2. Academic Validation
  3. Dual Inhibition of Mycobacterium tuberculosis and the Host TGFBR1 by an Anilinoquinazoline

Dual Inhibition of Mycobacterium tuberculosis and the Host TGFBR1 by an Anilinoquinazoline

  • J Med Chem. 2023 Nov 9;66(21):14724-14734. doi: 10.1021/acs.jmedchem.3c01273.
Meganathan Nandakumar 1,  Anja Ollodart 2,  Neil Fleck 2,  Nirav R Kapadia 1,  Andrew Frando 2,  Vishant Boradia 2,  Jeffery L Smith 1,  Junxi Chen 2,  William J Zuercher 1,  Timothy M Willson 1,  Christoph Grundner 2 3 4
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2 Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, United States.
  • 3 Department of Pediatrics, University of Washington, Seattle, Washington 98195, United States.
  • 4 Department of Global Health, University of Washington, Seattle, Washington 98105, United States.
PMID: 37871287 DOI: 10.1021/acs.jmedchem.3c01273
Abstract

Tuberculosis (TB) control is complicated by the emergence of drug resistance. Promising strategies to prevent drug resistance are the targeting of nonreplicating, drug-tolerant Bacterial populations and targeting of the host, but inhibitors and targets for either are still rare. In a cell-based screen of ATP-competitive inhibitors, we identified compounds with in vitro activity against replicating Mycobacterium tuberculosis (Mtb), and an anilinoquinazoline (AQA) that also had potent activity against nonreplicating and persistent Mtb. AQA was originally developed to inhibit human transforming growth factor receptor 1 (TGFBR1), a host kinase that is predicted to have host-adverse effects during Mtb Infection. The structure-activity relationship of this dually active compound identified the pyridyl-6-methyl group as being required for potent Mtb inhibition but a liability for P450 metabolism. Pyrrolopyrimidine (43) emerged as the optimal compound that balanced micromolar inhibition of nonreplicating Mtb and TGFBR1 while also demonstrating improved metabolic stability and pharmacokinetic profiles.

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