Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4-O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4-N, 4-S, and 4-O derivatives vs mu-oxo dimeric heme, measure binding constants for monomeric vs dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs CQR malaria.

Systematic variation of the branching and basicity of the side chain of chloroquine yielded a series of new 7-chloro-4-aminoquinoline derivatives exhibiting high in vitro activity against four different strains of P. falciparum. Many of the compounds tested showed excellent potency against chloroquine sensitive and resistant strains. In particular 4b, 5a, 5b, 5d, 17a, and 17b were found to be significantly more potent than chloroquine against the resistant strains Dd2 and FCB.

A procedure for nucleophilic addition of diethylzinc to trifluoromethyl ketones was developed. The TMEDA-catalyzed method converts aromatic substrates to the corresponding 2-aryl-1,1,1-trifluorobutan-2-ols in up to 99% yield, and it is also applicable to less reactive aliphatic ketones if stoichiometric ligand amounts are employed. The first asymmetric variant producing tertiary alcohols with up to 61% ee when TBOX is used as catalyst is described.

We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolylderived sulfonamides 3-8 and 11-26, ureas 19-22, thioureas 23-26, and amides 27-54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of P. falciparum) and low resistance indices were obtained in most cases. Systematic variation of the side chain length and introduction of fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In particular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high antiplasmodial potency with a low resistance index and showed IC 50 's of 17.5 nM and 22.7 nM against HB3 and Dd2 parasites.

Page 3915. We inadvertently overlooked previous work by Sasaki et al. which discusses the enantioselective synthesis of tertiary alcohols via addition of diethylzinc to trifluoromethyl ketones in the presence of nitrogen-containing polydentate ligands. We apologize for this oversight.The following reference citation should be included: Higashiyama, K.; Sasaki, S.; Kubo, H.; Yamauchi, T.; Ishii, A.; Kanai, M. Japanese Patent