Decavanadate-Bearing Guanidine Derivatives Developed as Antimicrobial and Antitumor Species

Abstract

To obtain biologically active species, a series of decavanadates (Hpbg)₄[H₂V₁₀O₂₈]·6H₂O (1) (Htbg)₄[H₂V₁₀O₂₈]·6H₂O; (2) (Hgnd)₂(Hgnu)₄[V₁₀O₂₈]; (3) (Hgnu)₆[V₁₀O₂₈]·2H₂O; and (4) (pbg = 1-phenyl biguanide, tbg = 1-(o-tolyl)biguanide, gnd = guanidine, and gnu = guanylurea) were synthesized and characterized by several spectroscopic techniques (IR, UV-Vis, and EPR) as well as by single crystal X-ray diffraction. Compound (1) crystallizes in space group P-1 while (3) and (4) adopt the same centrosymmetric space group P21/n. The unusual signal identified by EPR spectroscopy was assigned to a charge-transfer π(O)→d(V) process. Both stability in solution and reactivity towards reactive oxygen species (O₂^- and OH·) were screened through EPR signal modification. All compounds inhibited the development of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis bacterial strains in a planktonic state at a micromolar level, the most active being compound (3). However, the experiments conducted at a minimal inhibitory concentration (MIC) indicated that the compounds do not disrupt the biofilm produced by these bacterial strains. The cytotoxicity assayed against A375 human melanoma cells and BJ human fibroblasts by testing the viability, lactate dehydrogenase, and nitric oxide levels indicated compound (1) as the most active in tumor cells.

Keywords: DFT calculations; antimicrobial; cytotoxicity; decavanadate; guanidine; guanylurea.

Scheme 1

Synthesis route of the decavanadates: ADV, (Hpbg)₄[H₂V₁₀O₂₈]·6H₂O (1), (Htbg)₄[H₂V₁₀O₂₈]·6H₂O (2), (Hgnd)₂(Hgnu)₄[V₁₀O₂₈] (3), and (Hgnu)₆[V₁₀O₂₈]·2H₂O (4) (in DV structure the red dots represent vanadium atoms and yellow dots oxygen atoms).

Figure 1

The asymmetric unit with the atom-labelling scheme of (1).

Figure 2

Perspective view of the crystal structure of (1) showing (a) hydrogen bond interactions between anionic and cationic units and (b) noncovalent π–π interactions.

Figure 3

The asymmetric unit with the atom-labelling scheme of (3) (a) and (4) (b).

Figure 4

Extended hydrogen bond networks in compounds (3) (a) and (4) (b).

Figure 5

IR spectra of compounds ADV (a), (1) (b), (2) (c), (3) (d), and (4) (e) registered in KBr pellets. The characteristic bands of the DV core were highlighted with blue circles, the ammonium group with magenta rhomb, the C=N group of the guanidine moiety with red circles, and the amide group of the urea moiety with green stars.

Figure 6

X-band powder EPR spectra of the ADV and (1–4) compounds.

Figure 7

Selected bacteria inhibition by the complexes ADV (a), (1) (b), (2) (c), (3) (d), and (4) (e) at different concentrations, as well as the MIC values (f) for the selected bacterial strains.

Figure 8

Cytotoxicity assay of the obtained compounds against human normal and cancerous cells; the MTT viability assay (a) and LDH release (b) of A375 cells; the MTT viability assay (c) and LDH release (d) of BJ cells; the bars marked with different letters are significantly different from the others between concentrations of the same compound, and those marked with a letter and ‘#’ are significantly different within the same concentration as well (p < 0.05 according to the Tukey test); bars marked with ‘*’ are significantly different from the rest according to one way ANOVA (*** p < 0.0001, and * p < 0.01).

Figure 9

EPR spectra of the ADV and (1–4) compounds in a 50 mM DMSO solution where KO₂ and H₂O₂ were added as O₂⁻ and OH⁻ radical donors.

Figure 10

Docking poses of the DV unit in the cytochrome bc₁ structure as simulated with the AutoDock-Vina algorithm: successful docking of the DV unit (green) in the Q_i site; the forced pose of the DV unit (red) in the Q₀ site (energetically disfavored docking, see text). Both poses represent a guide for the eye to locate Q_i and Q₀ sites (a); a representation of chain C of the enzyme (b); and a full representation of the dimeric enzyme structure (c). More details can be found in Supplementary Figure S3.