Discovery, synthesis and evaluation of a novel ketol-acid reductoisomerase inhibitor.

Discovery, synthesis and evaluation of a novel ketol-acid reductoisomerase inhibitor. Chemistry. 2020 Mar 21;: Authors: Bayaraa T, Kurz JL, Patel KM, Hussein WM, Bilyj JK, West NP, Schenk G, McGeary RP, Guddat LW Abstract Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway, is a potential drug target for bacterial infections including Mycobacterium tuberculosis . Here, we have screened the Medicines for Malaria Venture Pathogen Box against purified M. tuberculosis ( Mt ) KARI and identified two compounds that have K i values below 200 nM. In Mt cell susceptibility assays one of these compounds exhibited an IC 50 value of 0.8 μM. Co-crystallization of this compound, 3-((methylsulfonyl)methyl)-2 H -benzo[ b ][1,4]oxazin-2-one (MMV553002), in complex with Staphylococcus aureus KARI, which has 56% identity with Mt KARI, NADPH and Mg 2+ yielded a structure to 1.72 Å resolution. However, only a hydrolyzed product of the inhibitor ( i.e. 3-(methylsulfonyl)-2-oxopropanic acid, missing the 2-aminophenol attachment) is observed in the active site. Surprisingly, Mt cell susceptibility assays showed that the 2-aminophenol product is largely responsible for the anti-TB activity of the parent compound. Thus, we have identified 3-(methylsulfonyl)-2-oxopropanic acid is a potent KARI inhibitor that could be further explored as a potential biocidal agent and we have shown 2-aminophenol, as an a...
Source: Chemistry - Category: Chemistry Authors: Tags: Chemistry Source Type: research