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

Author(s):Show less -

McCarron, Pauraic ^{[1, 2]} ; McCann, Malachy ^[2] ; Devereux, Michael ^[1] ; Kavanagh, Kevin ^[3] ; Skerry, Ciaran ^[4] ; Karakousis, Petros C. ^[4] ; Aor, Ana C. ^[5] ; Mello, Thais P. ^[5] ; Santos, Andre L. S. ^[5] ; Campos, Debora L. ^[6] ; Pavan, Fernando R. ^[6]

Affiliation

^[1] Dublin Inst Technol, Focas Res Inst, Ctr Biomimet & Therapeut Res, Dublin - Ireland

^[2] Natl Univ Ireland, Maynooth Univ, Chem Dept, Maynooth, Kildare - Ireland

^[3] Natl Univ Ireland, Maynooth Univ, Biol Dept, Maynooth, Kildare - Ireland

^[4] Johns Hopkins Sch Med, Ctr TB Res, Div Infect Dis, Dept Med, Baltimore, MD - USA

^[5] Univ Fed Rio de Janeiro, Inst Microbiol Paulo de Goes, Dept Microbiol Geral, Rio De Janeiro - Brazil

^[6] Univ Estadual Paulista, Fac Ciencias Farmaceut, Araraquara, SP - Brazil

• Document type: Journal article
• Source: FRONTIERS IN MICROBIOLOGY; v. 9, JUL 2 2018.
• Web of Science Citations: 1

Abstract

Mycobacterium tuberculosis 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 M. tuberculosis. The water-soluble Mn(II) complexes, {[}Mn-2(oda)(phen)(4)(H2O)(2)]{[}Mn-2(oda)(phen)(4)(oda)(2)]center dot 4H(2)O (1) and [{[}Mn(3,6,9-tdda)(phen)2]center dot 3H(2)O center dot EtOH]n (3) (odaH(2) = octanedioic acid, phen = 1,10-phenanthroline, tddaH(2) = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, {[}Mn(ph)(phen)(H2O)(2)] (5), {[}Mn(ph)(phen)(2)(H2O)]center dot 4H(2)O (6), {[}Mn-2(isoph)(2)(phen)(3)]center dot 4H(2)O (7), [{[}Mn(phen)(2)(H2O)(2)]](2)(isoph)(2)(phen)center dot 12H(2)O (8) and {[}Mn(tereph)(phen)(2)]center dot 5H(2)O (9) (phH(2) = phthalic acid, isophH(2) = isophthalic acid, terephH(2) = terephthalic acid), robustly inhibited the viability of M. tuberculosis strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (1), {[}Cu-2(oda)(phen)(4)](ClO4)(2)center dot 2.76H(2)O center dot EtOH (2), was significantly less effective against both strains. Whilst (3) retarded H37Rv growth much better than its soluble Cu(II) equivalent, [{[}Cu(3,6,9-tdda)(phen)(2)]center dot 3H(2)O center dot EtOH]n (4), 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, in vivo studies using Galleria mellonella 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. (AU)

• FAPESP's process: 13/14957-5 - Research potential against tuberculosis of a new class of furoxan compounds and nanostructured compounds of the ruthenium(II) and copper (II)
• Grantee: Fernando Rogério Pavan
• Support Opportunities: Research Grants - Young Investigators Grants