Antiprotozoal activities of symmetrical bishydroxamic acids

Symmetrical bishydroxamic acids along with their sodium salts containing an alkyl spacer between two aromatic rings were synthesized, and their antiparasitic activities were evaluated. Bishydroxamic acids were conveniently prepared from the alkylation of methyl 4-hydroxybenzoate with various dihalo-alkane, -alkene, and -ether followed by reaction with hydroxylamine. Surprisingly, the bishydroxamic acids and their sodium salts possess strong inhibitory activities against Plasmodium falciparum parasites with IC50 values in the range of 0.26-3.2 microM. Bishydroxamic acid 3 and its sodium salt 12 also inhibit the growth of Leishmania donovani, albeit at higher concentrations. The corresponding biscarboxylic acids and bismethyl esters are inactive. Presumably, the ability of bishydroxamic acids to complex with metallic iron in hemoglobin may be responsible for antimalarial activity of these compounds.