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Bioorg Med Chem. 2018 May 15;26(9):2640-2650. doi: 10.1016/j.bmc.2018.04.032. Epub 2018 Apr 17.

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.

Author information

1
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
2
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
3
Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 14203, United States.
4
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.

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.

KEYWORDS:

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

PMID:
29691153
PMCID:
PMC5967623
[Available on 2019-05-15]
DOI:
10.1016/j.bmc.2018.04.032

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