Tetraazamacrocyclic derivatives and their metal complexes as antileishmanial leads.

A total of 44 bis-aryl-monocyclic polyamines, monoaryl-monocyclic polyamines and their transition metal complexes were prepared, chemically characterized, and screened in vitro against the Leishmania donovani promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells. The IC50 and/or IC90 values showed that 10 compounds were similarly active at about 2-fold less potent than known drug pentamidine against promastigotes. The most potent compound had an IC50 of 2.82 µM (compared to 2.93 µM for pentamidine). Nine compounds were 1.1-13.6-fold more potent than pentamidine against axenic amastigotes, the most potent one being about 2-fold less potent than amphotericin B. Fourteen compounds were about 2-10 fold more potent than pentamidine, the most potent one is about 2-fold less potent than amphotericin B against intracellular amastigotes in THP1 cells. The 2 most promising compounds (FeL7Cl2 and MnL7Cl2), with strong activity against both promastigotes and amastigotes and no observable toxicity against the THP1 cells are the Fe2+- and Mn2+- complexes of a dibenzyl cyclen derivative. Only 2 of the 44 compounds showed observable cytotoxicity against THP1 cells. Tetraazamacrocyclic monocyclic polyamines represent a new class of antileishmanial lead structures that warrant follow up studies.

Discovery of Antischistosomal Drug Leads Based on Tetraazamacrocyclic Derivatives and Their Metal Complexes.

Praziquantel (PZQ) is the only drug available for the treatment of schistosomiasis, and since its large-scale use might be associated with the onset of resistance, new antischistosomal drugs should be developed. A series of 26 synthetic tetraazamacrocyclic derivatives and their metal complexes were synthesized, characterized, and screened for antischistosomal activity by application of a phased screening program. The compounds were first screened against newly transformed schistosomula (NTS) of harvested Schistosoma mansoni cercariae, then against adult worms, and finally, in vivo using the mouse model of S. mansoni infection. At a concentration of 33 µM, incubation with a total of 12 compounds resulted in the mortality of NTS at the 62% to 100% level. Five of these showing 100% inhibition of viability of NTS at 10 µM were selected for further screening for determination of the 50 inhibitory concentrations (IC50s) against both NTS and adult worms. Against NTS, all 5 compounds showed IC50s comparable to the IC50 of the standard drug, PZQ (0.87 to 9.65 µM for the 5 compounds versus 2.20 µM for PZQ). Three of these, which are the bisquinoline derivative of cyclen and its Fe(2+) and Mn(2+) complexes, showed micromolar IC50s (1.62 µM, 1.34 µM, and 4.12 µM, respectively, versus 0.10 µM for PZQ) against adult worms. In vivo, the worm burden reductions were 12.3%, 88.4%, and 74.5%, respectively, at a single oral dose of 400 mg/kg of body weight. The Fe(2+) complex exhibited activity in vivo comparable to that of PZQ, pointing to the discovery of a novel drug lead for schistosomiasis.

Acetate as a model for aspartate-based CXCR4 chemokine receptor binding of cobalt and nickel complexes of cross-bridged tetraazamacrocycles.

A number of disease states including WHIM syndrome, HIV infection and cancer have been linked to the chemokine receptor CXCR4. High-affinity CXCR4 antagonist transition metal complexes of configurationally restricted bis-tetraazamacrocyclic ligands have been identified in previous studies. Recently synthesised and structurally characterised Co2+/Co3+ and Ni2+ acetate complexes of mono-macrocycle cross-bridged ligands have been used to mimic their known coordination interaction with the aspartate side chains on binding to CXCR4. Here, X-ray crystal structures for three Co2+/Co3+ acetate complexes and five Ni2+ acetate complexes are presented and demonstrate flexibility in the mode of binding to the acetate ligand concomitantly with the requisite cis-V-configured cross-bridged tetraazamacrocyle. Complexes of the smaller Co3+ metal ion exclusively bind acetate by chelating both oxygens of acetate. Larger Co2+ and Ni2+ metal ions in cross-bridged tetraazamacrocycles show a clear tendency to coordinate acetate in a monodentate fashion with a coordinated water molecule completing the octahedral coordination sphere. However, in unbridged tetraazamacrocycle acetate structures reported in the literature, the coordination preference is to chelate both acetate oxygens. We conclude that the short ethylene cross-bridge restricts the equatorial bulk of the macrocycle, prompting the metal ion to fill the equator with the larger monodentate acetate plus water ligand set. In unbridged ligand examples, the flexible macrocycle expands equatorially and generally only allows chelation of the sterically smaller acetate alone. These results provide insight for generation of optimised bis-macrocyclic CXCR4 antagonists utilising cobalt and nickel ions.