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

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

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: eov@hi.is.
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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