Functionalized regioisomers of the natural product phenazines myxin and iodinin as potent inhibitors of Mycobacterium tuberculosis and human acute myeloid leukemia cells

  • Eur J Med Chem. 2025 Mar 5:285:117244. doi: 10.1016/j.ejmech.2025.117244.
Goraksha Machhindra Khose  1 ,  Siva Krishna Vagolu  2 ,  Reidun Aesoy  3 ,  Ísak Máni Stefánsson  1 ,  Snorri Geir Ríkharðsson  1 ,  Dagmar Ísleifsdóttir  1 ,  Maonian Xu  1 ,  Håvard Homberset  2 ,  Tone Tønjum  4 ,  Pål Rongved  5 ,  Lars Herfindal  3 ,  Elvar Örn Viktorsson  6
Affiliations
  • 1. School of Health Sciences, Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107, Reykjavik, Iceland.
  • 2. Unit for Genome Dynamics, Department of Microbiology, University of Oslo, N-0316, Oslo, Norway.
  • 3. Centre for Pharmacy, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, N-5021, Bergen, Norway.
  • 4. Unit for Genome Dynamics, Department of Microbiology, University of Oslo, N-0316, Oslo, Norway; Unit for Genome Dynamics, Department of Microbiology, Oslo University Hospital, N-0424, Oslo, Norway.
  • 5. School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316, Oslo, Norway.
  • 6. School of Health Sciences, Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107, Reykjavik, Iceland. Electronic address: [email protected].
PMID: 39788066 DOI: 10.1016/j.ejmech.2025.117244
Abstract

The natural bioactive products myxin and iodinin are phenazine 5,10-dioxides possessing potent anti-bacterial and anti-cancer activity in vitro. This work describes the synthesis and derivatization of new myxin and iodinin regioisomers, developed from 1,3-dihydroxyphenazine 5,10-dioxide. Compounds were evaluated for activity towards M. tuberculosis (Mtb) strains, a human AML cell line (MOLM-13), and two non-cancerous mammalian cell lines (NRK and H9c2). Highly potent analogs were developed having IC50 values against MTB down to 20 nM and 1.4 μM for human AML cells. 1-OH-3-O-alkyl substituted derivatives demonstrated high efficacy against Mtb and low toxicity in normal cells. 2,3-substituted regioisomers of myxin and iodinin were shown to be inactive, highlighting the importance of oxygen substituent in position 1 of the scaffold. A strong positive correlation between anti-MTB and anti-AML activity was revealed, suggesting a common mechanism of action in bacteria and Cancer cells. These findings demonstrate the therapeutic potential of 1,3-O-functionalized phenazine 5,10-dioxides in chemotherapy for Mtb and AML and contribute to the structure-activity understanding of phenazine 5,10-dioxides with respect to their biological activity.

Keywords
Acute myeloid leukemia; Cellular toxicity studies; Mycobacterium tuberculosis; Phenazine 5,10-dioxides; Structure-activity relationships (SAR).
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