SYNTHESIS OF PYRONARIDINE RELATED COMPOUNDS AND COMPARISON OF ANTIMALARIAL ACTIVITIES

The paper reports the synthesis of pyronaridine(Ⅰ) related compounds Ⅱ～Ⅴ for exploring whether the antimalarial activity of pyronaridine is by virtue of a nitrogen atom at position 1 in the ring and a pair of pyrrolidinyl Mannich base side chains in its structure. The condensation of 2-methoxy-6, 9-dichloroacridine or 4, 7-dichloro-1, 5-naphthyridine with 4-hydroxy-3, 5-bis-(pyrrolidinyl-1′-methyl) aniline yielded the related compound Ⅱ, 1-deazapyronaridine, or Ⅴ, 5-azabispyroquine, respectively. 2-Methoxy-7, 10-dichlorobenzo (b) 1, 5-naphthyridine or 4, 7-dichloro-1, 5-naphthyridine was condensed with 4-diethylamino-1-methylbutylamine to obtain the related compound Ⅲ, azacrin, or Ⅳ, 5-azachloroquine, respectively. The results of in vivo tests against Plasmodium berghei chloroquine-resistant ANKA strain, drug—sensitive P. berghei N line and drug-resistant P. yoelii nigeriensis line showed that all the related compounds Ⅱ～Ⅴ were less effective than pyronaridine(Ⅰ). It suggests that the nitrogen atom at position 1 and pyrrolidinyl Mannich base side chains on the structure of pyronaridine play an important and indispensable role for antimalarial activity of pyronaridine. The pyrrolidinyl Mannieh bases impart increased activity to the corresponding compounds.