Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans

Abstract

BackgroundChagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic. Hence, the aim of this work is to find a good antitrypanosomal drug with less toxicity. The use of simple organism models has become increasingly attractive for planning and simplifying efficient drug discovery. Within these models, Caenorhabditis elegans has emerged as a convenient and versatile tool with significant advantages for the toxicological potential identification for new compounds.MethodsTrypanocidal activity:Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC50).Toxicity assays:Lethal dose 50% (LD50) and Body Area were determined by Caenorhabditis elegans N2 strain (wild type) after acute exposure.Structure-activity relationship:A classificatory model was built using 3D descriptors.ResultsTwo of these coumarins demonstrated near equipotency to Nifurtimox (IC50 = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC50 = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC50 = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD50 assay and the evaluation of the development of worms. It is possible to observe that the efficacy between Nfx and the synthesized compounds (11 h and 11 g) are similar. On the other hand, the toxicity of Nfx is approximately three times higher than that of the compounds. Results from the QSAR-3D study indicate that the volume and hydrophobicity of the substituents have a significant impact on the trypanocidal activities for derivatives that cause more than 50% of inhibition. These results show that the C. elegans model is efficient for screening potentially toxic compounds.ConclusionTwo coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD50 and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs.

Analysis of Polysaccharide Fraction from Yerba Mate (Ilex paraguariensisSt. Hil.) on Regeneration of Planarian (Girardia tigrina)

“…This approach is widely used in toxicological studies using the nematode Caenorhabditis elegans . [ 31,32 ]…”

Effect of some plant extracts from Egyptian herbal plants against <i>Toxoplasma gondii</i> tachyzoites <i>in vitro</i>

“…Moreover, it has been revealed that apigenin was effective against Leishmania tropica amastigote [ 66 ]. In addition, previous reports have shown that coumarins exhibit activity against the promastigote form of Leishmania major and Trypanosma cruzi [ 53 , 87 ]. Therefore, future studies on the anti- Toxoplasma activities of these compounds that were identified in M. chamomilla ( German chamomile ) flowers are needed.…”

Review of pharmacological options for the treatment of Chagas disease

“…Considering this drug is effective in clearing T.cruzi as well in pre-clinical studies, an ongoing randomized, double-blind, placebo controlled trial is being carried out in Argentina, Bolivia and Spain to assess its efficacy in CD (NCT02498782). Interestingly, some natural compounds and dietary supplements such as microalgae extracts 147 , wasp venom 148 , coumarins 149 , South American Vernonieae 150 , curcumin 151 and Resveratrol 152 have been also studied for anti-tripanosomal activity, but more research is required This article is protected by copyright. All rights reserved to draw conclusions, and there is still close to no human clinical data.…”

“…Interestingly, some natural compounds and dietary supplements such as microalgae extracts, 174 wasp venom, 175 coumarins, 176 South American Vernonieae, 177 curcumin 178 and Resveratrol 179 have been also studied for anti‐trypanosomal activity, but more research is required to draw conclusions, and there is still close to no human clinical data. The use of natural compounds to treat known diseases might lead to effective benefit–cost resources, considering that many of these compounds are not subject to patent restrictions and may be widely available.…”