Title

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

DOI

10.1016/j.bmc.2018.04.032

Document Type

Journal Article

Publication Date

5-15-2018

Publication Title

Bioorganic and Medicinal Chemistry

Volume

26

Issue

9

First Page

2640

Last Page

2650

ISSN

9680896

Keywords

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

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.

Open Access

Green Accepted

Share

COinS