Synthesis and Antibacterial Activity of Ionic Liquids and Organic Salts Based on Penicillin G and Amoxicillin hydrolysate Derivatives against Resistant Bacteria

Abstract

The preparation and characterization of ionic liquids and organic salts (OSILs) that contain anionic penicillin G [secoPen] and amoxicillin [seco-Amx] hydrolysate derivatives and their in vitro antibacterial activity against sensitive and resistant Escherichia coli and Staphylococcus aureus strains is reported. Eleven hydrolyzed β-lactam-OSILs were obtained after precipitation in moderate-to-high yields via the neutralization of the basic ammonia buffer of antibiotics with different cation hydroxide salts. The obtained minimum inhibitory concentration (MIC) data of the prepared compounds showed a relative decrease of the inhibitory concentrations (RDIC) in the order of 100 in the case of [C2OHMIM][seco-Pen] against sensitive S. aureus ATCC25923 and, most strikingly, higher than 1000 with [C16Pyr][seco-Amx] against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. These outstanding in vitro results showcase that a straightforward transformation of standard antibiotics into hydrolyzed organic salts can dramatically change the pharmaceutical activity of a drug, including giving rise to potent formulations of antibiotics against deadly bacteria strains.

Antimicrobial Activities of Highly Bioavailable Organic Salts and Ionic Liquids from Fluoroquinolones

“…The cation hydroxides are prepared immediately before their addition from the corresponding halide salts by anion exchange from a hydroxide resin such as Amberlyst IRA-400 (OH). Whenever this methodology is performed with zwitterionic APIs [19,22] such as fluoroquinolones, it is required that the reaction proceeds in ammonia buffer solution so that complete ionisation can occur. The pure API-OSILs were isolated in very high yields (93-100%) after recrystallisation from chloroform/methanol mixtures.…”

“…For more than a decade, active pharmaceutical ingredients as organic salts and ionic liquids (API-OSILs) have risen in academia as an alternative formulation for low bioavailable drugs [9][10][11][12]. This third generation of ionic liquids [9] consists on the combination of APIs as cations or anions with organic counterions, thereby inducing distinctive physicochemical properties over the original drugs and reduced toxicity to healthy cells, thus rendering a potentially enhanced pharmaceutical activity in comparison to the API [13][14][15][16][17][18][19][20][21][22][23][24][25]. Our works involving the preparation of API-OSILs from, e.g., β-lactam (ampicillin [18][19][20][21], penicillin [22] and amoxicillin [22]) and fluoroquinolone [18,23] antibiotics, NSAIDs (ibuprofen [17,18], naproxen [18]), bone antiresorptive agents (zoledronic [24] and alendronic [25] acids), among others, have shown that the combination of an API, either as a cation or as an anion, with suitable biocompatible counter-ions can increase the water solubility of the parent drug and even change its biological effect [10,17,[23][24][25][26][27][28].…”

Alendronic Acid as Ionic Liquid: New Perspective on Osteosarcoma

“…The selection of protonated organic superbases (1,1,3,3-tetramethylguanidinium [TMGH] and 1,5-diazabicyclo(4.3.0)non-5-enium [DBNH]) and quaternary ammonium (cholinium [Ch] and 1-(2-hydroxyethyl)-3-methyl-1H-imidazol-3-ium [C 2 OHMIM]) cations relied on the known information about their biocompatibility [15,23]. Despite their low toxicity, the combination of these cations with other APIs has rendered highly active API-OSILs in the past, in particular antimicrobial and anti-tumoral [19,20,22]. The preparation of compounds 1-4 consisted of the addition of the diluted superbases to a dispersion of ALN (pathway A).…”

“…Ionic Liquids (ILs) are defined as salts with a melting point below 100 • C, which display peculiar properties such as negligible vapor pressure, high thermal and chemical stability and tunable physicochemical properties according to the cation-anion combinations. These novel API-OSILs can improve the drug performance in terms of stability, solubility, permeability, biological activity and delivery [10][11][12][13][14][15][16][17][18][19][20][21][22]. Recent achievements showed that the suitable combination between different families of pharmaceutical drugs such as NSAIDs (e.g., ibuprofen and naproxen [15,16]), β-lactam (e.g., ampicillin, amoxicillin, penicillin [16][17][18][19][20]) and fluoroquinolone (ciprofloxacin, norfloxacin [16,21]) antibiotics and bone antiresorptive agents (zoledronic acid [22]) rendered novel pharmaceutical drug formulations based on OSILs.…”

Ionic Liquids and Deep Eutectic Solvents for Application in Pharmaceutics

“…By following one previously published methodology for the preparation of ampicillin-based OSILs [ 5 ], Ferraz & Branco and co-workers [ 3 ] reported the preparation of amoxicillin and penicillin antibiotics as OSILs bearing hydrolyzed β-lactam moieties (respectively seco -AMX- and seco -Pen-OSILs). Despite this shortcoming, on one hand, two of the hydrolyzed seco -Pen-OSILs showed up to a 100-fold increase in antimicrobial activity in vitro against sensitive S. aureus ([C 2 OHMIM][ seco -Pen]) and E. coli ([TEA][ seco -Pen]) strains compared to parent non-hydrolyzed antibiotics.…”