2. Academic Validation
  3. Advancing the antituberculosis activity of nitropicolinic acids and amides

Advancing the antituberculosis activity of nitropicolinic acids and amides

  • Eur J Med Chem. 2026 Jan 15;302(Pt 2):118324. doi: 10.1016/j.ejmech.2025.118324.
Andrew M Thompson 1,  Chen-Yi Cheung 2,  Matthew B McNeil 3,  Ashley C Campbell 4,  Monika Záhorszká 5,  Jana Korduláková 5,  Giovanni Stelitano 6,  Deborah Recchia 6,  Maria Rosalia Pasca 6,  Baojie Wan 7,  Shahebraj Khan 7,  Dejan S Nikolic 7,  Gauri S Shetye 7,  Scott G Franzblau 7,  William A Denny 8,  Gregory M Cook 3,  Kurt L Krause 4
Affiliations

Affiliations

  • 1 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. Electronic address: [email protected].
  • 2 Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, 9054, New Zealand.
  • 3 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, 9054, New Zealand.
  • 4 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand; Department of Biochemistry, University of Otago, Dunedin, 9054, New Zealand.
  • 5 Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15, Bratislava, Slovakia.
  • 6 Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.
  • 7 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612, United States.
  • 8 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
PMID: 41202651 DOI: 10.1016/j.ejmech.2025.118324
Abstract

Ambitious milestones set by the World Health Organisation (WHO) to end the tuberculosis epidemic by 2030 currently appear out of reach, and there remains an urgent need to develop more effective novel therapies. While exploring dipicolinic acid derivatives as putative glutamate racemase inhibitors, we recently discovered 6-nitropicolinamides as promising antituberculosis agents. SAR studies on the non-cytotoxic N-[4-(trifluoromethoxy)benzyl] hit 20 (MIC90 1.4 μM) confirmed the importance of the 6-nitro group and amide NH; side chain extension enhanced potency but reduced aqueous solubility, and some analogues were rapidly metabolised. The best new candidate (77: MIC90 0.30 μM) was well tolerated in mice and provided an adequate pharmacokinetic profile, although a time-kill assay indicated largely bacteriostatic activity. An analysis of its effects on cell wall lipids and mycolic acids revealed changes consistent with inhibiting arabinogalactan biosynthesis, and further testing against mutant or overexpressing mycobacterial strains identified the enzyme target as decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1).

Keywords

DprE1 inhibitor; Drug discovery; Nitropyridine; Pharmacokinetics; Pyridine carboxamide; Time-kill assay; Tuberculosis.

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