Lupeol Acetate and α-Amyrin Terpenes Activity against Trypanosoma cruzi : Insights into Toxicity and Potential Mechanisms of Action.

Autor: Pardo-Rodriguez D; Grupo de Enfermedades Infecciosas, Pontificia Universidad Javeriana, Bogotá 110231, Colombia.; Grupo de Investigación Fitoquímica Universidad Javeriana (GIFUJ), Pontificia Universidad Javeriana, Bogotá 110231, Colombia.; Grupo de Productos Naturales, Universidad del Tolima, Tolima 730006299, Colombia., Cifuentes-López A; Department of Chemistry, Rutgers University, Newark, NJ 07102, USA., Bravo-Espejo J; Grupo de Enfermedades Infecciosas, Pontificia Universidad Javeriana, Bogotá 110231, Colombia., Romero I; Escuela de Pregrados, Dirección Académica, Vicerrectoría de Sede, Universidad Nacional de Colombia, Sede, De La Paz 202010, Colombia., Robles J; Grupo de Investigación Fitoquímica Universidad Javeriana (GIFUJ), Pontificia Universidad Javeriana, Bogotá 110231, Colombia., Cuervo C; Grupo de Enfermedades Infecciosas, Pontificia Universidad Javeriana, Bogotá 110231, Colombia., Mejía SM; Grupo de Investigación Fitoquímica Universidad Javeriana (GIFUJ), Pontificia Universidad Javeriana, Bogotá 110231, Colombia., Tellez J; Escuela de Pregrados, Dirección Académica, Vicerrectoría de Sede, Universidad Nacional de Colombia, Sede, De La Paz 202010, Colombia.
Jazyk: angličtina
Zdroj: Tropical medicine and infectious disease [Trop Med Infect Dis] 2023 May 03; Vol. 8 (5). Date of Electronic Publication: 2023 May 03.
DOI: 10.3390/tropicalmed8050263
Abstrakt: Background: Chagas disease is a potentially fatal disease caused by the parasite Trypanosoma cruzi . There is growing scientific interest in finding new and better therapeutic alternatives for this disease's treatment.
Methods: A total of 81 terpene compounds with potential trypanocidal activity were screened and found to have potential T. cruzi cysteine synthase (TcCS) inhibition using molecular docking, molecular dynamics, ADME and PAIN property analyses and in vitro susceptibility assays.
Results: Molecular docking analyses revealed energy ranges from -10.5 to -4.9 kcal/mol in the 81 tested compounds, where pentacyclic triterpenes were the best. Six compounds were selected to assess the stability of the TcCS-ligand complexes, of which lupeol acetate (ACLUPE) and α-amyrin (AMIR) exhibited the highest stability during 200 ns of molecular dynamics analysis. Such stability was primarily due to their hydrophobic interactions with the amino acids located in the enzyme's active site. In addition, ACLUPE and AMIR exhibited lipophilic characteristics, low intestinal absorption and no structural interferences or toxicity. Finally, selective index for ACLUPE was >5.94, with moderate potency in the trypomastigote stage (EC 50 = 15.82 ± 3.7 μg/mL). AMIR's selective index was >9.36 and it was moderately potent in the amastigote stage (IC 50 = 9.08 ± 23.85 μg/mL).
Conclusions: The present study proposes a rational approach for exploring lupeol acetate and α-amyrin terpene compounds to design new drugs candidates for Chagas disease.
Databáze: MEDLINE
Externí odkaz: