Browsing by Author "Moita, Diana"
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- 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.
- New 4-aminoacridine-cinnamic acid conjugates as multi-stage antimalarial hitsPublication . Fonte, Mélanie; Fontinha, Diana; Moita, Diana; Prades, Omar; Padilla, Yunuen; Ferraz, Ricardo; Fernàndez-Busquets, Xavier; Prudêncio, Miguel; Gomes, Paula; Teixeira, CátiaThe eradication of malaria remains to be achieved, mainly due to the continued spread of drugresistant parasites. To overcome this, multi-stage drugs have been prioritized in antimalarial drug discovery, since targeting more than one process in the Plasmodium’s life cycle may increase efficiency, while decreasing the chances of resistance emergence by the parasite. Quinacrine (QN) was the first synthetic antiplasmodial drug active against blood forms of the Plasmodium parasite but was rapidly superseded by chloroquine (CQ) which has greater safety, efficiency, and bioavailability. Analysing the QN structure, its acridine core is a fusion between the heterocycle core of CQ and primaquine (PQ), another antiplasmodial drug active against liver forms of the parasite, and able to block malaria transmission. A new family of QN derivatives reported by us, 4-aminoacridines, corresponding to the merge of CQ core and PQ, showed moderate dual-stage antimalarial activity. We have now developed a second generation of 4-aminoacridines (Fig.1) through their conjugation to cinnamic acids (CA) of natural origin that have been reported to enhance antimalarial activity when conjugated to antimalarials. In this communication, we will present the chemical synthesis of this new family of N-cinnamoyl-4-aminoacridines and the in vitro assessment or their activity against a) liver stages of P. berghei, b) erythrocytic forms of P. falciparum, and c) early and mature gametocytes of P. falciparum. Results demonstrate that the conjugation of the CA moiety to the 4-aminoacridine core delivers new compounds with enhanced in vitro activity against all three stages of the malaria parasite lifecycle inside mammalian hosts.
- 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.
- 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.