From Weakly Active Insoluble Pyrazoles Not Clinically Administrable, New Potent Antibacterial Water-Soluble Nanoparticles Using Cationic Dendrimers as Solubilizing Agents

Based on the widely reported antimicrobial effects possessed by the pyrazole nucleus and the worldwide need for new antimicrobial agents, we test two home-made pharmacologically active pyrazole derivatives, namely CR232 and BBB4 to evaluate their antibacterial effects. Nevertheless, due to their water-insolubility, the results from microbiologic experiments on CR232 were not clear, and the future clinical application of both compounds would have remained utopic unless first, water-soluble formulations had not been prepared. To this end, before implementing further biological evaluations, BBB4 and CR232 were physically entrapped in biodegradable non-cytotoxic cationic dendrimers containing lysine (K) (namely G4K and G5K), without using harmful solvents as DMSO, or surfactants. The obtained BBB4-loaded and CR232-loaded nanoparticles (BBB4-G4K and CR232-G5K NPs) were water-soluble and showed from good to very high values of drug loading (DL%), and encapsulation efficiency (EE%). Additionally, while a biphasic quantitative release profile governed by first-order kinetics was observed after 24h for BBB4-G4K NPs, a complex but anyway quantitative release profile governed by Weibull kinetics, was observed for CR232-G5K NPs. Both nano-formulations were characterized by ATR-FTIR spectroscopy, also processed by multivariate analyses (MVA), NMR, SEM, dynamic light scattering analysis (DLS), and potentiometric titration experiments. While before the nanotechnological manipulation, BBB4 and CR232 were completely water-insoluble, in the form of BBB4-G4K and CR232-G5K NPs, their water-solubility resulted 105-fold and 2311-fold respectively higher than those of the pristine forms, thus establishing the feasibility of their clinical application. As reported in detail in the poster session, BBB4-G4K NPs demonstrated potent antibacterial effects specifically against Staphylococci including methicillin-resistant strains of Staphylococcus aureus and S. epidermidis, while CR232-G5K NPs proved very potent broad-spectrum bactericidal effects against several strains of several genera of both Gram-positive and Gram-negative species, regardless their resistance pattern.