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- Antitumor Activity of Ionic Liquids Based on AmpicillinPublication . Ferraz, Ricardo; Costa-Rodrigues, Joao; Fernandes, Maria H.; Santos, Miguel M.; Marrucho, Isabel M.; Rebelo, Luís Paulo N.; Prudêncio, Cristina; Noronha, João Paulo; Petrovski, Željko; Branco, Luís C.Significant antiproliferative effects against various tumor cell lines were observed with novel ampicillin salts as ionic liquids. The combination of anionic ampicillin with appropriate ammonium, imidazolium, phosphonium, and pyridinium cations yielded active pharmaceutical ingredient ionic liquids (API-ILs) that show potent antiproliferative activities against five different human cancer cell lines: T47D (breast), PC3 (prostate), HepG2 (liver), MG63 (osteosarcoma), and RKO (colon). Some API-ILs showed IC50 values between 5 and 42 nm, activities that stand in dramatic contrast to the negligible cytotoxic activity level shown by the ampicillin sodium salt. Moreover, very low cytotoxicity against two primary cell lines—skin (SF) and gingival fibroblasts (GF)—indicates that the majority of these API-ILs are nontoxic to normal human cell lines. The most promising combination of antitumor activity and low toxicity toward healthy cells was observed for the 1-hydroxyethyl-3-methylimidazolium–ampicillin pair ([C2OHMIM][Amp]), making this the most suitable lead API-IL for future studies.
- Antibacterial activity of ionic liquids based on betalactamantibiotics against resistant bacteriaPublication . Dias, Vitorino; Santos, Miguel; Prudêncio, Cristina; Noronha, João P.; Grilo, Inês R.; Sobral, Rita G.; Dias, Ana Rita; Branco, Luís C.; Ferraz, RicardoThe cases of antibiotic resistance are increasing and becoming more and more common, giving rise to a new problem for public health. Therefore, the discovery of new antibiotics is important and necessary.
- A Novel Approach for Bisphosphonates: Ionic Liquids and Organic Salts from Zoledronic AcidPublication . Teixeira, Sónia; Santos, Miguel M.; Ferraz, Ricardo; Prudêncio, Cristina; Fernandes, Maria H.; Costa-Rodrigues, Joao; Branco, Luís C.Novel ionic liquids and organic salts based on mono- or dianionic zoledronate and protonated superbases, choline and n-alkylmethylimidazolium cations, were prepared and characterized by spectroscopic and thermal analyses. Most of the prepared salts display amorphous structures and very high solubility in water and saline solutions, especially the dianionic salts. Among the zoledronate-based ionic compounds, those containing choline [Ch] and methoxyethylmethylimidazolium [C3 OMIM] cations appear to have significant cytotoxicity against human osteosarcoma cells (MG63) and low toxicity toward healthy skin fibroblast cells. Because osteosarcoma is a bone pathology characterized by an increase in bone turnover rate, the results presented herein may be a promising starting point for the development of new ionic pharmaceutical drugs against osteosarcoma.
- Tackling bacterial resistance using antibiotics as ionic liquids and organic saltsPublication . Santos, Miguel M.; Grilo, Inês R.; Ferraz, Ricardo; Madeira, Diogo A.; Soares, Bárbara M.; Inácio, Núria; Pinheiro, Luís; Petrovski, Zeljko; Prudêncio, Cristina; Sobral, Rita G.; Branco, Luís C.Bacterial resistance to current antibiotics has a major impact on worldwide human health, leading to 700K deaths every year. The development of novel antibiotics did not present significant progress, namely regarding clinical trials, over the last years due to low returns. Thus, innovative alternatives must be devised to tackle the continuous rise of antimicrobial resistance. Ionic Liquids and Organic Salts from Active Pharmaceutical Ingredients (API-OSILs) have risen in academia for over 10 years as an efficient formulation for drugs with low bioavailability and permeability, as well as reduction or elimination of polymorphism, thereby potentially enhancing their pharmaceutical efficiency. To the best of our knowledge, our group is the first to perform research on the development of API-OSILs from antibiotics as a way to improve their efficiency. More specifically, we have successfully combined ampicillin, penicillin and amoxicillin as anions with biocompatible organic cations such as choline, alkylpyridiniums and alkylimidazoliums. In this communication, we present our latest developments in the synthesis and physicochemical (DSC) characterization of OSILs from these antibiotics, in addition to in vitro antimicrobial activity data, in particular towards MRSA and multi-resistant E. coli, as well as sensitive strains of gram-positive and gram-negative bacteria.
