Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ‑Butyrobetaine Hydroxylase

γ-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to l-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)­propanoate (mildronate), which is an approved, clinically used cardioprotective drug, is a relatively poor BBOX inhibitor and requires high daily doses. In this paper we describe the design, synthesis, and properties of 51 compounds, which include both GBB and mildronate analogues. We have discovered novel BBOX inhibitors with improved IC₅₀ values; the best examples are in the nanomolar range and about 2 orders of magnitude better when compared to mildronate. For six inhibitors, crystal structures in complex with BBOX have been solved to explain their activities and pave the way for further inhibitor design

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<i>N</i>-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of <i>E. coli</i> leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure–activity relationship analysis. Enzymatic assays revealed that <i>N</i>-leucinyl benzenesulfonamides display remarkable selectivity for <i>E. coli</i> leucyl-tRNA synthetase compared to <i>S. aureus</i> and human orthologues. The simplest analogue of the series, <i>N</i>-leucinyl benzenesulfonamide (R = H), showed the highest affinity against <i>E. coli</i> leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, <i>E. coli</i> ATCC 25922), which renders it as a promising template for antibacterial drug discovery