Browsing by Author "Silva, Ana Teresa"
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- Antiproliferative organic salts derived from betulinic acid: Disclosure of an ionic liquid selective against lung and liver cancer cellsPublication . Silva, Ana Teresa; Cerqueira, Maria João; Prudêncio, Cristina; Fernandes, Maria Helena; Costa-Rodrigues, João; Teixeira, Cátia; Gomes, Paula; Ferraz, RicardoIn the last few years, we have been witnessing an increasing interest in ionic liquids (ILs) and organic salts, given their potential applications in biological and pharmaceutical sciences. We report the synthesis and in vitro evaluation of novel organic salts combining betulinate, known for its anticancer properties, with antimalarial drugs, primaquine, chloroquine, and mepacrine, and also with the trihexyltetradecylphosphonium ([P6,6,6,14]) cation. The salts were screened for their in vitro activity against tumor lines HepG2 (liver), MG63 (osteosarcoma), T47D (breast), A459 (lung), and RKO (colon), and also on normal human fibroblasts. All betulinates prepared displayed antiproliferative properties, with the trihexyltetradecylphosphonium betulinate standing out for its higher selectivity. This unprecedented disclosure of a betulinic acid (BA)-derived IL with selective antitumor activity constitutes a relevant first step toward development of novel anticancer therapies based on BA-derived IL.
- Building on Surface-Active Ionic Liquids for the Rescuing of the Antimalarial Drug ChloroquinePublication . Silva, Ana Teresa; Lis, Lobo; Oliveira, Isabel S.; Gomes, Joana; Teixeira, Cátia; Nogueira, Fátima; Marques, Eduardo F.; Ferraz, Ricardo; Gomes, PaulaIonic liquids derived from classical antimalarials are emerging as a new approach towards the cost-effective rescuing of those drugs. Herein, we disclose novel surface-active ionic liquids derived from chloroquine and natural fatty acids whose antimalarial activity in vitro was found to be superior to that of the parent drug. The most potent ionic liquid was the laurate salt of chloroquine, which presented IC50 values of 4 and 110 nM against a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum, respectively, corresponding to an 11- and 6-fold increase in potency as compared to the reference chloroquine bisphosphate salt against the same strains. This unprecedented report opens new perspectives in both the fields of malaria chemotherapy and of surface-active ionic liquids derived from active pharmaceutical ingredients.
- Cinnamic acid conjugates in the rescuing and repurposing of classical antimalarial drugsPublication . Silva, Ana Teresa; Bento, Clara M.; Pena, Ana C.; Figueiredo, Luísa M.; Prudêncio, Cristina; Aguiar, Luísa; Silva, Tânia; Ferraz, Ricardo; Gomes, Maria Salomé; Teixeira, Cátia; Gomes, PaulaCinnamic acids are compounds of natural origin that can be found in many different parts of a wide panoply of plants, where they play the most diverse biological roles, often in a conjugated form. For a long time, this has been driving Medicinal Chemists towards the investigation of the therapeutic potential of natural, semi-synthetic, or fully synthetic cinnamic acid conjugates. These efforts have been steadily disclosing promising drug leads, but a wide chemical space remains that deserves to be further explored. Amongst different reported approaches, the combination or conjugation of cinnamic acids with known drugs has been addressed in an attempt to produce either synergistic or multi-target action. In this connection, the present review will focus on efforts of the past decade regarding conjugation with cinnamic acids as a tool for the rescuing or the repurposing of classical antimalarial drugs, and also on future perspectives in this particular field of research.
- Combining natural bile acids with old basic drugs affords new triple stage antimalarial surface-active ionic liquidsPublication . Silva, Ana Teresa; Oliveira, Isabel; Duarte, Denise; Moita, Diana; Prudêncio, Miguel; Nogueira, Fátima; Ferraz, Ricardo; Marques, Eduardo F.; Gomes, PaulaIonic liquids (ILs) are special organic salts that have been gaining momentum in medicinal chemistry. Despite their simple and cost-effective synthesis, ILs offer an easy access to structures of biological interest by combining bioactive molecules with opposite polarities, e.g., via simple ionic pairing of an acid with a base. This makes ILs of special interest for treating malaria. Since this disease is prevalent mainly in low-to-middle income countries, novel chemotherapeutic strategies must be kept affordable. Malaria is caused by Plasmodium parasites, whose complex life cycle includes three developmental stages in the host: the blood stage, the liver stage, and the gametocyte stage. This complexity turns the development of new effective drugs quite difficult, which is aggravated by the fast emergence of drug-resistant strains. This fact has often led to the disuse of several antimalarials, driving the need to find new ones with multiple-stage action. In this context, we have been working on new antimalarial ILs by mixing antimalarial aminoquinolines—chloroquine and primaquine—with natural lipids. Two new families of salts derived from those antimalarial drugs and naturally-occurring bile acids were now produced by acid-base neutralization, and evaluated for their antiplasmodial action. The chloroquine-derived bile salts were found active against all the three stages of parasite development in the host. Their behavior as surface-active ionic liquids (SAILs), i.e. their interfacial and self-aggregation properties, were also investigated, as they may contribute critically to their delivery and therapeutic action.
