Authors: Bekhit A.A., Saudi M.N., Hassan A.M.M., Fahmy S.M., Ibrahim T.M., Ghareeb D., El-Seidy A.M., Nasralla S.N., Bekhit A.E.-D.A.
Author Affiliations: Bekhit, A.A., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt, Pharmacy Program, Pharmacology Stream, Allied Health Department, College of Health Sciences, University of Bahrain, P.O. Box 32038, Bahrain; Saudi, M.N., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; Hassan, A.M.M., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; Fahmy, S.M., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; Ibrahim, T.M., Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, 33516, Egypt, Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo, Egypt; Ghareeb, D., Department of Biohemistry, Faculty of Science, Alexandria University, Alexandria, Egypt; El-Seidy, A.M., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; Nasralla, S.N., Pharmacy Program, Pharmacology Stream, Allied Health Department, College of Health Sciences, University of Bahrain, P.O. Box 32038, Bahrain; Bekhit, A.E.-D.A., Food Sciences, University of Otago, Dunedin, New Zealand
Publication Date: 2019
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 150 mg/kg via oral route and 75 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. © 2018 Elsevier Masson SAS
Eshan2020-11-28T18:19:36+00:00
