Development of Enantioselective Agents and Heme-Targeted Antimalarials
Iwaniuk, Daniel Patrick
Several chiral 3,5-dinitrobenzoyl-derived amides were prepared and applied in enantioselective NMR analysis of protected amines. It was found that (R)-N-(1-(naphthalen-1-yl)ethyl)-3,5-dinitrobenzamide is a very effective chiral solvating agent (CSA) that gives diastereomeric complexes exhibiting sharp and well resolved NMR signals with a wide range of substrates. Crystallographic analysis showed that this CSA forms a chiral cleft that can selectively bind one enantiomer of a substrate through simultaneous hydrogen bonding, π–π stacking, and CH/π interactions. The enantioselective complex formation results in strong upfield shifts in the proton NMR spectrum even in the presence of only 5 mol % of the CSA.Five stereodynamic ICD probes based on a &ldquofrictionless&rdquo arylacetylene framework and terminal aldehyde units, such as 1,4-bis(2(2-formylphenylethynyl)phenylethynyl)benzene, were prepared through a series of Sonogashira cross-coupling reactions. The CD silent sensors generate a strong chiroptical response to substrate-controlled induction of axial chirality upon selective [1+1]-, [2+2]-, and [1+2]-condensation with amines. The chiral amplification results in intense Cotton effects that can be exploited for in situ ICD analysis of the absolute configuration and ee of a wide range of amines.The continuous need for antimalarials that overcome resistance of Plasmodium falciparum to current antimalarial drugs, in particular chloroquine, has been addressed. Forty-two novel heme-targeted antimalarial drug candidates were prepared by systematic variations of the side chain length, basicity, branching and heteroatom substitution at the 4-position in the quinoline backbone. The basic chloroquine side chain and quinolyl N are known to facilitate the accumulation of the drug in the acidic digestive vacuole of the malaria parasite. Many of the compounds tested showed excellent potency against chloroquine sensitive and resistant strains which established several important structure activity relationships.
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