Antiplasmodial, Trypanocidal, and Genotoxicity Assessment of New Hybrid α,α-Difluorophenylacetamide-statin Derivatives.

Background: Statins present a plethora of pleiotropic effects including anti-inflammatory and antimicrobial responses. A,α-difluorophenylacetamides, analogs of diclofenac, are potent pre-clinical anti-inflammatory non-steroidal drugs. Molecular hybridization based on the combination of pharmacophoric moieties has emerged as a strategy for the development of new candidates aiming to obtain multitarget ligands.

MEFAS, a hybrid of artesunate-mefloquine active against asexual stages of Plasmodium vivax in field isolates, inhibits malaria transmission.

Human malaria continues to be a public health problem and an important cause of morbidity and mortality in the world. Malaria control is achieved through both individual protection against mosquito bites and drug treatment, which is hampered by the spread of Plasmodium falciparum resistance to most antimalarials, including artemisinin derivatives. One of the key pharmacological strategies for controlling malaria is to block transmission of the parasites to their mosquito vectors.

Commercial drugs containing flavonoids are active in mice with malaria and in vitro against chloroquine-resistant Plasmodium falciparum.

BACKGROUND The main strategy to control human malaria still relies on specific drug treatment, limited now by Plasmodium falciparum-resistant parasites, including that against artemisinin derivatives. Despite the large number of active compounds described in the literature, few of them reached full development against human malaria. Drug repositioning is a fast and less expensive strategy for antimalarial drug discovery, because these compounds are already approved for human use.

A systems biology approach to antimalarial drug discovery.

In spite of significant efforts to reduce malaria deaths, this disease still kills around 445,000 people every year. Overcoming drug resistance is one of the main goals of current malaria research programs. This is challenging, since the biology of Plasmodium is not fully understood, requiring the development of advanced models for data analysis in the search for new antimalarials.

Mesoporous silica nanocarriers encapsulated antimalarials with high therapeutic performance.

The use of nanocarriers in drug delivery is a breakeven research and has received a clarion call in biomedicine globally. Herein, two newly nano-biomaterials: MCM-41 encapsulated quinine (MCM-41 ⊃ QN) (1) and 3-phenylpropyl silane functionalized MCM-41 loaded QN (pMCM-41 ⊃ QN) (2) were synthesized and well characterized. 1 and 2 along with our two already reported nano-antimalarial drugs (MCM-41 ⊃ ATS) (3) and 3-aminopropyl silane functionalized MCM-41 contained ATS (aMCM-41 ⊃ ATS) (4) were screened in vitro for their activity against P.

Transmission-Blocking Potential of MEFAS, a Hybrid Compound Derived from Artesunate and Mefloquine.

Most antimalarial drugs target asexual parasites without reducing gametocyte formation or development. Drugs with dual roles, i.e.

Antiplasmodial activity of iron(II) and ruthenium(II) organometallic complexes against Plasmodium falciparum blood parasites.

This work reports the in vitro activity against Plasmodium falciparum blood forms (W2 clone, chloroquine-resistant) of tamoxifen-based compounds and their ferrocenyl (ferrocifens) and ruthenocenyl (ruthenocifens) derivatives, as well as their cytotoxicity against HepG2 human hepatoma cells. Surprisingly with these series, results indicate that the biological activity of ruthenocifens is better than that of ferrocifens and other tamoxifen-like compounds. The synthesis of a new metal-based compound is also described.

Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part II: experimental studies withAspidosperma ramiflorum in vivo and in vitro.

Several species of Aspidosperma plants are used to treat diseases in the tropics, including Aspidosperma ramiflorum, which acts against leishmaniasis, an activity that is experimentally confirmed. The species, known as guatambu-yellow, yellow peroba, coffee-peroba and matiambu, grows in the Atlantic Forest of Brazil in the South to the Southeast regions. Through a guided biofractionation of A.

In vivo antimalarial activity and mechanisms of action of 4-nerolidylcatechol derivatives.

4-Nerolidylcatechol (1) is an abundant antiplasmodial metabolite that is isolated from Piper peltatum roots. O-Acylation or O-alkylation of compound 1 provides derivatives exhibiting improved stability and significant in vitro antiplasmodial activity. The aim of this work was to study the in vitro inhibition of hemozoin formation, inhibition of isoprenoid biosynthesis in Plasmodium falciparum cultures, and in vivo antimalarial activity of several 4-nerolidylcatechol derivatives.

Evaluation of antimalarial activity and toxicity of a new primaquine prodrug.

Plasmodium vivax is the most prevalent of the five species causing malaria in humans. The current available treatment for P. vivax malaria is limited and unsatisfactory due to at least two drawbacks: the undesirable side effects of primaquine (PQ) and drug resistance to chloroquine.

Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against Plasmodium falciparum in vitro and in mice malaria studies.

Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials as treatment for malarial infection, 19 quinone derivatives with previously reported structures were also evaluated for blood schizonticide activity against the malaria parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol (13) and phenazines (12-20). Their cytotoxicities were also evaluated against human hepatoma and normal monkey kidney cell lines.

Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part I: Aspidosperma nitidum (Benth) used as a remedy to treat fever and malaria in the Amazon.

Infusions of Aspidosperma nitidum (Apocynaceae) wood bark are used to treat fever and malaria in the Amazon Region. Several species of this family are known to possess indole alkaloids and other classes of secondary metabolites, whereas terpenoids, an inositol and the indole alkaloids harmane-3 acid and braznitidumine have been described in A. nitidum .

Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites.

Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax.

Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.

The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH) has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P.

The utility of anti-trypomastigote lytic antibodies for determining cure of Trypanosoma cruzi infections in treated patients: an overview and perspectives.

In previous work, we proposed alternative protocols for following patients with treated Chagas disease and these are reviewed herein. Evidence was provided to support the following: (i) functional anti-trypomastigote antibodies are indicative of ongoing chronic Trypanosoma cruzi infections; (ii) specific antibodies detected by conventional serology (CS) with epimastigote extracts, fixed trypomastigotes or other parasite antigens may circulate years after parasite elimination; (iii) functional antibodies are evidenced by complement-mediated lysis of freshly isolated trypomastigotes, a test which is 100% specific, highly sensitive, and the first to revert after T. cruzi elimination and (iv) the parasite target for the lytic antibodies is a glycoprotein of high molecular weight (gp160) anchored at the parasite surface.

Antimalarial activity of betulinic acid and derivatives in vitro against Plasmodium falciparum and in vivo in P. berghei-infected mice.

Malaria is one of the most important tropical diseases and mainly affects populations living in developing countries. Reduced sensitivity of Plasmodium sp. to formerly recommended antimalarial drugs places an increasing burden on malaria control programs as well as on national health systems in endemic countries.

Antimalarial drug discovery: screening of Brazilian medicinal plants and purified compounds.

Background: Malaria is the most important parasitic disease and its control depends on specific chemotherapy, now complicated by Plasmodium falciparum that has become resistant to most commonly available antimalarials. Treatment of the disease requires quinine or drug combinations of artemisinin derivatives and other antimalarials. Further drug resistance is expected.

Synthesis, antimalarial activity, and intracellular targets of MEFAS, a new hybrid compound derived from mefloquine and artesunate.

A new synthetic antimalarial drug, a salt derived from two antimalarial molecules, mefloquine (MQ) and artesunate (AS), here named MEFAS, has been tested for its pharmacological activity. Combinations of AS plus MQ hydrochloride are currently being used in areas with drug-resistant Plasmodium falciparum parasites; although AS clears parasitemia in shorter time periods than any other antimalarial drug, it does not cure infected patients; in addition, MQ causes side effects and is rather expensive, important problems considering that malaria affects mostly populations in poor countries. Here, we show that MEFAS is more effective than the combination of AS and MQ, tested in parallel at different mass proportions, against P.

Malaria vectors in areas of Plasmodium falciparum epidemic transmission in the Amazon region, Brazil.

The main vectors of malaria in Brazil are Anopheles darlingi, An. aquasalis, and some species of the An. albitarsis complex, whereas others have questionable importance with regard to the disease transmission.

Enhanced activity of mefloquine and artesunic acid against Plasmodium falciparum in vitro and P. berghei in mice by combination with ciprofloxacin.

The antimalarial activity of combinations of mefloquine or artesunic acid with ciprofloxacin and other synthetic fluoroquinolone was tested in vitro against Plasmodium falciparum using a strain (BHz26/86) partially resistant to chloroquine and a resistant clone (W2); both are sensitive to mefloquine. Inhibition of parasite growth was measured in relation to controls without drugs, either by counting parasitemia in Giemsa-stained blood smears or by measuring the reduction in [(3)H]-hypoxanthine uptake. Combinations containing artesunic acid or mefloquine with ciprofloxacin had significant in vitro activity, inhibiting by more than 90% of the growth of both strains of P.

Association of the IgG response to Plasmodium falciparum merozoite protein (C-terminal 19 kD) with clinical immunity to malaria in the Brazilian Amazon region.

The antibody response to the C-terminal 19-kD fragment of Plasmodium falciparum merozoite surface protein-1 (PfMSP1-19) was investigated in groups of subjects living in areas of Brazil with different levels of malaria transmission. The prevalence and the levels of IgG to PfMSP1-19 increased with the time of exposure and were positively correlated with the absence of clinical symptoms in parasitemic patients. The frequency of positive response and the mean level of IgG were higher in areas where malaria prevalence was more intense, especially among asymptomatic patients.