Virtual screening and crystallographic studies reveal an unexpected γ-lactone derivative active against MptpB as a potential antitubercular agent.
Cazzaniga G, Mori M, Meneghetti F, Chiarelli LR, Stelitano G, Caligiuri I, Rizzolio F, Ciceri S, Poli G, Staver D, Ortore G, Tuccinardi T, Villa S.
Mycobacterial resistance is a rapidly increasing phenomenon requiring the identification of new drugs effective against multidrug-resistant pathogens. The inhibition of protein tyrosine phosphatase B (MptpB), which interferes with host immune responses, may provide a new strategy to fight tuberculosis (TB), while preventing cross-resistance issues. On this basis, starting from a virtual screening (VS) campaign and subsequent structure elucidation studies guided by X-ray analyses, an unexpected γ-lactone derivative (compound 1) with a significant enzymatic activity against MptpB was identified. The structural characterization of compound 1 was described by means of NMR spectroscopy, HRMS, single crystal X-ray diffraction and Hirshfeld surface analysis, allowing a detailed conformational investigation. Notably, the HPLC separation of (±)-1 led to the isolation of the most active isomer, which emerged as a very promising MptpB inhibitor, with an IC<sub>50</sub> value of 31.1 μM. Overall, the new chemotype described herein might serve as a basis for the development of novel treatments against TB infections.