Synthesis of Novel 2-Alkoxy-3-amino-3-arylpropan-1-ols and 5-Alkoxy-4-aryl-1,3-oxazinanes with Antimalarial Activity

A variety of novel syn-2-alkoxy-3-amino-3-arylpropan-1-ols was prepared through LiAlH₄-promoted reductive ring-opening of cis-3-alkoxy-4-aryl-β-lactams in Et₂O. The latter γ-aminoalcohols were easily converted into cis-5-alkoxy-4-aryl-1,3-oxazinanes using formaldehyde in THF. Both series of compounds were evaluated against a chloroquine sensitive strain of Plasmodium falciparum (D10), revealing micromolar potency for almost all representatives. Eleven compounds exhibited antimalarial activity with IC₅₀ values of ≤30 μM, and the majority of these compounds did not show cytotoxicity at the concentrations tested.