jm401204g_si_002.pdf (21.23 MB)
Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7‑(Benzimidazol-1-yl)-2,4-diaminoquinazolines
journal contribution
posted on 2014-02-13, 00:00 authored by Thanh Lam, Mark T. Hilgers, Mark L. Cunningham, Bryan
P. Kwan, Kirk J. Nelson, Vickie Brown-Driver, Voon Ong, Michael Trzoss, Grayson Hough, Karen Joy Shaw, John FinnA new
series of dihydrofolate reductase (DHFR) inhibitors, the
7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized
for antibacterial potency and enzyme selectivity. The most potent
inhibitors in this series contained a five-membered heterocycle at
the 2-position of the benzimidazole, leading to highly potent and
selective compounds that exploit the differences in the size of a
binding pocket adjacent to the NADPH cofactor between the bacterial
and human DHFR enzymes. Typical of these compounds is 7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4
diaminoquinazoline, which is a potent inhibitor of S. aureus DHFR (Ki = 0.002 nM) with 46700-fold
selectivity over human DHFR. This compound also has high antibacterial
potency on Gram-positive bacteria with an MIC versus wild type S. aureus of 0.0125 μg/mL and a MIC versus trimethoprim-resistant S. aureus of 0.25 μg/mL. In vivo efficacy versus a S. aureus septicemia was demonstrated, highlighting the
potential of this new series.