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  3. Novel pyrimidine derivatives as promising antimycobacterial agents

Novel pyrimidine derivatives as promising antimycobacterial agents

  • Eur J Med Chem. 2025 Dec 18:304:118498. doi: 10.1016/j.ejmech.2025.118498.
Martin Kufa 1,  Vladimir Finger 1,  Ondrej Kovar 1,  Lukas Prchal 2,  Lubica Muckova 3,  Martin Novak 2,  Michaela Hympanova 2,  Jiri Janousek 2,  Marketa Benkova 2,  Jiri Kunes 4,  Jan Bartacek 5,  Ondrej Soukup 3,  Oto Pavlis 6,  Jana Zdarova-Karasova 3,  Jitka Odvarkova 3,  Karin Savkova 7,  Jana Kordulakova 7,  Jaroslav Roh 8,  Jan Korabecny 9
Affiliations

Affiliations

  • 1 Faculty of Pharmacy in Hradec Kralové, Charles University, Akademika Heyrovskeho 1203, 500 03, Hradec Kralove, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 2 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 3 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
  • 4 Faculty of Pharmacy in Hradec Kralové, Charles University, Akademika Heyrovskeho 1203, 500 03, Hradec Kralove, Czech Republic.
  • 5 Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10, Pardubice, Czech Republic.
  • 6 Biological Defense Department, Military Health Institute, 561 66, Techonin, Czech Republic.
  • 7 Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava, Ilkovicova 6, Mlynska dolina, 842 15, Bratislava, Slovakia.
  • 8 Faculty of Pharmacy in Hradec Kralové, Charles University, Akademika Heyrovskeho 1203, 500 03, Hradec Kralove, Czech Republic. Electronic address: [email protected].
  • 9 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic. Electronic address: [email protected].
PMID: 41443083 DOI: 10.1016/j.ejmech.2025.118498
Abstract

Tuberculosis (TB) remains a major global health challenge, particularly due to the rise of multidrug-resistance and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains. In addition to Mtb, many non-tuberculous mycobacterial (NTM) strains are associated with opportunistic infections in Animals and humans. In this study, we report the design, synthesis, and evaluation of novel pyrimidine derivatives as potential antimycobacterial agents. A systematic structure-activity relationship study was conducted, leading to the identification of several promising compounds. Among them, derivative 55a demonstrated the highest efficacy, exhibiting minimum inhibitory concentration (MIC99) of 8 μM against drug-susceptible Mtb, while retaining significant potency against multidrug-resistant and extensively drug-resistant clinical isolates. Additionally, compound 55a displayed excellent metabolic stability, with a half-life of 187 min and an intrinsic clearance rate of 7.41 μL/min/mg protein in human liver microsomes. Several compounds also revealed promising efficacy against M. kansasii as a representative from NTM strains. The most promising antimycobacterial agents showed no activity against Gram-positive or Gram-negative Bacterial strains, indicating their selectivity towards mycobacteria. These finding highlight 55a as a promising structural motif for further optimization in the development of novel anti-TB therapeutics.

Keywords

Metabolic stability; Mycobacterium tuberculosis; Pyrimidine derivatives; Structure-activity relationships; Tuberculosis.

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