2. Academic Validation
  3. Novel Pyrazole-Containing Compounds Active against Mycobacterium tuberculosis

Novel Pyrazole-Containing Compounds Active against Mycobacterium tuberculosis

  • ACS Med Chem Lett. 2019 Sep 18;10(10):1423-1429. doi: 10.1021/acsmedchemlett.9b00204.
Giovanna Poce 1,  Sara Consalvi 1,  Giulia Venditti 1,  Salvatore Alfonso 2,  Nicoletta Desideri 1,  Raquel Fernandez-Menendez 2,  Robert H Bates 2,  Lluis Ballell 2,  David Barros Aguirre 2,  Joaquin Rullas 2,  Alessandro De Logu 3,  Michelle Gardner 4,  Thomas R Ioerger 5,  Eric J Rubin 4,  Mariangela Biava 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy.
  • 2 Diseases of the Developing World, GlaxoSmithKline, Calle Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • 3 Department of Life and Environmental Sciences, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
  • 4 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, Massachusetts 02115, United States.
  • 5 Department of Computer Science, Texas A&M University, 3112 TAMU, College Station, Texas 77843, United States.
PMID: 31620228 DOI: 10.1021/acsmedchemlett.9b00204
Abstract

In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against Mycobacterium tuberculosis. Among them, only the 1,3,5-trisubstituted pyrazoles 5-49 exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile without cytotoxic effects. Three pyrazoles were subjected to an animal tuberculosis efficacy model, and compound 6 induced a statistically significant difference in lung Bacterial counts compared with untreated mice. Moreover, to determine the target of this series, resistors were generated, and whole genome Sequencing revealed mutations in the mmpL3 gene.

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