Structure-Activity Relationships of Pyrazolo[1,5-a]pyrimidin-7(4H)-ones as Antitubercular Agents

Sangmi Oh, M. Daben J. Libardo, Shaik Azeeza, Gary T. Pauly, Jose Santinni O. Roma, Andaleeb Sajid, Yoshitaka Tateishi, Caroline Duncombe, Michael Goodwin, Thomas R. Ioerger, Paul G. Wyatt, Peter C. Ray, David W. Gray, Helena I. M. Boshoff, Clifton E. Barry (Lead / Corresponding author)

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Pyrazolo[1,5-a]pyrimidin-7(4H)-one was identified through high-throughput whole-cell screening as a potential antituberculosis lead. The core of this scaffold has been identified several times previously and has been associated with various modes of action against Mycobacterium tuberculosis (Mtb). We explored this scaffold through the synthesis of a focused library of analogues and identified key features of the pharmacophore while achieving substantial improvements in antitubercular activity. Our best hits had low cytotoxicity and showed promising activity against Mtb within macrophages. The mechanism of action of these compounds was not related to cell-wall biosynthesis, isoprene biosynthesis, or iron uptake as has been found for other compounds sharing this core structure. Resistance to these compounds was conferred by mutation of a flavin adenine dinucleotide (FAD)-dependent hydroxylase (Rv1751) that promoted compound catabolism by hydroxylation from molecular oxygen. Our results highlight the risks of chemical clustering without establishing mechanistic similarity of chemically related growth inhibitors.

Original languageEnglish
Number of pages14
JournalACS Infectious Diseases
Early online date6 Jan 2021
Publication statusE-pub ahead of print - 6 Jan 2021


  • pyrazolo[1,5-a]pyrimidin-7(4H)-one
  • structure−activity relationship
  • tuberculosis
  • antitubercular activity
  • pyrazolo[1,5- A[pyrimidin-7(4 H)-one
  • structure-activity relationship

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