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Dive into the research topics where Francisca Lopes is active.

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Featured researches published by Francisca Lopes.


Journal of Medicinal Chemistry | 2012

Targeting the liver stage of malaria parasites: a yet unmet goal.

Tiago Rodrigues; Miguel Prudêncio; Rui Moreira; Maria M. Mota; Francisca Lopes

Tiago Rodrigues,† Miguel Prudencio,‡ Rui Moreira,*,† Maria M. Mota,‡ and Francisca Lopes† †Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal ‡Unidade de Malaŕia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal


Antimicrobial Agents and Chemotherapy | 2011

Design and evaluation of primaquine-artemisinin hybrids as a multistage antimalarial strategy.

Rita Capela; Ghislain G. Cabal; Philip J. Rosenthal; Jiri Gut; Maria M. Mota; Rui Moreira; Francisca Lopes; Miguel Prudêncio

ABSTRACT It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The “magic bullet” thought to be necessary to reach eradication should not only provide treatment for all Plasmodium spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared in vitro and in vivo with those of the parent compounds. Both hybrids displayed enhanced in vitro activities, relative to those of the parent compounds, against Plasmodium berghei liver stages. Both compounds were about as potent as artemisinin against cultured Plasmodium falciparum (50% inhibitory concentration [IC50], ∼10 nM). When used to treat a murine P. berghei infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.


Bioorganic & Medicinal Chemistry Letters | 2009

Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: Design, synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition

Rita Capela; Rudi Oliveira; L. M. Gonçalves; Ana Domingos; Jiri Gut; Philip J. Rosenthal; Francisca Lopes; Rui Moreira

A series of artemisinin-vinyl sulfone hybrid molecules with the potential to act in the parasite food vacuole via endoperoxide activation and falcipain inhibition was synthesized and screened for antiplasmodial activity and falcipain-2 inhibition. All conjugates were active against the Plasmodium falciparum W2 strain in the low nanomolar range and those containing the Leu-hPhe core inhibited falcipain-2 in low micromolar range.


ACS Medicinal Chemistry Letters | 2014

Novel Endoperoxide-Based Transmission-Blocking Antimalarials with Liver- and Blood-Schizontocidal Activities

Daniela Miranda; Rita Capela; Inês S. Albuquerque; Patrícia Meireles; Isa Paiva; Fátima Nogueira; Richard Amewu; Jiri Gut; Philip J. Rosenthal; Rudi Oliveira; Maria M. Mota; Rui Moreira; Francesc Marti; Miguel Prudêncio; Paul M. O’Neill; Francisca Lopes

In a search for effective compounds against both the blood- and liver-stages of infection by malaria parasites with the ability to block the transmission of the disease to mosquito vectors, a series of hybrid compounds combining either a 1,2,4-trioxane or 1,2,4,5-tetraoxane and 8-aminoquinoline moieties were synthesized and screened for their antimalarial activity. These hybrid compounds showed high potency against both exoerythrocytic and erythrocytic forms of malaria parasites, comparable to representative trioxane-based counterparts. Furthermore, they efficiently blocked the development of the sporogonic cycle in the mosquito vector. The tetraoxane-based hybrid 5, containing an amide linker between the two moieties, effectively cleared a patent blood-stage P. berghei infection in mice after i.p. administration. Overall, these results indicate that peroxide-8-aminoquinoline hybrids are excellent starting points to develop an agent that conveys all the desired antimalarial multistage activities in a single chemical entity and, as such, with the potential to be used in malaria elimination campaigns.


Bioorganic & Medicinal Chemistry | 2000

Acyloxymethyl as a drug protecting group. Part 6: N-Acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides as prodrugs of agents containing a secondary sulfonamide group

Francisca Lopes; Rui Moreira; Jim Iley

Tertiary N-acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides were synthesised and evaluated as novel classes of potential prodrugs of agents containing a secondary sulfonamide group. The chemical and plasma hydrolyses of the title compounds were studied by HPLC. Tertiary N-acyloxymethylsulfonamides are slowly and quantitatively hydrolysed to the parent sulfonamide in pH 7.4 phosphate buffer, with half-lives ranging from 20 h, for 7d, to 30 days, for 7g. Quantitative formation of the parent sulfonamide also occurs in human plasma, the half-lives being within 0.2-2.0 min for some substrates. The rapid rate of hydrolysis can be ascribed to plasma cholinesterase, as indicated by the complete inhibition observed at [eserine] = 0.10 mM. These results suggest that tertiary N-acyloxymethylsulfonamides are potentially useful prodrugs for agents containing a secondary sulfonamide group, especially with pKa < 8, combining a high stability in aqueous media with a high rate of plasma activation. In contrast, N-[(aminocarbonyloxy)methyl]sulfonamides 7h-j do not liberate the parent sulfonamide either in aqueous buffers or in human plasma and thus appear to be unsuitable for development as sulfonamide prodrugs.


