Browsing by Author "Marques, Eduardo F."
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- 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.
- 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.
- Serine-based surfactants active against antibioticresistant bacteriaPublication . Dias, Ana Rita; Silva, Sandra G.; Prudêncio, Cristina; Gomes, Paula; Ferraz, Ricardo; Marques, Eduardo F.; Vale, M. Luísa C.Bacterial resistance to antibiotics has been a recognized reality almost since the dawn of the antibiotic era, but only within the past twenty years has the emergence of dangerous, resistant strains occurred with a disturbing regularity. As no new antibiotics have been developed in the last twenty years, existing drugs are quickly becoming ineffective.
- 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.
- Surfing the third wave of ionic liquids: a brief review on the role of surface-active ionic liquids in drug development and DeliveryPublication . Silva, Ana Teresa; Teixeira, Cátia; Prudêncio, Cristina; Marques, Eduardo F.; Gomes, Paula; Ferraz, RicardoThe relevance of ionic liquids (ILs) is now well established in many fields, as their unique properties make them appealing as 1) greener alternatives to organic solvents (first-generation ILs), 2) tunable task-specific materials (second-generation ILs), and 3) multifunctional players in life and pharmaceutical sciences (third-generation ILs). This third wave of ILs encompasses a wide range of compounds, from bioactive molecules with single or even dual therapeutic action, to potential ingredient molecules for drug formulation and transport systems. In this context, the focus of this review is the emergent role of surface-active ionic liquids (SAILs) in drug development and delivery.
- Synthesis and physicochemical characterization of antimalarial surface-active ionic liquidsPublication . Silva, Ana Teresa; Oliveira, Isabel; Ferraz, Ricardo; Marques, Eduardo F.; Gomes, PaulaIonic liquids are a particular class of compounds that attract interest in medicinal chemistry due to the simplicity of their preparation. Novel structures with biological activity can be achieved through simple, cost-effective reactions.1 Reusing old ionizable drugs and improving their characteristics can be achieved economically and simply by mixing them with molecules of opposite charge. This approach is attractive for reviving old antimalarials, not only because of the prevalence of malaria in low- to middle-income countries, but also because several of these drugs are associated with malaria parasite resistance. In this context, our work has been focusing on synthesizing ionic liquids with potential antimalarial activity by mixing antimalarial aminoquinolines, specifically chloroquine, and primaquine, with natural lipids.2, 3 More recently, using an acid-base reaction between chloroquine and bile acids (Figure 1), we synthesized surface-active ionic liquids (SAILs), which proved to possess significant antiplasmodial activity in vitro. The presence of an amphiphilic anion in the ionic pair confers surfaceactive and self-aggregation properties to the ionic liquids. The interfacial and aggregations properties of these SAILs have been characterized by surface tension, electric conductivity, dynamic light scattering, and differential scanning microcalorimetry. Moreover, the interactions of SAILs with micelles of the block copolymer F127 have been studied with the aim of designing an efficient, robust, and biocompatible nanocarrier system for the encapsulation and in vivo release of these antimalarial ionic liquids.
- Synthesis od new surface-active ionic liquids derived from antimalarial drugs and bile acidsPublication . Silva, Ana Teresa; Oliveira, Isabel; Duarte, Denise; Moita, Diana; Prudêncio, Miguel; Nogueira, Fátima; Teixeira, Cátia; Ferraz, Ricardo; Marques, Eduardo F.; Gomes, PaulaMalaria is a parasitic disease that occurs mostly in low-income countries, thus its containment or, ultimately, eradication demands new methodologies and synthetic strategies that are simple and inexpensive. Ionic liquids (ILs) may assume a prominent role in this scenario, as they are catching the attention of the Medicinal Chemistry community owing to their intrinsic biological activity and affordable synthesis through straightforward methods. In this context, our focus consists of using an acid-base reaction between basic antimalarial aminoquinolines, such as chloroquine and primaquine, and natural amphiphilic acids, such as fatty and bile acids. The resulting ILs are expected to preserve the parent aminoquinolines' antimalarial action, while retaining the surface activity of the parent amphiphilic acids, thus facilitating the permeation of the whole IL structure through important biological barriers. In other words, our aim is to develop surface-active ionic liquids (SAILs) with intrinsic antimalarial properties. Results obtained thus far will be presented, demonstrating that SAILs can be produced which are active against different stages of malaria parasite development in the human host. Self-aggregation properties of these SAILs are currently under investigation and will be timely reported.