Two series of compounds were designed to mimic the transition state and high-energy intermediates (HEI) of the enzymatic reaction of 6-phosphogluconate dehydrogenase (6PGDH). Sulfoxide analogues (7-11) were designed to mimic the transition state during the oxidation of the substrate to 3-keto-6-phosphogluconate, an enzyme-bound intermediate of the enzyme. Hydroxamate and amide derivatives of d-erythronic acid were designed to mimic the 1,2-cis-enediol HEI of the 6PGDH reaction. These two series of compounds were assayed as competitive inhibitors of the Trypanosoma brucei and sheep liver enzymes, and their selectivity value (ratio sheep/parasite) was calculated. The sulfoxide transition-state analogues showed weak and selective inhibition of the T. brucei enzyme. The hydroxamic derivatives showed potent and selective inhibition of the T. brucei 6PGDH with a Ki in the nanomolar range.

Incubation of Leishmania tarentolae promastigotes in 1.0 microgram/ml Berenil for 96 hr resulted in approximately 33% inhibition of cell growth and approximately 42.5% dyskinetoplasty in the cell population. The buoyant density of kinetoplast DNA (kDNA), p = 1.703 g/ml, remained unchanged after 96-hr exposure to the drug. Endogenous respiration as well as proline- and glucose-induced respiration dropped markedly after 36-hr exposure to Berenil. This drop occurred approximately 12 hr before the onset of dyskinetoplasty, a result which suggests that this drug adversely affects mitochondrial respiratory activity of the promastigotes.

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The compounds show significant cytotoxicity against human tumor cell lines and weak activity against the pathogens of tropical diseases.