Journal of Medicinal Chemistry | 2014

Tetraoxane–Pyrimidine Nitrile Hybrids as Dual Stage Antimalarials

Rudi Oliveira; Rita C. Guedes; Patrícia Meireles; Inês S. Albuquerque; L. M. Gonçalves; Elisabete Pires; Maria R. Bronze; Jiri Gut; Philip J. Rosenthal; Miguel Prudêncio; Rui Moreira; Paul M. O’Neill; Francisca Lopes

The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.


ChemMedChem | 2013

An Endoperoxide-Based Hybrid Approach to Deliver Falcipain Inhibitors Inside Malaria Parasites

Rudi Oliveira; Ana S. Newton; Rita C. Guedes; Daniela Miranda; Richard Amewu; Abhishek Srivastava; Jiri Gut; Philip J. Rosenthal; Paul M. O'Neill; Stephen A. Ward; Francisca Lopes; Rui Moreira

The emergence of artemisinin‐resistant Plasmodium falciparum malaria in Southeast Asia has reinforced the urgent need to discover novel chemotherapeutic strategies to treat and control malaria. To address this problem, we prepared a set of dual‐acting tetraoxane‐based hybrid molecules designed to deliver a falcipain‐2 (FP‐2) inhibitor upon activation by iron(II) in the parasite digestive vacuole. These hybrids are active in the low nanomolar range against chloroquine‐sensitive and chloroquine‐resistant P. falciparum strains. We also demonstrate that in the presence of FeBr2 or within infected red blood cells, these molecules fragment to release falcipain inhibitors with nanomolar protease inhibitory activity. Molecular docking studies were performed to better understand the molecular interactions established between the tetraoxane‐based hybrids and the cysteine protease binding pocket residues. Our results further indicate that the intrinsic activity of the tetraoxane partner compound can be masked, suggesting that a tetraoxane‐based delivery system offers the potential to attenuate the off‐target effects of known drugs.


Bioorganic & Medicinal Chemistry Letters | 2009

Design, synthesis and structure-activity relationships of (1H-pyridin-4-ylidene)amines as potential antimalarials

Tiago Rodrigues; Rita C. Guedes; Daniel Santos; Marta P. Carrasco; Jiri Gut; Philip J. Rosenthal; Rui Moreira; Francisca Lopes

(1H-Pyridin-4-ylidene)amines containing lipophilic side chains at the imine nitrogen atom were prepared as potential clopidol isosteres in the development of antimalarials. Their antiplasmodial activity was evaluated in vitro against the Plasmodium falciparum W2 (chloroquine-resistant) and FCR3 (atovaquone-resistant) strains. The most active of these derivatives, 4m, had an IC(50) of 1microM against W2 and 3microM against FCR3. Molecular modeling studies suggest that (1H-pyridin-4-ylidene)amines may bind to the ubiquinol oxidation Q(o) site of cytochrome bc(1).


Journal of Medicinal Chemistry | 2013

Quinolin-4(1H)-imines are potent antiplasmodial drugs targeting the liver stage of malaria.

Tiago Rodrigues; Filipa P. da Cruz; Maria J. Lafuente-Monasterio; Daniel Gonçalves; Ana S. Ressurreição; Ana Raquel Sitoe; Maria R. Bronze; Jiri Gut; Gisbert Schneider; Maria M. Mota; Philip J. Rosenthal; Miguel Prudêncio; Francisco-Javier Gamo; Francisca Lopes; Rui Moreira

We present a novel series of quinolin-4(1H)-imines as dual-stage antiplasmodials, several-fold more active than primaquine in vitro against Plasmodium berghei liver stage. Among those, compounds 5g and 5k presented low nanomolar IC50 values. The compounds are metabolically stable and modulate several drug targets. These results emphasize the value of quinolin-4(1H)-imines as a new chemotype and their suitable properties for further drug development.


Bioorganic & Medicinal Chemistry | 2015

From hybrid compounds to targeted drug delivery in antimalarial therapy

Rudi Oliveira; Daniela Miranda; Joana Magalhães; Rita Capela; Maria de Jesus Perry; Paul M. O’Neill; Rui Moreira; Francisca Lopes

The discovery of new drugs to treat malaria is a continuous effort for medicinal chemists due to the emergence and spread of resistant strains of Plasmodium falciparum to nearly all used antimalarials. The rapid adaptation of the malaria parasite remains a major limitation to disease control. Development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the emergence of resistant parasite strains. This review presents the journey that started with simple combinations of two active moieties into one chemical entity and progressed into a delivery/targeted system based on major antimalarial classes of drugs. The rationale for providing different mechanisms of action against a single or additional targets involved in the multiple stages of the parasites life-cycle is highlighted. Finally, a perspective for this polypharmacologic approach is presented.

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Tiago Rodrigues

Instituto de Medicina Molecular

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Jiri Gut

University of California

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Miguel Prudêncio

Instituto de Medicina Molecular

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Maria M. Mota

Instituto de Medicina Molecular

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