37 documents found, page 1 of 4
Unexpected rearrangement of ivermectin in the synthesis of new derivatives with...
Sulik, Michał; Fontinha, Diana; Steverding, Dietmar; Sobczak, Szymon; Antoszczak, Michał; Prudêncio, Miguel; Huczyński, AdamIvermectin is a sixteen-membered macrolactone "wonder drug" of Nobel prize-honored distinction that exhibits a wide range of antiparasitic activities. It has been used for almost four decades in the treatment of various parasitic diseases in humans and animals. In this paper, we describe the synthesis of the first-in-class ivermectin derivatives obtained via derivatization of the C13 position, along with the un...
A novel 4-aminoquinoline chemotype with multistage antimalarial activity and la...
Ferreira, Letícia Tiburcio; Cassiano, Gustavo Capatti; Alvarez, Luis Carlos Salazar; Okombo, John; Calit, Juliana; Fontinha, Diana; Gil-Iturbe, EvaArtemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs. In this study, we...
Facile Access to Structurally Diverse Antimalarial Indoles Using a One-Pot A3 C...
da Silva, Gustavo; Luz, André F. S.; Duarte, Denise; Fontinha, Diana; Silva, Vera L. M.; Almeida Paz, Filipe A.; Madureira, Ana M.; Simões, SandraA multistep and diversity-oriented synthetic route aiming at the A3 coupling/domino cyclization of o-ethynyl anilines, aldehydes and s-amines is described. The preparation of the corresponding precursors included a series of transformations, such as haloperoxidation and Sonogashira cross-coupling reactions, amine protection, desilylation and amine reduction. Some products of the multicomponent reaction underwen...
Facile access to structurally diverse antimalarial indoles using a one‐pot A3 c...
Silva, Gustavo Da; Luz, André F. S.; Duarte, Denise; Fontinha, Diana; Silva, Vera L. M.; Almeida Paz, Filipe A.; Madureira, Ana MargaridaA multistep and diversity-oriented synthetic route aiming at the A3 coupling/domino cyclization of o-ethynyl anilines, aldehydes and s-amines is described. The preparation of the corresponding precursors included a series of transformations, such as haloperoxidation and Sonogashira cross-coupling reactions, amine protection, desilylation and amine reduction. Some products of the multicomponent reaction underwen...
New 4-(N-cinnamoylbutyl)aminoacridines as potential multi-stage antiplasmodial ...
Fonte, Mélanie; Fontinha, Diana; Moita, Diana; Caño-Prades, Omar; Avalos-Padilla, Yunuen; Fernàndez-Busquets, Xavier; Prudêncio, Miguel; Gomes, PaulaA novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei, (ii) erythrocytic forms of Plasmodium falciparum, and (iii) early and mature gametocytes of Plasmodium falciparum. The mos...
New 4-aminoacridine-cinnamic acid conjugates as multi-stage antimalarial hits
Fonte, Mélanie; Fontinha, Diana; Moita, Diana; Prades, Omar; Padilla, Yunuen; Ferraz, Ricardo; Fernàndez-Busquets, Xavier; Prudêncio, MiguelThe 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 antipl...
A Histone Deacetylase (HDAC) inhibitor with pleiotropic in vitro anti-toxoplasm...
Jublot, Delphine; Cavaillès, Pierre; Kamche, Salima; Francisco, Denise; Fontinha, Diana; Prudêncio, Miguel; Guichou, Jean-Francois; Labesse, GillesToxoplasmosis is a highly prevalent human disease, and virulent strains of this parasite emerge from wild biotopes. Here, we report on the potential of a histone deacetylase (HDAC) inhibitor we previously synthesized, named JF363, to act in vitro against a large panel of Toxoplasma strains, as well as against the liver and blood stages of Plasmodium parasites, the causative agents of malaria. In vivo administra...
Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) ...
Le Gal, Yann; Filatre-Furcate, Agathe; Lorcy, Dominique; Jeannin, Olivier; Roisnel, Thierry; Dorcet, Vincent; Fontinha, Diana; Francisco, DeniseThe biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)...
Discovery of spirooxadiazoline oxindoles with dual-stage antimalarial activity
Lopes, Elizabeth A.; Mestre, Raquel; Fontinha, Diana; Legac, Jenny; Pei, Jinxin V.; Sanches-Vaz, Margarida; Mori, Mattia; Lehane, Adele M.Malaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urgently required. For this reason, new antimalarial chemotypes with...
Pre-erythrocytic activity of M5717 in monotherapy and combination in preclinica...
Fontinha, Diana; Arez, Francisca; Gal, Isabella Ramella; Nogueira, Gonçalo; Moita, Diana; Baeurle, Tobias Hyun Ho; Brito, Catarina; Spangenberg, ThomasCombination therapies have emerged to mitigate Plasmodium drug resistance, which has hampered the fight against malaria. M5717 is a potent multistage antiplasmodial drug under clinical development, which inhibits parasite protein synthesis. The combination of M5717 with pyronaridine, an inhibitor of hemozoin formation, displays potent activity against blood stage Plasmodium infection. However, the impact of thi...