Synthesis, in silico experiments and biological evaluation of 1,3,4-trisubstituted pyrazole derivatives as antimalarial agents.
Eur J Med Chem
; 163: 353-366, 2019 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-30530172
ABSTRACT
New 1,3,4-trisubstituted pyrazole derivatives were synthesized and evaluated for their antiplasmodial activity. Compounds 4b, 4c, 7a and 7d were the most potent antiplasmodial agents against P. berghei with percent of suppression ranging from 90 to 100%. They were also screened for their in vitro antimalarial activity against the chloroquine resistant strain P. falciparum, (RKL9). Compound 4c displayed the highest in vitro antimalarial activity; 13-fold higher than standard chloroquine phosphate. Molecular docking of the most active compounds against the wildtype and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Furthermore, these compounds exhibited reasonable in silico drug-likeness and pharmacokinetic properties. Toxicity studies of the most active compounds revealed that all tested compounds were non-toxic and well-tolerated up to 150â¯mg/kg via oral route and 75â¯mg/kg via parentral route. According to RBC hemolysis assay, it was found that compound 7a was the most potent anti-inflammatory and least toxic derivative with IC50 value 71-fold higher than IC50 value related to the antimalarial activity. Moreover, cytotoxicity assessment revealed that compound 4c was the least toxic derivative with IC50 value 70000-fold higher than IC50 value related to the antimalarial activity.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Antimaláricos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2019
Tipo del documento:
Article