Tetranuclear and dinuclear Cu(<sc>ii</sc>) complexes with risedronate as anti-Trypanosoma cruzi and anti-Leishmania mexicana agents. Synthesis, crystal structures, and biological evaluation

The development of new biometal-based complexes containing antiparasitic bioactive ligands is a central field of coordination chemistry that impacts bioinorganic, medicinal, and biological chemistry. Herein, two novel water-soluble polynuclear Cu(II)-complexes with formula [Cu-4(4,4 '-dmbp)(4)(mu(3)-HRis)(2)Cl-2], 1 and [Cu-2(5,5 '-dmbp)(2)(mu(2)-HRis)(H2O)Cl] 2, (4,4 '-dmbp = 4,4 '-dimethyl-2,2 '-bipyridine, 5,5 '-dmbp = 5,5 '-dimethyl-2,2 '-bipyridine, HRis = risedronate), were synthesized by self-assembly solution reactions between the corresponding precursor complexes [Cu-2(dmbp)Cl-2] and the drug Na(2)Ris in aqueous media. Both Cu(II)-Ris complexes 1-2 were structurally described by single-crystal X-ray diffraction, characterized by spectroscopic tools (IR-ATR, HRMS, UV-Vis, EPR) and studied as antiparasitic agents against Trypanosoma cruzi causative agent of Chagas disease and Leishmania mexicana that is the etiological agent of cutaneous leishmaniasis. X-ray structural analysis reveals that 1 is an uncommon tetranuclear Cu-4 complex where four crystallographically independent units [Cu(4,4 ' dmbp)](2+) are double-bridged coordinated by two tetra-deprotonated ligands HRis containing the protonated pyridine ring. All Cu(II) centers show a distorted square-based pyramid geometry, and they are coordinated by two bisphosphonate fragments from HRis in a coordination environment mu(3) for each one. Crystal analysis of 2 displays a dinuclear Cu-2 complex where one ligand HRis coordinated to two different units [Cu(4,4 ' dmb)](2+) in a mu(2) mode, both Cu(II) present distorted square-based pyramid geometry. In general, complexes 1-2 are hydrostable in the millimolar concentration range and present low citotoxicity (<22% on the growth of cancer cell lines and healthy COS-7 cells) similar to the commercial drug, monosodium salt of risedronic acid (NaRis). Complexes 1-2 and NaRis were evaluated in vitro against T. cruzi epimastigotes and L. mexicana promastigotes. Results demonstrated that these Cu-Ris complexes improved the percentages of growth inhibition for T. cruzi. This inhibition ranged from 62-70% at concentrations of 5.0 mM after 24 h and 48 h incubation, compared to those observed for free, which has an inhibition of similar to 38%. Under the same concentration at 24 h incubation, complex 1 has a significantly greater inhibition effect against L. mexicana (63%) compared to free NaRis (50%). Reduction in parasite metabolisms and morphological changes included membrane damage, vacuolization, reduction of size and loss of flagellum were also observed. Importantly cytotoxicity to VERO cells was minor with the Cu(II)-Ris complexes compared with NaRis. The molecular docking analysis showed significant affinity towards the enzyme farnesyl diphosphate synthase from T. cruzi (TcFPPS), including simulations of the complexes Cu(II) at the TcFPPS binding site.