title: New heterocyclic hybrids of pyrazole and its bioisosteres: design, synthesis and biological evaluation as dual acting antimalarial-antileishmanial agents.
abstract: A new series of pyrazole derivatives were synthesized by hybridization with five-membered heterocyclic moieties such as thiazoles, thiazolidinones, 1,3,4-thiadiazoles and pyrazolines. The compounds were evaluated for their in vivo antimalarial activity against Plasmodium berghei infected mice and the most active derivatives were further examined for their in vitro antimalarial activity against chloroquine resistant (RKL9) strain of Plasmodium falciparum. Compounds 2c, 2d, 4b, 4c, 4d, 5a, 6c, 8c and 9b had more than 90% parasite suppression activity of that found with the antimalarial reference standard drug, chloroquine phosphate and had lower IC50 values than chloroquine. Compounds 4b and 9b were the most active derivatives, and their activities were 5-fold higher than chloroquine. All the newly synthesized compounds were evaluated for their in vitro antileishmanial activity against Leishmania aethiopica promastigotes and amastigote. The results showed that compounds 2c, 2d, 3d, 4b, 4c, 4d and 5a had lower or similar IC50 values than the reference standard drugs, amphotericin B and miltefosine. Compound 3d had the highest antileishmanial activity. Collectively, compounds 2c, 2d, 4b, 4c, 4d and 5a exhibited dual activity against malaria and leishmaniasis and were safe and well tolerated by the experimental animals orally up to 300 mg/kg and parenterally up to 100 mg/kg.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address: adnbekhit@pharmacy.alexu.edu.eg.
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Bekhit
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
authors.forename: Ahmed M M
authors.initials: AM
authors.lastname: Hassan
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
authors.forename: Heba A
authors.initials: HA
authors.lastname: Abd El Razik
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
authors.forename: Mostafa M M
authors.initials: MM
authors.lastname: El-Miligy
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
authors.forename: Eman J
authors.initials: EJ
authors.lastname: El-Agroudy
authors.affiliation: Food Science, University of Otago, Dunedin, New Zealand.
authors.forename: Alaa El-Din A
authors.initials: Ael-D
authors.lastname: Bekhit
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D002738:Chloroquine / Q000031:analogs & derivatives / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects / Q000472:pathogenicity; D007896:Leishmaniasis / Q000188:drug therapy; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D010962:Plasmodium berghei / Q000472:pathogenicity; D010963:Plasmodium falciparum / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D006571:Heterocyclic Compounds; D011720:Pyrazoles; D014344:Trypanocidal Agents; C031280:pyrazole; C023676:chloroquine diphosphate; D002738:Chloroquine
keywords: 1,3,4-Thiadiazole; Antileishmanial; Antimalarial; Pyrazole; Thiazole; Thiazolidinone