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There is currently no vaccine to protect against and only a handful of drugs are available to treat this disease. Leishmaniasis is curable, but its eradication and elimination are hindered by the emergence of multidrug resistant strains of the causative pathogens, accentuating the need for new and effective antileishmanial drugs. In search for such agents, nifuroxazide, a clinical antibiotic, was evaluated through investigation of its benzyl analogues for in vitro antileishmanial efficacy against promastigotes of various <jats:italic>Leishmania<\/jats:italic> (L.) strains. The monobenzylated analogues <jats:bold>1<\/jats:bold> and <jats:bold>2<\/jats:bold> were the most potent of all, possessing nanomolar activities up to 10\u2010fold higher than the parent drug nifuroxazide against all three tested <jats:italic>Leishmania<\/jats:italic> strains. 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