STUDIES ON ANTIMALARIALS.Ⅺ.SYNTHESIS AND ANTIMALARIAL EFFECTS OF 4-METHYL-5-SUBSTITUTED PHENOXY PRIMAQUINE ANALOGUES

In searching for a safe and radically curative agent for malaria and a causal prophylactic, six 4-methyl-5-substituted phenoxy-6-methoxy-8-(1-methyl-4-aminobutylamino) quinolines (Ⅲ_1～6) were prepared.Compounds Ⅲ_1～6 were synthesized from 2-nitro-4-methoxy-5-bromo-acetanilide by condensation with potassium salts of substituted phenols, hydrolysis with dilute alcoholic hydrochloric acid to give the corresponding 2-nitro-4-methoxy-5-substituted phenoxy anilines (Ⅵ) which underwent Skraup reaction to provide the key intermediates 4-methyl-5-substituted phenoxy-6-methoxy-8-nitroquinolines (Ⅶ). In the usual manner Ⅶ were reduced with iron powder, condensed with N-(4-bromopentyI) phthalimide and hydrolyzed with hydrazine hydrate to yield the final products.All compounds, with the exception of Ⅲ₃, exhibited both stronger suppressive antimalarial activity against P berghei in mice and greater prophylactic activity against P yoelii in mice than primaquine. Among them, Ⅲ₁ was found to be the most potent in both tests. Results were expressed both in terms of SD₅₀ (0.65 mg/kg) and SD₉₀ (1.60 mg/kg) in blood schizonticidal test, and in terms of minimal effective dose (2.5 mg/kg)and minimal fully active dose (5 mg/kg) in causal prophylactic screening.