Antimalarial Alkoxylated and Hydroxylated Chalones:  Structure−Activity Relationship Analysis

• Published in: Journal of medicinal chemistry Vol. 44; no. 25; pp. 4443 - 4452
• Main Authors: Liu, Mei, Wilairat, Prapon, Go, Mei-Lin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.12.2001; Amer Chemical Soc
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Chemistry, Medicinal; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; IN-VITRO; VIVO; GROWTH; PARASITE PLASMODIUM-FALCIPARUM; CHALCONES; MALARIA; DERIVATIVES; Antimalarial; Multivariate analysis; Plasmodium falciparum; Plasmodium berghei; Structure activity relation; Parasiticid; Aromatic compound; Chemical synthesis; Protozoa; Apicomplexa; Rodentia; Parasitosis; In vitro; Naphthalene derivatives; Infection; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Mouse; Animal; Phenols; Benzenic compound; Enone
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0101747

Chalcones with 2‘,3‘,4‘-trimethoxy, 2‘,4‘-dimethoxy, 4‘-methoxy, 4‘-ethoxy, 2‘,4‘-dihydroxy, and 4‘-hydroxy groups on ring B were synthesized and evaluated in vitro against Plasmodium falciparum (K1) in a [3H] hypoxanthine uptake assay. The other ring A was quinoline, pyridine, naphthalene, or phenyl rings with electron-donating or electron-withdrawing substituents of varying lipophilicities. Trimethoxy 6 and 27, dimethoxy 7, 8, 29, and methoxy 31 analogues had good in vitro activities (IC50 < 5 μM). 3-Quinolinyl ring A derivatives were well represented among the active compounds. Hydroxylated chalcones were less active than the corresponding alkoxylated analogues. When evaluated in vivo, 8 and 208 were comparable to chloroquine in extending the lifespan of infected mice. Multivariate data analysis showed that in vitro activity was mainly determined by the properties of ring B. Quantitative structure−activity relationship models with satisfactory predictive ability were obtained for various B ring chalcones using projections to latent structures. A model with good predictability was proposed for 19 active chalcones. Size and hydrophobicity were identified as critical parameters.