Quantum mechanical, molecular docking, molecular dynamics, ADMET and antiproliferative activity on Trypanosoma cruzi (Y strain) of chalcone (E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one derived from a natural product

Abstract

Chagas disease is a leading public health problem. More than 8 million people are affected by the disease, which is endemic in 21 countries in Latin America, generating an average annual cost of 7.2 billion dollars per year. The conventional treatment of Chagas disease is carried out by administering the drug benznidazole (BZN), which has caused numerous adverse reactions. Hence, the search for new, more efficient, and less toxic anti-chagasic agents is essential. Recently, chalcones have been researched to propose new therapies against neglected diseases, mainly Trypanosoma cruzi. The objective of this work was to evaluate for the first time the antiproliferative potential of chalcone derived from the natural product on T. cruzi strain Y. The molecular structure of the chalcone was confirmed by spectrometric data. The toxicity of chalcone in LLC-MK2 cells indicated that a concentration of 514.10 ± 62.40 μM was able to reduce cell viability by 50%. Regarding the effect of chalcone on epimastigote forms, an IC₅₀ value of 46.57 ± 9.81 μM was observed; 45.92 ± 8.42 and 16.32 ± 3.41 μM at times of 24, 48 and 72 hours, respectively. The chalcone was able to eliminate trypomastigote forms at all concentrations tested, except for 31.25 μM, with LC₅₀ values of 117.90 ± 12.60 μM, lower than the reference drug BZN (161.40 ± 31. 80 μM). The mechanism of action may be related to the membrane damage provoked by reduction of the mitochondrial potential. The anti-T. cruzi effect can be assigned through some structural aspects of the chalcone as the nitro group (NO₂) is present, which can be enzymatically reduced forming a nitro radical, and the presence of methoxyl groups in the A ring of the chalcone. In silico studies showed that the chalcone had a higher affinity for cruzain when compared to BZN and the co-crystallized inhibitor KB2, as it presented a more thermodynamically stable complex in the order of −6.9 kcal mol⁻¹. The pharmacokinetic prediction showed a significant probability of antiprotozoal activity, a good volume of distribution after being absorbed in the intestine, and a low chance of activity in the central nervous system. Therefore, these results suggest that the chalcone can become a potential cruzain enzyme inhibitor with trypanocidal activity.