SAR of 4-Alkoxybenzoic Acid Inhibitors of the Trypanosome Alternative Oxidase.

The SAR of 4-hydroxybenzaldehyde inhibitors of the trypanosome alternative oxidase (TAO), a critical enzyme for the respiration of bloodstream forms of trypanosomes, was investigated. Replacing the aldehyde group with a methyl ester resulted in a 10-fold increase in TAO inhibition and activity against . Remarkably, two analogues containing the 2-hydroxy-6-methyl scaffold ( and ) displayed single digit nanomolar TAO inhibition, which constitute the most potent 4-alkoxybenzoic acid derivatives described to date.