Non-hydroxamate inhibitors of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR): A critical review and future perspective.

1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) catalyzes the second step of the non-mevalonate (or MEP) pathway that functions in several organisms and plants for the synthesis of isoprenoids. DXR is essential for the survival of multiple pathogenic bacteria/parasites, including those that cause tuberculosis and malaria in humans. DXR function is inhibited by fosmidomycin (1), a natural product, which forms a chelate with the active site divalent metal (Mg/Mn) through its hydroxamate metal-binding group (MBG). Most of the potent DXR inhibitors are structurally similar to 1 and retain hydroxamate despite the unfavourable pharmacokinetic and toxicity profile of the latter. We provide our perspective on the lack of non-hydroxamate DXR inhibitors. We also highlight the fundamental flaws in the design of MBG in these molecules, primarily responsible for their failure to inhibit DXR. We also suggest that for designing next-generation non-hydroxamate DXR inhibitors, approaches followed for other metalloenzymes targets may be exploited.