Antimalarial cation-dimers synthesized in two steps from an inexpensive starting material, isonicotinic acid.

ABSTRACT

Malaria is one of the three major serious infectious diseases in the world. As the area affected by malaria includes a large proportion of developing countries, there is a need for new antimalarials that can be synthesized and supplied inexpensively. To generate low-cost antimalarials, the MAP series 6-10, bis-cation dimers, synthesized by amidating the carboxyl group of isonicotinic acid (11) with various amines and by cationizing the nitrogen atoms of the pyridine ring with the corresponding alkyl bromides, were designed. This design enabled expansion of the structural variations of bis-cation-type antimalarial compounds. The compounds bearing alkyl or phenyl groups in the amide moieties showed remarkable antimalarial activities in vitro. Moreover, 1,1'-(1,12-dodecanediyl)bis[4-[(buthylamino)carbonyl]pyridinium bromide], MAP-412 (6 d), exhibited a potent antimalarial activity (ED(50)=8.2 mg kg(-1)). Being prepared at low cost, our bis-cation-type antimalarial compounds may be useful as lead compounds for inexpensive antimalarials.