AUTHOR=McCarron Pauraic , McCann Malachy , Devereux Michael , Kavanagh Kevin , Skerry Ciaran , Karakousis Petros C. , Aor Ana C. , Mello Thaís P. , Santos André L. S. , Campos Débora L. , Pavan Fernando R. 

TITLE=Unprecedented in Vitro Antitubercular Activitiy of Manganese(II) Complexes Containing 1,10-Phenanthroline and Dicarboxylate Ligands: Increased Activity, Superior Selectivity, and Lower Toxicity in Comparison to Their Copper(II) Analogs

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.01432

DOI=10.3389/fmicb.2018.01432

ISSN=1664-302X

ABSTRACT=<p><italic>Mycobacterium tuberculosis</italic> is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against <italic>M. tuberculosis</italic>. The water-soluble Mn(II) complexes, [Mn<sub>2</sub>(oda)(phen)<sub>4</sub>(H<sub>2</sub>O)<sub>2</sub>][Mn<sub>2</sub>(oda)(phen)<sub>4</sub>(oda)<sub>2</sub>]·4H<sub>2</sub>O (<bold>1</bold>) and {[Mn(3,6,9-tdda)(phen)<sub>2</sub>]·3H<sub>2</sub>O·EtOH}n (<bold>3</bold>) (odaH<sub>2</sub> = octanedioic acid, phen = 1,10-phenanthroline, tddaH<sub>2</sub> = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(H<sub>2</sub>O)<sub>2</sub>] (<bold>5</bold>), [Mn(ph)(phen)<sub>2</sub>(H<sub>2</sub>O)]·4H<sub>2</sub>O (<bold>6</bold>), [Mn<sub>2</sub>(isoph)<sub>2</sub>(phen)<sub>3</sub>]·4H<sub>2</sub>O (<bold>7</bold>), {[Mn(phen)<sub>2</sub>(H<sub>2</sub>O)<sub>2</sub>]}<sub>2</sub>(isoph)<sub>2</sub>(phen)·12H<sub>2</sub>O (<bold>8</bold>) and [Mn(tereph)(phen)<sub>2</sub>]·5H<sub>2</sub>O (<bold>9</bold>) (phH<sub>2</sub> = phthalic acid, isophH<sub>2</sub> = isophthalic acid, terephH<sub>2</sub> = terephthalic acid), robustly inhibited the viability of <italic>M. tuberculosis</italic> strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (<bold>1</bold>), [Cu<sub>2</sub>(oda)(phen)<sub>4</sub>](ClO<sub>4</sub>)<sub>2</sub>·2.76H<sub>2</sub>O·EtOH (<bold>2</bold>), was significantly less effective against both strains. Whilst (<bold>3</bold>) retarded H37Rv growth much better than its soluble Cu(II) equivalent, {[Cu(3,6,9-tdda)(phen)<sub>2</sub>]·3H<sub>2</sub>O·EtOH}n (<bold>4</bold>), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, <italic>in vivo</italic> studies using <italic>Galleria mellonella</italic> larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents.</p>