Miguel Prudêncio

Miguel Prudêncio
Instituto de Medicina Molecular

Biochemistry - Biological Sciences - Malaria

About

216
Publications
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Publications

Publications (216)
Article
Full-text available
Hybrid-based drugs linked through a transition metal constitute an emerging concept for Plasmodium intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine (PQ) linked by gold(I), named [AuAQPQ]PF6. This c...
Article
Full-text available
Background Targeting the asymptomatic liver stage of Plasmodium infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality. Methods M5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refin...
Article
Full-text available
Malaria remains one of the world’s most prevalent infectious diseases. Several vaccination strategies currently under investigation aim at hampering the development of the Plasmodium parasite during the clinically silent liver stage of its life cycle in the mammalian host, preventing the subsequent disease-associated blood stage of infection. Immun...
Article
Malaria remains one of the major health problems worldwide. The lack of an effective vaccine and the increasing resistance of Plasmodium to the approved antimalarial drugs demands the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Harmiquins represent hybrids that combine two moieties with differe...
Article
Full-text available
Combination 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 agai...
Article
Full-text available
Toxoplasmosis 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 Plasmodiu...
Article
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 urge...
Article
While the liver and blood stages of the Plasmodium life cycle are commonly regarded as two separate fields of malaria research, several studies have pointed towards the existence of a bidirectional cross-talk, where one stage of mammalian infection may impact the establishment and progression of the other. Despite the constraints in experimentally...
Article
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With its strong effect on vector-borne diseases, and insecticidal effect on mosquito vectors of malaria, inhibition of sporogonic and blood-stage development of Plasmodium falciparum , as well as in vitro and in vivo impairment of the P. berghei development inside hepatocytes, ivermectin (IVM) continues to represent an antimalarial therapeutic wort...
Article
Inspired 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 activ...
Article
Full-text available
A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei hepatic infection and to decrease the viability of P. falciparum g...
Article
Full-text available
Malaria, a disease caused by Plasmodium parasites, remains a major threat to public health globally. It is the most common disease in patients with sleeping sickness, another parasitic illness, caused by Trypanosoma brucei . We have previously shown that a T . brucei infection impairs a secondary P . berghei liver infection and decreases malaria se...
Article
The rise of the resistance of the malaria parasite to the currently approved therapy urges the discovery and development of new efficient agents. Previously we have demonstrated that harmicines, hybrid compounds composed from β-carboline alkaloid harmine and cinnamic acid derivatives, linked via either triazole or amide bond, exert significant anti...
Article
In the last few decades, considerable efforts have been made towards the development of efficient vaccines against malaria. Whole‐sporozoite (Wsp) vaccines, which induce efficient immune responses against the pre‐erythrocytic (PE) stages (sporozoites and liver forms) of Plasmodium parasites, the causative agents of malaria, are among the most promi...
Article
The synthesis and anti-microbial activity of new spiro-β-lactams is reported. The design of the new molecules was based on the structural modulation of two previously identified lead spiro-penicillanates with dual activity against HIV and Plasmodium. The spiro-β-lactams synthesized were assayed for their in vitro activity against HIV-1, providing r...
Article
The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We...
Article
A series of morpholine analogs functionalized with hydroxyethylamine (HEA) pharmacophore was synthesized and assayed for the initial screening against Plasmodium falciparum 3D7 in culture, which suggested that analog 6k is a hit molecule with an inhibitory concentration of 5.059 ± 0.2036 μM.
Article
Full-text available
Plasmodium parasites, causative agents of malaria, scavenge host nutrients to sustain their intracellular replication. Modulation of the host's nutritional status can potentially help control infection by limiting the parasite's access to nutrients, or by boosting the immune system. Here, we show that dietary supplementation of mice employing a com...
Article
Multi‐stage drugs have been prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. Herein, we disclose two novel acridine‐based families of compounds that combine the structural features of...
Article
Full-text available
Harmicines represent hybrid compounds composed of β-carboline alkaloid harmine and cinnamic acid derivatives (CADs). In this paper we report the synthesis of amide-type harmicines and the evaluation of their biological activity. N-harmicines 5a-f and O-harmicines 6a-h were prepared by a straightforward synthetic procedure, from harmine-based amines...
