New Phenazine 5,10-Dioxide Carbamates Inspired by Iodinin and Myxin Exhibit Improved Potency in Human Leukemia Cells with High Cytotoxic Selectivity, Activity against Mycobacterium Tuberculosis and Low Toxicity to Zebrafish Larvae

Abstract Myxin and iodinin are phenazines known for antileukemic- and antimicrobial effects. Herein, we synthesized carbamate derivatives from an iodinin regioisomer and assessed their cytotoxicity in vitro toward leukemic and tubercular cells, as well as non-cancerous NRK and H9c2 cells, and evaluated their in vivo toxicity in zebrafish larvae. Myxin’ s antileukemic potency of 1.4 μM IC50 (MOLM-13 cells) was outperformed by several carbamate derivatives, including a methylsulfonyl-imidazolidinone analog (21) showing IC50 of 0.26 μM. The analogs showed large variation in cytotoxic selectivity toward MOLM-13 over normal cells, and in zebrafish larvae toxicity. An imidazolidinone derivative (22) was identified to be particularly favorable, combining high antileukemic- and antitubercular potency with low cytotoxicity to non-cancerous cells and undetected zebrafish toxicity at 200 μM. Furthermore, this derivative was less prone to liver metabolism than myxin. The findings establish carbamate functionalization as a promising strategy for developing new antileukemic and antitubercular phenazines.