Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors

Fragment‐based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38–90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5–125 μg/mL. These fragment scaffolds would be useful for anti‐tubercular drug design. A fragment‐based drug design paradigm consisting of design, synthesis, and biological screening was applied in the discovery of a series of Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors, to obtain active low‐molecular‐weight fragments as potential hits. These fragments exhibited IC50 values in the range of 38–90 µM versus Mtb DHFR and MIC values in the range of 31.5–125 µg/mL in the whole‐cell Resazurin microtiter assay.