTFrE) showed promising trypanosomicidal activity. AFfPD and PTFrE presented EC50 values 10.7 ± 2.8 μg/mL and 12.85 ± 1.52 μg/mL against intracellular forms (Tulahuen strain), respectively. Additionally, both were active upon bloodstream trypomastigotes (Y strain), exhibiting EC50 2.2 ± 1.0 μg/mL and 38.8 ± 2.1 μg/mL for AFfPD and PTFrE, respectively. Importantly, AFfPD is about five-fold more potent than Benznidazole (Bz), the reference drug for CD, also reaching lower EC90 value (7.92 ± 2.2 μg/mL) as compared to Bz (23.3 ± 0.6 μg/mL). Besides, anti-parasitic effect of eight purified botanic substances was also investigated. Aurelianolide A and B (compounds 1 and 2) from A. fasciculata and compound 8 from P. tuberculatum displayed the best trypanosomicidal effect. Compounds 1, 2 and 8 showed EC50 of 4.6 ± 1.3 μM, 1.6 ± 0.4 μM and 8.1 ± 0.9 μM, respectively against intracellular forms. In addition, in silico analysis of these three biomolecules was performed to predict parameters of absorption, distribution, metabolism and excretion. The studied compounds presented similar ADMET profile as Bz, without presenting mutagenicity and hepatotoxicity aspects as predicted for Bz. Our findings indicate that these natural products have promising anti-T. cruzi effect and may represent new scaffolds for future lead optimization.
Highlights
Chagas disease (CD) or American trypanosomiasis is a neglected disease that affects more than 6 million people worldwide with about 75 million people under risk of infection [1]
The first approach was the screening against intracellular amastigotes (Tulahuen-β gal strain, DTU VI) using a fixed concentration of 10 μg/mL, which corresponds to the 90% effective concentration (EC90)value of the reference drug (Bz) for CD (Table 1)
Natural products from fruit pulp of C. cujete have no trypanocidal effect at a concentration of 10 μg/mL
Summary
Chagas disease (CD) or American trypanosomiasis is a neglected disease that affects more than 6 million people worldwide with about 75 million people under risk of infection [1]. Benznidazole and nifurtimox are the only available medicines for CD Both are old drugs only effective in the early stages of the infection, as treatment of chronic patients has low and variable efficacy [1,2]. New therapeutic options are needed and research 2 of 13 on natural products from different sources (e.g., land, sea, plants, microbes and animals) can provide novel chemotype motifs with antiparasitic properties In this regard, botanic diversity inclnuodinnogvealwdriduge irsanavgaeiloafbleex[t4ra–c7t]s. Tfhraucst,inoenws, tahnedrappueuritfiicedopstuiobnsstaanrecensehedasedbeaennd research investigated ionnpnhaetnuoratyl ppircosdtuucdtsiefsrosemardcihffienrgenfot rsonuerwcebsi(oem.go.,lelacnudle, ssepar,epsleannttisn,gmaincrtio-bTe.scraunzdi animals) activity [8–10c].an provide novel chemotype motifs with antiparasitic properties. In this regard, botanic 316–8p, lTIannabtthleeixs3tr)sacdiaocnecbitnvvtstieaeavasrriiIntnsitnioyidget,tyad[hfo8triie–ufansdr1crcos0tlicmpi]uneo.rdnpneBiahssnrreeg(ainnTozato,ailtobswiytaulpuienrdisdcpefy1lsrroteaasursncnaderdgnieceeteo2snosm)stfebeupdeaedxorsytctsihrdhesaeideccnsrttgbeso8,eyxfnfopirAcreuaidnuctrytiertifewhoialeneindabstdni,osoaaxuamnfinbacdotssitlictpe-yaiTccunauu.rcnllcieeafidrsstueaap(dzcnvirosetaaiumsr-ceTb.tnpi.sfvtaotciasirnutcnuygniczcdeaiuosnas-f cthit-aiTvs.ibtcyreueoznfi lata, Clusia stu36daprltaiannt ae,xCtrraecstcseanntida fcruajcettieo,nMs (aTlapbiglehsia galnadbr2a), bPeispiedretse8ctponuiriiffioleidumsuabnstdanRcehsee(dcioampounds longifolia sam1p–l8e,s.TTabhlees3e) noabttuairnaeldpfrroodmucBtrsazwileiaren sfleolreactceodmbpaosseedd obny Apruerveliioanuasflaistceircautluatraevtahra.
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