Antimalarial activity of 4-(5-trifluoromethyl-1 H-pyrazol-1-yl)-chloroquine analogues

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 3; pp. 649 - 653
• Main Authors: Cunico, Wilson, Cechinel, Cleber A., Bonacorso, Helio G., Martins, Marcos A.P., Zanatta, Nilo, de Souza, Marcus V.N., Freitas, Isabela O., Soares, Rodrigo P.P., Krettli, Antoniana U.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.02.2006; Elsevier
• Subjects: 4,5-Dihydropyrazole; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarial; Antimalarials - pharmacology; Antimalarials - therapeutic use; Antiparasitic agents; Biological and medical sciences; Chloroquine - analogs & derivatives; Chloroquine - chemical synthesis; Chloroquine - pharmacology; Chloroquine - therapeutic use; Chloroquine analogues; Dose-Response Relationship, Drug; Humans; Malaria - drug therapy; Medical sciences; Parasitic Sensitivity Tests; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Antimalarial; 4,5-Dihydropyrazole; Chloroquine analogues; Protozoal disease; Five membered ring; Nitrogen heterocycle; Chloroquine; Antiprotozoal agent; Plasmodium falciparum; Plasmodium berghei; Structure activity relation; Tertiary alcohol; Bicyclic compound; Subcutaneous administration; Aromatic compound; Halogen Organic compounds; Protozoa; Apicomplexa; Haloalcohol; Malaria; Rodentia; Benzene derivatives; Oral administration; Quinoline derivatives; Parasitosis; In vitro; Infection; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Parasiticide
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.10.033

The antimalarial activity of 4,5-dihydropyrazole and pyrazole chloroquine analogues is reported. The antimalarial activity of chloroquine-pyrazole analogues, synthesized from the reaction of 1,1,1-trifluoro-4-methoxy-3-alken-2-ones with 4-hydrazino-7-chloroquinoline, has been evaluated in vitro against a chloroquine resistant Plasmodium falciparum clone. Parasite growth in the presence of the test drugs was measured by incorporation of [ 3H]hypoxanthine in comparison to controls with no drugs. All but one of the eight (4,5-dihydropyrazol-1-yl) chloroquine 2 derivatives tested showed a significant activity in vitro, thus, are a promising new class of antimalarials. The three most active ones were also tested in vivo against Plasmodium berghei in mice. However, the (pyrazol-1-yl) chloroquine 3 derivatives were mostly inactive, suggesting that the aromatic functionality of the pyrazole ring was critical.