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The diverse pharmacological properties of the diaryltriazenes have sparked the interest to investigate their potential to be repurposed as antitubercular drug candidates. In an attempt to improve the antitubercular activity of a previously constructed diaryltriazene library, eight new halogenated nitroaromatic triazenides were synthesized and underwent biological evaluation. The potency of the series was confirmed against the Mycobacterium tuberculosis lab strain H37Ra, and for the most potent derivative, we observed a minimal inhibitory concentration of 0.85 μm. The potency of the triazenide derivatives against M. tuberculosis H37Ra was found to be highly dependent on the nature of the halogenated phenyl substituent and less dependent on cationic species used for the preparation of the salts. Although the inhibitory concentration against J774A.1 macrophages was observed at 3.08 μm, the cellular toxicity was not mediated by the generation of nitroxide intermediate as confirmed by electron paramagnetic resonance spectroscopy, whereas no in vitro mutagenicity could be observed for the new halogenated nitroaromatic triazenides when a trifluoromethyl substituent was present on both the aryl moieties.

Antibiotic resistance poses a critical threat to global health care. Alkyl-and aryltriazene compounds have found utility as DNA-modifying agents and have been previously 2 assessed as potential anti-cancer therapeutics. However, their potential utility as antimicrobials has only recently been appreciated. Therefore, to further investigate the efficacy of these compounds as antibiotics, we synthesized a series of forty six diaryltriazene derivatives and evaluated their antimicrobial properties. Initial experiments showed activity of some diaryltriazene compounds against both methicillin-resistant strains of Staphylococus aureus (MRSA) and against Mycobacterium smegmatis with MICs of less than 0.02 and 1 μg/mL. Those diaryltriazene compounds with potent anti-staphylococcal and anti-mycobacterial activity were inactive as growth inhibitors of mammalian cell lines and yeast. Furthermore, we demonstrated that one of the most active anti-MRSA diaryltriazene derivatives was subject to very low frequencies of resistance at < 10 -9 . Whole genome sequencing of resistant isolates identified mutations in the enzyme that lysylates phospholipids. This could result in the modification of phospholipid metabolism and consequently the characteristics of the staphylococcal cell membrane, ultimately modifying the sensitivity of these pathogens to triazene challenge. Our work has therefore extended the potential range of triazenes, which could yield novel antimicrobials with low levels of resistance.

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Novel tetrachloridoruthenium(III) complex Na[trans-RuCl 4 (DMSO)(PyrDiaz)] (3) with pyridine-tethered diazenedi-was synthesized by direct coupling of PyrDiaz with sodium trans-bis(dimethyl sulfoxide)tetrachloridoruthenate(III) (Na-[trans-Ru(DMSO) 2 Cl 4 ]). Compound 3 is the analogue of the antimetastatic Ru(III) complex NAMI-A and NAMI-Pyr. Single crystal X-ray diffraction analysis revealed that the compound 3 is a polymeric complex with the ruthenium and sodium centres.