Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents

Khushbu Shah, Xin Lin, Sherry F. Queener, Vivian Cody, Jim Pace, Aleem Gangjee

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines. The best analogs displayed better potency (IC50) than PTX and high selectivity for pjDHFR versus hDHFR, with 4 exhibiting a selectivity for pjDHFR of 24-fold.

Original languageEnglish (US)
Pages (from-to)2640-2650
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number9
DOIs
StatePublished - May 15 2018

Keywords

  • DHFR inhibitors
  • Opportunistic infections
  • Pneumocystis pneumonia
  • Pyrrolo[2,3-d]pyrimidines
  • hDHFR
  • pjDHFR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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