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

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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

Fingerprint

Trimetrexate
Biguanides
Folic Acid Antagonists
Pneumocystis carinii
Mycobacterium avium
Trimethoprim
Toxoplasma
Observation
Liver

Keywords

  • Biguanide
  • Dihydrofolate reductase
  • Dihydrotriazine

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

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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.",
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T1 - Synthesis and biological evaluation of biguanide and dihydrotriazine derivatives as potential inhibitors of dihydrofolate reductase of opportunistic microorganisms

AU - Bag, Seema

AU - Tawari, Nilesh R.

AU - Queener, Sherry

AU - Degani, Mariam S.

PY - 2010

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