Design and synthesis of non-hydroxamate lipophilic inhibitors of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR): in silico, in vitro and antibacterial studies

Abstract

1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway operating in several pathogens, including Mycobacterium and Plasmodium. Since a DXR homologue is not present in humans, it is an important antimicrobial target. Fosmidomycin (FSM) and its analogues inhibit DXR function by chelating the divalent metal (Mn²⁺ or Mg²⁺) in its active site via a hydroxamate metal binding group (MBG). The latter, however, enhances the polarity of molecules and is known to display metabolic instability and toxicity issues. While attempts have been made to increase the lipophilicity of FSM by substituting the linker chain and prodrug approach, very few efforts have been made to replace the hydroxamate group with other lipophilic MBGs. We report a systematic in silico and experimental investigation to identify novel MBGs for designing non-hydroxamate lipophilic DXR inhibitors. The SAR studies with selected MBG fragments identified novel inhibitors of E. Coli DXR with IC₅₀ values ranging from 0.29 to 106 μM. The promising inhibitors were also screened against ESKAPE pathogens and M. tuberculosis.