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Fragment-Based Design of Symmetrical Bis-benzimidazoles as Selective Inhibitors of the Trimethoprim-Resistant, Type II R67 Dihydrofolate Reductase
The continuously increasing use of trimethoprim as a
common antibiotic
for medical use and for prophylactic application in terrestrial and
aquatic animal farming has increased its prevalence in the environment.
This has been accompanied by increased drug resistance, generally
in the form of alterations in the drug target, dihydrofolate reductase
(DHFR). The most highly resistant variants of DHFR are known as type
II DHFR, among which R67 DHFR is the most broadly studied variant.
We report the first attempt at designing specific inhibitors to this
emerging drug target by fragment-based design. The detection of inhibition
in R67 DHFR was accompanied by parallel monitoring of the human DHFR,
as an assessment of compound selectivity. By those means, small aromatic
molecules of 150–250 g/mol (fragments) inhibiting R67 DHFR
selectively in the low millimolar range were identified. More complex,
symmetrical bis-benzimidazoles and a bis-carboxyphenyl were then assayed
as fragment-based leads, which procured selective inhibition of the
target in the low micromolar range (<i>K</i><sub>i</sub> = 2–4 μM). The putative mode of inhibition is discussed
according to molecular modeling supported by in vitro tests