Article
A small library of "half-sandwich" cyclopentadienylruthenium(II) compounds of the general formula [(η5-C5R5)Ru(PPh3)(N-N)][PF6], a scaffold hitherto absent from the toolbox of antiplasmodials, was screened for activity against the blood stage of CQ-sensitive 3D7-GFP, CQ-resistant Dd2, and artemisinin-resistant IPC5202 Plasmodium falciparum strains...
Article
Full-text available
Malaria remains one of the most prevalent infectious diseases worldwide, primarily affecting some of the most vulnerable populations around the globe. Despite achievements in the treatment of this devastating disease, there is still an urgent need for the discovery of new drugs that tackle infection by Plasmodium parasites. However, de novo drug de...
Article
Full-text available
For some diseases, successful vaccines have been developed using a nonpathogenic counterpart of the causative microorganism of choice. The nonpathogenicity of the rodent Plasmodium berghei ( Pb ) parasite in humans prompted us to evaluate its potential as a platform for vaccination against human infection by Plasmodium falciparum ( Pf ), a causativ...
Article
The anticancer, antimicrobial and antiplasmodial activities of six gold(III) bis(dithiolene) complexes were studied. Complexes (1-6) showed relevant anticancer properties against A2780/A2780cisR ovarian cancer cells (IC50 values of 0.08-2 µM), also being able to overcome cisplatin resistance on A2780cisR cells. Complex 1 also exhibited significant...
Preprint
p> A small library of “half-sandwich” cyclopentadienylruthenium(II) compounds of general formula [( η<sup>5</sup>-C<sub>5</sub>R<sub>5</sub>)Ru(PPh<sub>3</sub>)(N-N)][PF<sub>6</sub>], a scaffold hitherto unfeatured in the toolbox of antiplasmodials, was screened for activity against the blood stage of CQ-sensitive 3D7-GFP, CQ-resistant Dd2 and arte...
Article
Ivermectin is a powerful endectocide, which reduces the incidence of vector-borne diseases. Besides its strong insecticidal effect on mosquito vectors of the disease, ivermectin inhibits Plasmodium falciparum sporogonic and blood stage development, as well as impairs P. berghei development inside hepatocytes, both in vitro and in vivo. Herein, we p...
Article
Full-text available
Coendemicity between the human immunodeficiency virus (HIV) and Plasmodium parasites, the causative agents of acquired immunodeficiency syndrome (AIDS) and malaria, respectively, occurs in several regions around the world. Although the impact of the interaction between these two organisms is not well understood, it is thought that the outcome of ei...
Article
Full-text available
Plasmodium parasites undergo a dramatic transformation during the liver stage of their life cycle, amplifying over 10,000-fold inside infected hepatocytes within a few days. Such a rapid growth requires large-scale interactions with, and manipulations of, host cell functions. Whereas hepatocyte polarity is well-known to be critical for liver functi...
Article
Aims To extend our previous studies on spirocyclic-β-lactams with anti-HIV and antiplasmodial properties to new spirocyclic-lactams in order to further explore structure-activity relationships. Background We have previously reported the synthesis of chiral spirocyclic-β-lactam derivatives via 1,3-dipolar cycloaddition of 6-diazopenicillanates with...
Article
Full-text available
Background: The transmissible forms of Plasmodium parasites result from a process of sporogony that takes place inside their obligatory mosquito vector and culminates in the formation of mammalian-infective parasite forms. Ivermectin is a member of the avermectin family of endectocides, which has been proposed to inhibit malaria transmission due i...
Article
Full-text available
Sleeping sickness and malaria are parasitic diseases with overlapping geographical distributions in sub-Saharan Africa. We hypothesized that the immune response elicited by an infection with Trypanosoma brucei, the etiological agent of sleeping sickness, would inhibit a subsequent infection by Plasmodium, the malaria parasite, decreasing the severi...
Article
The restricted pipeline of drugs targeting the liver stage of Plasmodium infection reflects the scarcity of cell models that mimic the human hepatic phenotype and drug metabolism, as well as Plasmodium hepatic infection. Using stirred-tank culture systems, spheroids of human hepatic cell lines were generated, sustaining a stable hepatic phenotype o...
Article
Full-text available
This paper describes a continuation of our efforts in the pursuit of novel antiplasmodial agents with optimized properties. Following our previous discovery of biologically potent asymmetric primaquine (PQ) and halogenaniline fumardiamides (1–6), we now report their significant in vitro activity against the hepatic stages of Plasmodium parasites. F...
Article
Primaquine homodimers, e.g. symmetric PQ-diamides of dicarboxylic acids containing 4 to 8 carbon atoms, were evaluated against Plasmodium berghei hepatic stages and P. falciparum blood stages, as well as against three cancer cell lines. Novel PQ-homodimers exerted much higher activity against hepatic stages, but less pronounced activity against blo...
