Biguanide-transition metals complexes as potential drug for hyperglycemia treatment.

Coordination compounds of Cu(ii), Ni(ii), Co(ii), and Zn(ii) with a type of biguanide (known commercially as metformin) have been synthesized and characterized using spectroscopic techniques (FT-IR, UV/VIS), X-ray diffraction techniques and thermal analysis. For all compounds, single crystals were obtained for single-crystal X-ray diffraction. For the first time, an octahedral cobalt compound with the formula [Co(C4H11N5)3]Cl2·2H2O that crystallizes in the monoclinic space group C2/c with one molecule in the asymmetric unit has been obtained. Also, a novel nickel compound with the formula [Ni(C4H11N5) (C4H10N5)]Cl·H2O that crystallizes in the monoclinic space group P21/c with two molecules in the asymmetric unit was obtained. Finally, we obtained copper and zinc compounds that crystallize in the monoclinic space groups P21/n and P21/c with the general formula [Cu(C4H11N5)2]Cl2·H2O and [Zn(C4H12N5)Cl3], respectively. A structural and supramolecular analysis was developed for all compounds using Hirshfeld surface analysis and electrostatic potential maps. The cell viability of the obtained compounds was evaluated in C2C12 (ATCCCRL-1772™) mouse muscle cells and HepG2 (ATCC HB-8065™) human liver carcinoma cells by the MTT assay to determine the potential of the compounds as new safe drugs. The results demonstrate that the compounds exhibit low cytotoxicity at doses less than 250 µg mL-1 with a cell viability greater than 80%.

The Akt-like kinase of Leishmania panamensis: As a new molecular target for drug discovery.

The Akt-like kinase of Leishmania spp. is a cytoplasmic orthologous protein of the serine/threonine kinase B-PKB/human-Akt group, which is involved in the cellular survival of these parasites. By the application of a computational strategy we obtained two specific inhibitors of the Akt-like protein of L. panamensis (UBMC1 and UBMC4), which are predicted to bind specifically to the pleckstrin domain (PH) of the enzyme. We show that the Akt-like of Leishmania panamensis is phospho-activated in parasites under nutritional and thermic stress, this phosphorylation is blocked by the UBMC1 and UMBC2 and such inhibition leads to cell death. Amongst the effects caused by the inhibitors on the parasites we found high percentage of hypodiploidy and loss of mitochondrial membrane potential. Ultrastructural studies showed highly vacuolated cytoplasm, as well as shortening of the flagellum, loss of nuclear membrane integrity and DNA fragmentation. Altogether the presented results suggest that the cell death caused by UMBC1 and UMBC4 may be associated to an apoptosis-like process. The compounds present an inhibitory concentration (IC50) over intracellular amastigotes of L. panamensis of 9.2±0.8µM for UBMC1 and 4.6±1.9µM for UBMC4. The cytotoxic activity for UBMC1 and UBMC4 in human macrophages derived from monocytes (huMDM) was 29±1.2µM and >40µM respectively. Our findings strongly support that the presented compounds can be plausible candidates as a new therapeutic alternative for the inhibition of specific kinases of the parasite.