- Drug-derived surface-active ionic liquids: a cost-effective way to expressively increase the blood-stage antimalarial activity of primaquinePublication . Silva, Ana Teresa; Oliveira, Isabel S.; Gomes, Joana; Aguiar, Luísa; Fontinha, Diana; Duarte, Denise; Nogueira, Fátima; Prudêncio, Miguel; Marques, Eduardo F.; Teixeira, Cátia; Ferraz, Ricardo; Gomes, PaulaInspired by previous disclosure of room-temperature ionic liquids derived from primaquine and cinnamic acids, which displayed slightly enhanced blood-stage activity compared to the parent drug, we have now combined this emblematic antimalarial with natural fatty acids. This affords surface-active ionic liquids whose liver-stage antiplasmodial activity is either retained or slightly enhanced, while revealing blood-stage antiplasmodial activity at least one order of magnitude higher than that of the parent compound. These findings open new perspectives towards the cost-effective recycling of classical drugs that are either shelved or in decline, and which is not limited to antimalarial agents.
- High efficacy of chloroquine-derived bile salts in Pluronic F127 micelles against blood-stage Plasmodium falciparumPublication . Silva, Ana Teresa; Prudêncio, Miguel; Oliveira, Isabel S.; Nogueira, Fátima; Morais, Inês; Santana, Sofia; Ferraz, Ricardo; Workneh, Eyob A.; Gomes, Paula; Marques, Eduardo F.; Ferraz, RicardoColloidal nanocarriers can play a key role in the efficacious delivery of drugs, including antimalarials. Here, we investigated the ability of polymeric micelles of the block copolymer F127 to act as nanovehicles for two organic salts derived from chloroquine and human bile acids, namely, chloroquinium cholate (iCQP1) and chloroquinium glycocholate (iCQP1g). We have previously reported the strong in vitro antiplasmodial activity of these salts, which displayed IC50 values of 13 and 15 nM against blood forms of Plasmodium falciparum, respectively. By deriving from amphiphilic lipids, iCQP1 and iCQP1g also enclose the ability to act as surface-active ionic liquids (SAILs). The micellization properties of neat F127 and of the F127/SAIL mixtures were initially investigated to gain physicochemical insight into the interaction between polymer and bioactive SAILs, resorting to differential scanning calorimetry, surface tension measurements and dynamic light scattering. Micelle formation by F127 is an endothermic process strongly temperature and concentration dependent. Interestingly, this process is significantly changed when the molar fraction of SAIL (xSAIL) in the F127/SAIL mixture is varied between 0.33 and 0.90. Both SAILs favor the formation of mixed micelles by decreasing the micellization temperature, and (observed only when for xSAIL = 0.33) by synergistically decreasing the cmc. Concomitantly, the micellar size is reduced from 18 to 13 nm as xSAIL is increased from 0.33 to 0.90. Crucially, in vitro assays show that when the SAILs are loaded into F127 polymeric micelles, their antiplasmodial efficacy is substantially enhanced, with a significant drop in IC50, especially for the iCQP1/F127 system. This opens new possibilities for the nanoformulations of antimalarial compounds.
- Improving the antimycobacterial drug Clofazimine through formation of organic salts by combination with fluoroquinolonesPublication . Bento, Clara M.; Silva, Ana Teresa; Mansano, Bruno; Aguiar, Luísa; Teixeira, Cátia; Gomes, Maria Salomé; Gomes, Paula; Silva, Tânia; Ferraz, RicardoThis work reports the synthesis, structural and thermal analysis, and in vitro evaluation of the antimicrobial activity of two new organic salts (OSs) derived from the antimycobacterial drug clofazimine and the fluoroquinolones ofloxacin or norfloxacin. Organic salts derived from active pharmaceutical ingredients (API-OSs), as those herein disclosed, hold promise as cost-effective formulations with improved features over their parent drugs, thus enabling the mitigation of some of their shortcomings. For instance, in the specific case of clofazimine, its poor solubility severely limits its bioavailability. As compared to clofazimine, the clofazimine-derived OSs now reported have improved solubility and thermostability, without any major deleterious effects on the drug’s bioactivity profile.
