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The aim the present study was to investigate the impact of novel pentavalent organobismuth and organoantimony complexes on membrane integrity and their interaction with DNA, activity against Sb(III)-sensitive and -resistant Leishmania strains and toxicity in mammalian peritoneal macrophages. Ph 3 M(L) 2 type complexes were synthesized, where M = Sb(V) or Bi(V) and L = deprotonated 3-(dimethylamino)benzoic acid or 2-acetylbenzoic acid. Both organobismuth(V) and organoantimony(V) complexes exhibited efficacy at micromolar concentrations against Leishmania amazonensis and L. infantum but only the later ones demonstrated biocompatibility. Ph 3 Sb(L1) 2 and Ph 3 Bi(L1) 2 demonstrated distinct susceptibility profiles compared to inorganic Sb(III)-resistant strains of MRPA-overexpressing L. amazonensis and AQP1-mutated L. guyanensis. These complexes were able to permeate the cell membrane and interact with the Leishmania DNA, suggesting that this effect may contribute to the parasite growth inhibition via apoptosis. Taken altogether, our data substantiate the notion of a distinct mechanism of uptake pathway and action in Leishmania for these organometallic complexes, distinguishing them from the conventional inorganic antimonial drugs., (© 2024 Wiley Periodicals LLC.)

Clinically available drugs for mucocutaneous and cutaneous leishmaniases (CL) include mainly pentavalent antimony (Sb(V)) complexes, liposomal amphotericin B, and miltefosine (HePC). However, they present at least one of the following limitations: long-term parenteral administration through repeated doses, severe side effects, drug resistance, and high cost. HePC is the only oral drug available, but the appearance of resistance has resulted in changes of its use from monotherapy to combination therapy. Amphiphilic Sb(V) complexes, such as SbL8 obtained from reaction of Sb(V) with N-octanoyl-N-methylglucamide, were recently found to be orally active against experimental CL. The property of SbL8 to self-assemble in aqueous solution, forming nanostructures, led us to investigate the incorporation of HePC into SbL8 nanoassemblies and the therapeutic efficacy of SbL8/HePC nanoformulation by oral route in a murine model of CL. HePC incorporation into the SbL8 nanosystem was evidenced by using a fluorescent analog of HePC. The antileishmanial activity of SbL8/HePC nanoassemblies was evaluated after daily oral administration for 30 days in Leishmania amazonensis-infected BALB/c mice, in comparison with monotherapies (SbL8 or HePC) and saline control. All the treatments resulted in significant reduction in the lesion size growth, when compared with control. Strikingly, only SbL8/HePC nanoassemblies promoted a significant decrease of the parasite burden in the lesion. This work establishes the therapeutic benefit of SbL8/HePC association by oral route in a CL model and constitutes an important step towards the development of new orally active drug combination.

Novel organobismuth(V) and organoantimony(V) complexes of Ph3ML2 type were synthesized, in which L = deprotonated 2-acetylbenzoic acid (2AcBH), 4-acetylbenzoic acid (4AcBH) or 5-acetylsalicylic acid (5AcSH) and M = bismuth(V) or antimony(V). Complexes [Ph3Bi(2AcB)2] (1) [Ph3Sb(4AcB)2] (2), [Ph3Bi(4AcB)2] (3) and [Ph3Sb(5AcS)2(.)CHCl3] (4) were characterized by elemental analysis, IR, and NMR. Crystal structures of 2 and 4 were determined by single crystal X-ray diffraction. In vitro cytotoxic activities against cancerous (human chronic myelogenous leukemia, K562 and murine metastatic melanoma, B16F10) and healthy non-cancerous (murine fibroblasts, L929 and murine melanocytes, Melan-A) cells showed that, compared to free ligands, both of the metal complexes are more active as anticancer agents at low concentration in cancerous cell lines, but also possessed toxic effect at comparatively higher concentration towards the non-cancerous cells. The organobismuth(V) complex Ph3Bi(2AcB)2 was found to be more active than the Ph3BiCl2 metal precursor against the tumor cell lines and exhibited the highest selectivity index. Moreover, evaluation of the pro-apoptotic activity of Ph3Bi(2AcB)2 in B16F10 cells, by quantifying the cellular DNA using flow cytometry, indicates that cell cycle arrest and cell apoptosis contribute to the drug cytotoxicity. This work supports the great potential of organobismuth(V) dicarboxylate complexes as anticancer agents., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Two novel organoantimony(V) and two organobismuth(V) complexes of the type ML2 were synthesized, with L = acetylsalicylic acid (HL1) or 3-acetoxybenzoic acid (HL2) and M = triphenylantimony(V) (M1) or triphenylbismuth(V) (M2). Complexes, [M1(L1)2] (1), [M1(L2)2]∙CHCl3 (2), [M2(L1)2], (3) and [M2(L2)2] (4), were characterized by elemental analysis, IR and NMR. Crystal structures of triphenylantimony(V) dicarboxylate complexes 1 and 2 were determined by single crystal X-ray diffraction. Structural analyses revealed that 1 and 2 adopt five-coordinated extremely distorted trigonal bipyramidal geometries, binding with three phenyl groups in the equatorial position and two deprotonated organic ligands (L) in the axial sites. The metal complexes, their metal salts and ligands were evaluated in vitro for their activities against Leishmania infantum and amazonensis promastigotes and Staphylococcus aureus and Pseudomonas aeruginosa bacteria. Both the metal complexes showed antileishmanial and antibacterial activities but the bismuth complexes were the most active. Intriguingly, complexation of organobismuth(V) salt reduced its activity against Leishmania, but increased it against bacteria. In vitro cytotoxic test of these complexes against murine macrophages showed that antimony(V) complexes were the least toxic. Considering the selectivity indexes, organoantimony(V) complexes emerge as the most promising antileishmanial agents and organobismuth(V) complex 3 as the best antibacterial agent.

Previous studies have shown that the association of the drug meglumine antimoniate (MA) with β-cyclodextrin can improve its bioavailability by the oral route. In this work, ribose and maltose were investigated for their ability to form mixed or association complexes with MA, release MA and modulate the serum levels of Sb after oral administration in mice. Analysis of the MA/ribose composition by high performance liquid chromatography coupled to mass spectrometry (LCMS-IT-TOF) revealed the presence of mixed meglumine-Sb-ribose and Sb-ribose complexes. Analysis of the MA/maltose composition suggested the formation of MA-maltose association compounds. Circular dichroism characterization of these compositions following dilution in water at 37 °C suggested a partial and slow dissociation of the association compounds. When the MA/ribose composition was administered orally and compared to MA, the serum concentration of Sb was significantly lower after 1 h and greater after 3 h. On the other hand, the MA/maltose composition showed similar serum Sb concentration after 1 h and higher level of Sb after 3 h, when compared to MA. In conclusion, the present study has demonstrated the formation of mixed or association complexes of MA with sugars, such as maltose and ribose, which promoted sustained serum level of Sb after oral administration.