Article
Full-text available
Intracellular Plasmodium parasites develop inside a parasitophorous vacuole (PV), a specialized compartment enclosed by a membrane (PVM) that contains proteins of both host and parasite origin. Although exported protein 1 (EXP1) is one of the earliest described parasitic PVM proteins, its function throughout the Plasmodium life cycle remains insuff...
Article
Full-text available
The paper is focused on the synthesis and screening of the antiplasmodial activity of novel fumardiamides 5-10 with the mefloquine pharmacophore and a Michael acceptor motif. Multi-step reactions leading to the title compounds included two amide bond formations. The first amide bond was achieved by the reaction of (E)-ethyl 4-chloro-4-oxobut-2-enoa...
Article
Major progress has been made in the control of malaria leading to significantly reduce the number of cases and deaths. However, to reach the elimination stage, new tools will be needed, including combination of drugs capable of blocking the spread of malaria through chemoprophylaxis. M5717 is a first-in-class compound that targets the Plasmodium Eu...
Article
Structure-activity relationship studies involving N-aryl-3-trifluoromethyl pyrido[1,2-a] benzimidazoles (PBI) identified several compounds possessing potent in vitro activities against the asexual blood, liver and gametocyte stages of the Plasmodium parasite with no cross-resistance to chloroquine. Frontrunner lead compounds with good in vitro abso...
Article
A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against Plasmodium parasite’s life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liv...
Article
Full-text available
There is a pressing need for safe and highly effective Plasmodium falciparum (Pf) malaria vaccines. The circumsporozoite protein (CS), expressed on sporozoites and during early hepatic stages, is a leading target vaccine candidate, but clinical efficacy has been modest so far. Conversely, whole-sporozoite (WSp) vaccines have consistently shown high...
Article
Full-text available
Malaria: Pre-clinical characterization of transgenic malaria vaccine PbVac is a transgenic malaria parasite expressing circumsporozoite antigen from the human parasite Plasmodium falciparum. PbVac elicits neutralizing P. falciparum antibodies and can infect human hepatocytes but not erythrocytes, suggesting that humans would be non-permissive. Migu...
Article
Novel primaquine-cell penetrating peptide conjugates were synthesised and tested in vitro against liver stage Plasmodium berghei parasites. Generally, the conjugates were more active than the parent peptides and, in some...
Article
Full-text available
We report the synthesis of SAHAquines and related primaquine (PQ) derivatives. SAHAquines are novel hybrid compounds that combine moieties of suberoylanilide hydroxamic acid (SAHA), an anticancer agent with weak antiplasmodial activity, and PQ, an antimalarial drug with low antiproliferative activity. The preparation of SAHAquines is simple, cheap,...
Article
Hybrid compounds may play a critical role in the context of the malaria eradication agenda, which will benefit from therapeutic tools active against the symptomatic erythrocytic stage of Plasmodium infection, and also capable of eliminating liver stage parasites. To address the need for efficient multistage antiplasmodial compounds, a small library...
Article
Fifteen Amaryllidaceae alkaloids (1–15) of various structural types were isolated by standard chromatographic methods from fresh bulbs of Narcissus poeticus cv. Pink Parasol. The chemical structures were elucidated by MS, and 1D and 2D NMR spectroscopic analyses, and by comparison with literature data. Narcipavline (5) and narcikachnine (6) are rep...
Article
Four series of primaquine (PQ) derivatives were screened for antitubercular and antiplasmodial activity: amides 1a-k, ureas 2a-s, semicarbazides 3a-c and bis-ureas 4a-u. Antimycobacterial activity of PQ derivatives against Mycobacterium tuberculosis (MTB), M. avium complex (MAC) and M. avium subsp. paratuberculosis (MAP) were evaluated in vitro and...
Article
Chloroquine is an antimalarial agent with strong activity against the blood stage of Plasmodium infection, but with low activity against the parasite’s liver stage. In addition, the resistance to chloroquine...
Article
Full-text available
Recent WHO guidelines on control of human immunodeficiency virus (HIV) call for the widespread use of antiretroviral (AR) therapy (ART) for people living with HIV. Given the considerable overlap between infections by HIV and Plasmodium, the causative agent of malaria, it is important to understand the impact of AR compounds and ART regimens on infe...
Data
In vivo experimental setup. (A) Schedules and doses of administration of antiretroviral drugs. (B) Schematic illustration of the in vivo experimental setup, highlighting the schedules of drug treatment employed.
Article
Full-text available
Prior to infecting erythrocytes and causing malaria symptoms, Plasmodium parasites undergo an obligatory phase of invasion and extensive replication inside their mammalian host’s liver cells that depends on the parasite’s ability to obtain the nutrients it requires for its intra-hepatic growth and multiplication. Here, we show that L-arginine (Arg)...