1-OH-3-O-Akyl derivatives 11(University of Iceland)

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.