- A new strategy against malaria – antimalarial ionic liquids derived from aminoquinolines and fatty acidsPublication . Silva, Ana Teresa; Teixeira, Cátia; Fontinha, Diana; Prudêncio, Cristina; Prudêncio, Miguel; Gomes, Paula; Ferraz, RicardoBased on the recent promising results obtained by us, where ionic liquids (ILs) derived from primaquine were found as triple-stage antimalarial hits, we have now produced, by simple, quantitative, and low-cost methods, new ILs via simple acid-base titration of antimalarial aminoquinolines (primaquine and chloroquine) with natural fatty acids (Figure 1). We have also synthesized, in good to high yields, the covalent amide analogues of these ILs (Figure 1), in order to establish how the nature of the chemical bond (ionic ammonium carboxylate versus covalent amide) between both building blocks influences the physico-chemical and biological properties of the final compounds. Results obtained thus far allow us to conclude that both ionic and covalent compounds (i) have higher thermostability than the parent drugs, and (ii) display remarkable in vitro activity against liver-stage malaria parasites.
- Poderão os líquidos iónicos revolucionar a indústria farmacêutica?Publication . Silva, Ana Teresa; Ferraz, Ricardo; Teixeira, Cátia; Prudêncio, Cristina; Gomes, PaulaOs líquidos iónicos definem-se, atualmente, como sais (com pelo menos um ião orgânico) estáveis acima do seu ponto de fusão. Este tipo especial de sais apresenta propriedades muito interessantes a nível físico, químico e biológico. Recentemente, os líquidos iónicos despertaram a atenção da indústria farmacêutica e das Ciências da Vida, na medida em que algumas das características daqueles compostos podem ser relevantes tendo em vista as suas potenciais aplicações terapêuticas. Nomeadamente, os líquidos iónicos poderão apresentar propriedades físico-químicas mais favoráveis como, por exemplo, hidrossolubilidade, para além do facto de os líquidos iónicos (líquidos à temperatura ambiente e/ou à temperatura do corpo humano) não apresentarem polimorfismo, um aspeto que frequentemente limita as condições de uso e a eficácia terapêutica de ingredientes farmacêuticos ativos sólidos. Adicionalmente, uma escolha criteriosa dos iões a emparelhar permite afinar essas propriedades, oferecendo ainda a possibilidade de combinar duas moléculas bioativas que tenham grupos ionizáveis de carga oposta, formando líquidos iónicos com efeito terapêutico dual. Em virtude desta e de outras características apelativas dos líquidos iónicos, poderão estes vir a revolucionar a indústria farmacêutica?
- Surface-active ionic liquids derived from antimalarial drugs and natural lipids that display multi-stage antiplasmodial activityPublication . Ferraz, Ricardo; Silva, Ana Teresa; Oliveira, Isabel S.; Duarte, Denise; Moita, Diana; Nogueira, Fátima; Prudêncio, Miguel; Gomes, Paula; Marques, Eduardo F.The use of Ionic Liquids (ILs) in Medicinal and Pharmaceutical Chemistry has been greatly evolving since they were first used as alternative solvents for the chemical synthesis of active pharmaceutical ingredients (APIs). ILs are now used with other purposes in this area, such as adjuvants in drug formulation and delivery, or even as bioactive compounds per se. New ionic structures with biologically relevant properties can be easily obtained through straightforward reactions, as nearly all APIs are ionizable and can be paired with counter-ions that could be either inert or offer additional beneficial biological effects. This efficient, cost-effective strategy for the rescuing and repurposing of drugs is particularly appealing for finding new options to combat "diseases of poverty" like malaria. We implemented this approach to “recycle” classical antimalarial aminoquinolines, namely, chloroquine (CQ) and primaquine (PQ), by pairing them with natural acidic lipids through acid-base reactions. Our goal was to create novel ILs capable of targeting multiple stages of the Plasmodium parasite’s life cycle. Additionally, we were interested in that such ILs could act as surface-active ionic liquids (SAILs), able to self-assemble into nanostructures displaying adequate bioavailability. For this purpose, we paired the antimalarial drugs with either fatty acids or bile acids, due to their biocompatibility and amphiphilic nature. The antiplasmodial activity and self-aggregation properties of the new SAILs were determined. PQ fatty acid salts preserved the liver-stage antiplasmodial activity of the original drug, while exhibiting significantly enhanced activity against blood-stage parasites. In the case of bile salts, those derived from PQ retained the efficacy of the parent drug, whereas the CQ-derived salts proved to be novel triple-stage antiplasmodial agents. The SAILs obtained from bile acids showed a remarkable ability to self-aggregate, with a notably lower critical micelle concentration compared to their respective sodium salts. Overall, these findings open a new strategy for drug repurposing, extending beyond antimalarials and other anti-infective therapies.