- Ionic liquids as active pharmaceutical ingredientsPublication . Ferraz, Ricardo; Branco, Luís C.; Prudêncio, Cristina; Noronha, João Paulo; Petrovski, ŽeljkoIonic liquids (ILs) are ionic compounds that possess a melting temperature below 100 °C. Their physical and chemical properties are attractive for various applications. Several organic materials that are now classified as ionic liquids were described as far back as the mid-19th century. The search for new and different ILs has led to the progressive development and application of three generations of ILs: 1) The focus of the first generation was mainly on their unique intrinsic physical and chemical properties, such as density, viscosity, conductivity, solubility, and high thermal and chemical stability. 2) The second generation of ILs offered the potential to tune some of these physical and chemical properties, allowing the formation of “task-specific ionic liquids” which can have application as lubricants, energetic materials (in the case of selective separation and extraction processes), and as more environmentally friendly (greener) reaction solvents, among others. 3) The third and most recent generation of ILs involve active pharmaceutical ingredients (API), which are being used to produce ILs with biological activity. Herein we summarize recent developments in the area of third-generation ionic liquids that are being used as APIs, with a particular focus on efforts to overcome current hurdles encountered by APIs. We also offer some innovative solutions in new medical treatment and delivery options.
- Bioactivity of ionic liquids based on valproate in SH-SY5Y human neuroblastoma cell linePublication . Dias, Ana Rita; Ferraz, Ricardo; Costa-Rodrigues, João; Santos, Andreia F. M.; Jacinto, Manuel L.; Prudêncio, Cristina; Noronha, João Paulo; Branco, Luís C.; Petrovsk, ŽeljkoThe search for alternative and effective therapies to fight cancer is one of the main goals of the pharmaceutical industry. Recently, ionic liquids (ILs) have emerged as potential therapeutic agents with antitumor properties. The goal of this study was to synthesize and evaluate the bioactivity of different ILs coupled with the active pharmaceutical ingredient (API) valproate (VPA) as an antitumor agent. The toxicity of the prepared ionic liquids was evaluated by the MTT cell metabolic assay in human neuroblastoma SH-SY5Y and human primary Gingival Fibroblast (GF) cell lines, in which they showed inhibitory effects during the study period. In addition, low cytotoxicity against GF cell lines was observed, suggesting that these compounds are not toxic to human cell lines. [C2OHDMiM][VPA] demonstrated an outstanding antitumor activity against SH-SY5Y and lower activity against the non-neoplastic GF line. The herein assessed compounds played an important role in the modulation of the signaling pathways involved in the cellular behavior. This work also highlights the potential of these ILs-API as possible antitumor agents.
- Synthesis and Antibacterial Activity of Ionic Liquids and Organic Salts Based on Penicillin G and Amoxicillin hydrolysate Derivatives against Resistant BacteriaPublication . Ferraz, Ricardo; Silva, Dário; Dias, Ana Rita; Dias, Vitorino; Santos, Miguel M.; Pinheiro, Luís; Prudêncio, Cristina; Noronha, João Paulo; Petrovski, Željko; Branco, Luís C.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 Escherichiacoli and Staphylococcusaureus 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.
- Ionic Liquids – From organic solvents to pharmaceutical applicationsPublication . Ferraz, Ricardo; Costa-Rodrigues, João; Fernandes, Maria Helena; Branco, Luís C.; Noronha, João Paulo; Petrovski, Eljko; Fernandes, Rúben; Prudêncio, CristinaIonic liquids are compounds that have melting temperature below 100ºC and they have been evolved from traditional high temperature molten salts.. The quest for useful molten salts with lower melting temperatures led to inorganic chloroaluminates, to organic chloroaluminates and to organic salts now being developed for green chemistry applications and recently has been a major emphasis placed on ionic liquids as bearers of desired biological activity.
- Biological activity of ionic liquids based on bis-pyridinium in Gram-positive and Gram- negative bacteriaPublication . Ferreira, Joana; Ferraz, Ricardo; Vieira, Mónica; Fernandes, Rúben; Branco, Luís C.; Noronha, João Paulo; Petrovski, eljko; Prudêncio, CristinaResistance to antibiotics is becoming a public health problem and is the subject of concern from various global entities. In this context, finding new alternatives to combat microbial infections is critical. Ionic liquids (ILs) come up as a resource to be used in the pharmaceutical industry, especially in the synthesis of new antibiotics. The ILs have shown the ability to improve the characteristics of active pharmaceutical ingredients. However this is not the only the relevance of these compounds, antimicrobial properties also have been described. The bis-pyridinium ILs are now being studied as antimicrobial agents in the present study.
- Bioactivity of ionic liquids based on valproate in the human osteoclastogenesisPublication . Correia, Joana; Ferraz, Ricardo; Costa-Rodrigues, João; Fernandes, Maria Helena; Branco, Luís C.; Noronha, João Paulo; Petrovski, eljko; Prudêncio, CristinaIonic Liquids (ILs) are salts (with at least one organic cation), that have a melting point lower than 100º C. The interest in these compounds has been increasing as well as the number of applications where they can be used. Their first applications were on batteries and in organic synthesis and soon they started to be applied on health sciences. With this work we intend to study the biological properties of ILs based on valproate, and evaluate their modulation potential on human osteoclastogenesis.