A dual-target approach in anti-tuberculosis therapy: new MptpB/MbtI inhibitors

Tuberculosis (TB) is an ancient disease and, despite the global effort to reduce the incidence of the pathology and related deaths, it’s the world's top killer among infectious diseases.1 TB is caused by Mycobacterium tuberculosis (Mtb) and spreads through respiratory droplets produced by infected individuals.2 As shown in the last WHO Global TB Report, 7 million people were diagnosed and treated for TB and 1.5 million people died from TB in 2018.1 New and more effective anti-TB drugs acting on novel targets are needed to shorten treatment time, and to contrast drug resistance and progressive loss of antibiotic efficacy. An innovative strategy consists in the development of selective multi-target drugs: Mtb protein tyrosine phosphatases (PTPs), MptpB, and salicylate synthase, MbtI, were found to be promising targets for the development of innovative antitubercular agents. MptpB dephosphorylates phosphoserine/threonine, phosphotyrosine, and phosphoinositide substrates, playing a key role in the survival of the bacilli during the infection. It can attenuate the immune response of the host by interfering with cellular signal transduction pathways, activated by IFN-γ. Moreover, it inhibits macrophage apoptosis, by activating Akt and blocking caspase 3 activity, and depletes PI3P, arresting the maturation of the vacuoles.3 MbtI is a magnesium-dependent salicylate synthase, which catalyses the first step of the synthesis of siderophores, iron-chelating molecules that bind iron and internalize it into the cell. Since iron is essential for the survival of the bacilli during the infection, the inhibition of siderophores synthesis is an important target for innovative antitubercular agents.4 On these bases, the aim of this study was the design, synthesis, characterization, and biological evaluation of innovative MptpB/MbtI inhibitors. With this purpose, we selected the most potent 5-phenylfuran-2-carboxylic acid derivatives of our in-house library of MbtI inhibitors and tested them against MptpB. These studies indicated 5-(2-hydroxy-4-nitrophenyl)furan-2-carboxylic acid as a promising dual-target inhibitor. Therefore, we focused our attention on the exploration of the chemical space around this compound: we investigated the effect of a variety of different substituents in the ortho position, maintaining the NO2 group in the para position to ensure the activity on MbtI. Among the tested compounds, the derivatives characterized by the presence, in ortho position, of a NH2 and a Br substituent, respectively, exhibited a promising dual-target inhibitory activity.