Naturally occurring Diels-Alder-type adducts from Morus nigra as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B

• Published in: European journal of medicinal chemistry 2018-01, Vol.144, p.277-288
• Main Authors: Mascarello, Alessandra, Orbem Menegatti, Angela Camila, Calcaterra, Andrea, Martins, Priscila Graziela Alves, Chiaradia-Delatorre, Louise Domeneghini, D'Acquarica, Ilaria, Ferrari, Franco, Pau, Valentina, Sanna, Adriana, De Logu, Alessandro, Botta, Maurizio, Botta, Bruno, Terenzi, Hernán, Mori, Mattia
• Format: Article
• Language: English
• Subjects: Diels-Alder-type adducts; Kuwanones; Natural products; PtpB inhibitors; Tuberculosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.11.087

Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatases A and B (PtpA and PtpB) have been recognized as potential molecular targets for the development of new therapeutic strategies against tuberculosis (TB). In this context, we have recently reported that the naturally occurring Diels-Alder-type adduct Kuwanol E is an inhibitor of PtpB (Ki = 1.6 ± 0.1 μM). Here, we describe additional Diels-Alder-type adducts isolated from Morus nigra roots bark that inhibit PtpB at sub-micromolar concentrations. The two most potent compounds, namely Kuwanon G and Kuwanon H, showed Ki values of 0.39 ± 0.27 and 0.20 ± 0.01 μM, respectively, and interacted with the active site of the enzyme as suggested by kinetics and mass spectrometry studies. Molecular docking coupled with intrinsic fluorescence analysis and isothermal titration calorimetry (ITC) further characterized the interaction of these promising PtpB inhibitors. Notably, in an Mtb survival assay inside macrophages, Kuwanon G showed inhibition of Mtb growth by 61.3%. All these results point to the common Diels-Alder-type adduct scaffold, and highlight its relevance for the development of PtpB inhibitors as candidate therapeutics for TB. [Display omitted] •Novel PtpB inhibitors extracted from Morus nigra are described.•PtpB binding is characterized by multiple biochemical and spectroscopic tools.•Anti-tubercular activity was evaluated on lead candidates.•Two compounds emerged as sub-micromolar PtpB inhibitors, one active in macrophages.