Synthesis and characterization of bismuth(III) and antimony(V) porphyrins: high antileishmanial activity against antimony-resistant parasite.
Two bismuth(III) porphyrins-5,10,15,20-tetrakis(phenyl)porphyrinatobismuth(III) nitrate, [Bi(III)(TPP)]NO3, and the unprecedent 5,10,15,20-tetrakis(4-carbomethoxyphenyl)porphyrinatobismuth(III) nitrate, [Bi(III)(T4CMPP)]NO3, and two unprecedented antimony(V) porphyrins dichlorido(5,10,15,20-tetrakis(phenyl)porphyrinato)antimony(V) bromide, [Sb(V)(TPP)Cl2]Br, and dibromido(5,10,15,20-tetrakis(4-carbomethoxyphenyl)porphyrinato)antimony(V) bromide, [Sb(V)(T4CMPP)Br2]Br,-were synthesized by reacting the corresponding porphyrin ligand with Bi(NO3)3·5H2O or SbCl3. All compounds were characterized by UV-vis, (1)H NMR spectroscopy, and mass spectrometry. The new compounds were also characterized by elemental analysis. Because antimony and bismuth compounds have been widely applied in medicine, the activity of these complexes was tested against Sb-sensitive and -resistant Leishmania amazonensis parasites. [Sb(V)(T4CMPP)Br2]Br was more active against the promastigote form of Sb-resistant mutant strain as compared to the sensitive parental strain, with IC50 in the micromolar range. These data contrasted with those obtained using the Sb(III) drug potassium antimony tartrate, which displayed IC50 of 110 μmol L(-1) against the Sb-sensitive parasite and was almost inactive against the Sb-resistant strain. The H2T4CMPP ligand also showed antileishmanial activity against Sb-resistant and -sensitive strains, but with IC50 at least tenfold greater than that of the complex. The Sb(V)-porphyrin complex was also active against intracellular amastigotes and showed a higher selectivity index than the conventional Sb(V) drug glucantime, in both Sb-sensitive and -resistant strains. The greater antileishmanial activity of this complex could be attributed to an increased cellular uptake of Sb. Thus, [Sb(V)(T4CMPP)Br2]Br constitutes a new antileishmanial drug candidate.
Departamento de Química, ICEx, Universidade Federal de Minas Gerais (UFMG), Av. Antônio Carlos 6627, Belo Horizonte, MG, 31270-901, Brazil.
Marcela Luísa
ML
Gomes
Gilson
G
DeFreitas-Silva
Priscila Gomes
PG
dos Reis
Maria Norma
MN
Melo
Frédéric
F
Frézard
Cynthia
C
Demicheli
Ynara Marina
YM
Idemori
D000965:Antimony / Q000737:chemistry* / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001729:Bismuth / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial / Q000187:drug effects*; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D008665:Metalloporphyrins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship
D000981:Antiprotozoal Agents; D008665:Metalloporphyrins; D000965:Antimony; D001729:Bismuth