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 IC50 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.

Virtual screening and crystallographic studies reveal an unexpected γ-lactone derivative active against MptpB as a potential antitubercular agent / G. Cazzaniga, M. Mori, F. Meneghetti, L.R. Chiarelli, G. Stelitano, I. Caligiuri, F. Rizzolio, S. Ciceri, G. Poli, D. Staver, G. Ortore, T. Tuccinardi, S. Villa. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 234:(2022 Apr 15), pp. 114235.1-114235.13. [10.1016/j.ejmech.2022.114235]

Virtual screening and crystallographic studies reveal an unexpected γ-lactone derivative active against MptpB as a potential antitubercular agent

G. Cazzaniga
Primo
;
M. Mori
Secondo
;
F. Meneghetti;S. Ciceri;S. Villa
Ultimo
2022-04-15

Abstract

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 IC50 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.
Mycobacterium tuberculosis; LMW-Phosphatases; Immune escape mechanisms; Tuberculosis; Molecular modeling; SC-XRD;
Settore CHIM/08 - Chimica Farmaceutica
5-mar-2022
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/915811
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