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

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.