Synthesis and biological evaluation of biguanide and dihydrotriazine derivatives as potential inhibitors of dihydrofolate reductase of opportunistic microorganisms

Seema Bag, Nilesh R. Tawari, Sherry F. Queener, Mariam S. Degani

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Twenty-one biguanide and dihydrotriazine derivatives were synthesized and evaluated as inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms: Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma), and rat liver (rl). The most potent compound in the series was B2-07 with 12nM activity against tgDHFR. The most striking observation was that B2-07 showed similar potency to trimetrexate, ∼233-fold improved potency over trimethoprim and ∼7-fold increased selectivity as compared to trimetrexate against tgDHFR. Molecular docking studies in the developed homology model of tgDHFR rationalized the observed potency of B2-07. This molecule can act as a good lead for further design of molecules with better selectivity and improved potency.

Original languageEnglish (US)
Pages (from-to)331-339
Number of pages9
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume25
Issue number3
DOIs
StatePublished - Apr 30 2010

Keywords

  • Biguanide
  • Dihydrofolate reductase
  • Dihydrotriazine

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

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