title: p-Alkyloxybenzhydroxamic acids, effective inhibitors of the trypanosome glycerol-3-phosphate oxidase.
abstract: Energy production in bloodstream forms of African trypanosomes of the genus Trypanosoma involves two pathways unique to the parasite and which can be blocked by a combination of salicylhydroxamic acid (SHAM) and glycerol. Although this leads to rapid parasite destruction both in vitro and in vivo, the toxicity of SHAM precludes practical use of SHAM/glycerol as a therapeutic regimen. Based on our hypothesis that SHAM operates by interfering with ubiquinone, we attempted to develop this approach by synthesizing and screening a series of hydroxamic acids which more closely resemble ubiquinone: the p-n-alkyloxybenzhydroxamic acids. We also examined a variety of mono-, di- and trisubstituted benzhydroxamic acids together with a selected group of secondary heterocyclic hydroxamic acids. We found an increase in activity of the p-n-alkyloxy compounds with increasing chain length up to 12 carbon atoms with longer chains offering little advantage. The most active compound, p-n-tetradecyloxybenzhydroxamic acid, had an apparent Ki of 0.43 microM indicating a specific activity 70 times greater than SHAM. Although this represents a vast improvement, the low water solubility of these compounds reduces their bioavailability to the point where they are not practical substitutes for SHAM. Consequently, improvement in the SHAM/glycerol approach to chemotherapy appears to lie with improving solubility by altering lipophilicity of the alkyl side chain.
mesh_terms: D000818:Animals; D005990:Glycerol / Q000494:pharmacology; D005993:Glycerolphosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D012457:Salicylamides / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; D012457:Salicylamides; D014451:Ubiquinone; C005703:salicylhydroxamic acid; D005993:Glycerolphosphate Dehydrogenase; C036140:L-alpha-glycerol-phosphate oxidase; D005990:Glycerol