title: Synthesis and in vitro trypanocidal activity of some novel iron chelating agents.
abstract: This report describes the syntheses and in vitro trypanocidal activity of a number of iron (III) chelators against epimastigotes of Trypanosoma cruzi. The compounds examined included a number of lipophilic N-alkyl derivatives of 2-ethyl- and 2-methyl-3-hydroxypyrid-4-ones, N,N'-bis(o-hydroxybenzyl)-(+/-)-trans-1,2-diaminocyclohexane, cyclotetrachromotropylene and four commercially available carboxy derivatives of pyridine, pyrazine, and pyarazole. Benznidazole, the drug clinically used in the treatment of Chagas' disease in humans, served as standard. All compounds were screened in vitro against Trypanosoma cruzi epimastigotes at 50 and 100 micrograms/ml for 72 h of exposure. At 100 micrograms/ml dosage, at least 4 compounds exhibited high epimastigote growth inhibition (65-69%) comparable to benznidazole (72%), whereas 9 compounds showed moderate to fair activity (53-64%) in the in vitro assay. At the lower concentration (50 micrograms/ml), the inhibitory activity of the best of these compounds was reduced significantly (39-48%) compared to the standard drug (59%). The activity of all the carboxylic acids remained in the lower range (4-25%). It is hypothesized that the enhanced activity of some of the compounds is due to their increased lipophilicity which enables them to successfully pass through the cellular membrane of Trypanosoma cruzi epimastigotes. The trypanocidal activities of the most effective compounds were significantly reduced when tested in the presence of added ferric ion.
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Singh
authors.forename: M M
authors.initials: MM
authors.lastname: Jones
authors.forename: J E
authors.initials: JE
authors.lastname: Lane
authors.forename: A
authors.initials: A
authors.lastname: Nesset
authors.forename: L J
authors.initials: LJ
authors.lastname: Zimmerman
authors.forename: R
authors.initials: R
authors.lastname: Ribeiro-Rodrigues
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.forename: M R
authors.initials: MR
authors.lastname: Stenger
authors.forename: C E
authors.initials: CE
authors.lastname: Carter
mesh_terms: D000818:Animals; D007501:Iron / Q000737:chemistry; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development
chemical_list: D007502:Iron Chelating Agents; D014344:Trypanocidal Agents; D007501:Iron