Malaria causal prophylactic activity of imidazolidinedione derivatives

Jian Guan, Xihong Wang, Kirsten Smith, Arba Ager, Montip Gettayacamin, Dennis E. Kyle, Wilbur K. Milhous, Michael P. Kozar, Alan J. Magill, Ai J. Lin

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

A series of acid-stable carboxamide derivatives of 2- guanidinoimidazolidinedione (5a-c and 6a-c) were prepared as potential malaria prophylactic and radical cure agents. The new compounds showed moderate to good causal prophylactic activity in mice infected with Plasmodium yoelii sporozoites. Three compounds were further tested for causal prophylactic activity in Rhesus monkeys infected with Plasmodium cynomolgi sporozoites, and all showed a delay in patency from 13 to 40 days at 30 mg/kg/day x 3 days by IM dosing. Two out of four compounds tested for radical curative activity in Rhesus showed cure at 30 mg/kg/day x 3 days. The other two compounds showed delay in relapse from 16 to 68 days. Conversion of new carboxamides (5 and 6) to s-triazine derivatives (7) was demonstrated in mouse and human microsomal preparations and in rat plasma. The results suggest the metabolites, s-triazine derivatives 7, may be the active species of the new carboxamides 5a-c and 6a-c prepared in this study.

Original languageEnglish (US)
Pages (from-to)6226-6231
Number of pages6
JournalJournal of Medicinal Chemistry
Volume50
Issue number24
DOIs
StatePublished - Nov 29 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Guan, J., Wang, X., Smith, K., Ager, A., Gettayacamin, M., Kyle, D. E., Milhous, W. K., Kozar, M. P., Magill, A. J., & Lin, A. J. (2007). Malaria causal prophylactic activity of imidazolidinedione derivatives. Journal of Medicinal Chemistry, 50(24), 6226-6231. https://doi.org/10.1021/jm7009815