Preparation and Physicochemical Characterization of Water-Soluble Pyrazole-Based Nanoparticles by Dendrimer Encapsulation of an Insoluble Bioactive Pyrazole Derivative

Abstract

2-(4-Bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4) was synthetized and successfully evaluated concerning numerous biological activities, except for antimicrobial and cytotoxic effects. Due to the antimicrobial effects possessed by pyrazole nucleus, which have been widely reported, and the worldwide need for new antimicrobial agents, we thought it would be interesting to test BBB4 and to evaluate its possible antibacterial effects. Nevertheless, since it is water-insoluble, the future clinical application of BBB4 will remain utopic unless water-soluble BBB4 formulations are developed. To this end, before implementing biological evaluations, BBB4 was herein re-synthetized and characterized, and a new water-soluble BBB4-based nano-formulation was developed by its physical entrapment in a biodegradable non-cytotoxic cationic dendrimer (G4K), without recovering harmful solvents as DMSO or surfactants. The obtained BBB4 nanoparticles (BBB4-G4K NPs) showed good drug loading (DL%), satisfying encapsulation efficiency (EE%), and a biphasic quantitative release profile governed by first-order kinetics after 24 h. Additionally, BBB4-G4K was characterized by ATR-FTIR spectroscopy, NMR, SEM, dynamic light scattering analysis (DLS), and potentiometric titration experiments. While, before the nanotechnological manipulation, BBB4 was completely water-insoluble, in the form of BBB4-G4K NPs, its water-solubility resulted in being 105-fold higher than that of the pristine form, thus establishing the feasibility of its clinical application.

Pyrazole-Based Water-Soluble Dendrimer Nanoparticles as a Potential New Agent against Staphylococci

“…The biodegradable cationic dendrimer NPs loaded with BBB4 (BBB4-G4K NPs) used in this study were recently synthesized according to the synthetic procedure reported by Alfei and collaborators [ 16 ]. The experimental details and characterization data are available in the Supplementary Materials (SM) (Section S1, including Sections S1.1–S1.8, Figures S1–S5, Scheme S1, and Tables S1 and S2) .…”

“…Concerning the development of new antibacterial drugs, active where common antibiotics no longer work, the five-membered heterocyclic diazole ring of pyrazole has been shown to have numerous biological activities, including antimicrobial effects [ 16 , 17 ]. The pyrazole derivatives are mainly of synthetic derivation, and only a few molecules containing the pyrazole nucleus are of natural origin.…”

“…The pyrazole nucleus possesses almost all kinds of pharmacological activities, but, while several of its medicinal properties have been reported since the year 1944, the first studies reporting the antimicrobial effects of the pyrazole derivatives have been published much more recently, particularly after the year 2000 [ 19 , 20 ]. Consequently, the 2-(4-bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4, Figure 1 ), synthetized for the first time by Bondavalli et al and found to be active as an analgesic, hypotensive, anti-inflammatory, local anaesthetic, inhibitor of motor activity in mice and rats, and as an antiplatelet aggregative agent in vitro in 1998 [ 16 ], has never been studied for its possible antimicrobial properties.…”

“…In this field, due to their nonpareil physicochemical properties, dendrimers are extensively applicated [ 24 , 26 , 27 , 28 , 29 , 30 ]. Accordingly, using a dendrimer found to be non-cytotoxic for HeLa cells as a solubilizing agent, we have recently prepared water-soluble BBB4-loaded nanoparticles (NPs) (BBB4-G4K NPs) with improved physicochemical properties, suitable both for performing reliable antimicrobial essays and for a future clinical application [ 16 ].…”

“…In this alarming scenario, made of missing epidemiologic evidence, a plethora of uncertainties, also due to the interindividual responses of patients to existing antibiotics, and of a decreasing efficacy of available drugs, the development of new curative options against MRSA infections is urgent. Consequentially, the overall merit of the present study consists of having identified a new powerful antibacterial agent based on nanotechnologically modified BBB4 (BBB4-G4K NPs), which, thanks to its previously demonstrated [ 16 ] physicochemical characteristics, could be advisable for biomedical applications. Such NPs have proven to be selectively active against different species of the Staphylococcus genus, and to be able to inhibit their growth whatever their resistance to methicillin or their resistance to existing antibiotics, amoxicillin and linezolid included.…”