Antimalarial alkoxylated and hydroxylated chalones: Structure-activity relationship analysis

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 eval uated in vitro against Plasmodium falciparum (K1) in a [H-3] hypoxanthine u ptake assay. The other ring A was quinoline, pyridine, naphthalene, or phen yl rings with electron-donating or electron-withdrawing substituents of var ying lipophilicities. Trimethoxy 6 and 27, dimethoxy 7, 8, 29, and methoxy 31 analogues had good in vitro activities (IC50 < 5 muM). 3-Quinolinyl ring A derivatives were well represented among the active compounds. Hydroxylat ed chalcones were less active than the corresponding alkoxylated analogues. When evaluated in vivo, 8 and 208 were comparable to chloroquine in extend ing the lifespan of infected mice. Multivariate data analysis showed that i n vitro activity was mainly determined by the properties of ring B. Quantit ative structure-activity relationship models with satisfactory predictive a bility were obtained for various B ring chalcones using projections to late nt structures. A model with good predictability was proposed for 19 active chalcones. Size and hydrophobicity were identified as critical parameters.