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Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans
- Source :
- BMC Pharmacology and Toxicology, Vol 20, Iss S1, Pp 1-13 (2019), COLIBRI, Universidad de la República, instacron:Universidad de la República, BMC Pharmacology & Toxicology
- Publication Year :
- 2019
- Publisher :
- BMC, 2019.
-
Abstract
- Background Chagas 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. Methods Trypanocidal 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. Results Two 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. Conclusion Two 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.
- Subjects :
- Chagas disease
Antiparasitic
medicine.drug_class
Trypanosoma cruzi
Pharmacology
01 natural sciences
Median lethal dose
Lethal Dose 50
Inhibitory Concentration 50
03 medical and health sciences
Parasitic Sensitivity Tests
Coumarins
lcsh:RA1190-1270
medicine
Animals
Pharmacology (medical)
Nifurtimox
Caenorhabditis elegans
030304 developmental biology
lcsh:Toxicology. Poisons
0303 health sciences
Molecular Structure
biology
Chemistry
Research
lcsh:RM1-950
medicine.disease
biology.organism_classification
Structure-activity relationship
Trypanocidal Agents
0104 chemical sciences
010404 medicinal & biomolecular chemistry
lcsh:Therapeutics. Pharmacology
Benznidazole
Toxicity
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 20506511
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- BMC Pharmacology and Toxicology
- Accession number :
- edsair.doi.dedup.....1e19169d40b161a3648036b78803d94b