Identification of Inhibitors for Mycobacterial Protein Tyrosine Phosphatase B (MptpB) by Biology-Oriented Synthesis (BIOS)

Protein phosphatases have recently emerged as important targets for research in chemical biology and medicinal chemistry, and new classes of phosphatase inhibitors are in high demand. BIOS (biology‐oriented synthesis) employs the criteria of relevance to nature and biological prevalidation for the design and synthesis of compound collections. In an application of the BIOS principle, an efficient solid‐phase synthesis of highly substituted indolo[2,3‐a]quinolizidines by using a vinylogous Mannich–Michael reaction in combination with phosgene‐ or acid‐mediated ring closure was developed. Screening of this library for phosphatase inhibitors yielded a new inhibitor class for the Mycobacterium tuberculosis phosphatase MptpB. Inspired by nature: The first class of inhibitors for a mycobacterial phosphatase required for survival of the bacterium in the host is developed by means of biology‐oriented synthesis. The highly substituted indolo[2,3‐a]quinolizidines are produced by a combination of a vinylogous Mannich–Michael reaction and phosgene‐ or acid‐mediated ring closure.