ferroquine and Malaria

Despite significant scientific progress over the last two decades, malaria remains a global burden that causes thousands of deaths every year. In the absence of effective and practical preventive measures, the only current option for reducing the mortality and morbidity of malaria is chemotherapy. However, due to the minimal stock of active antiparasitic analogs, issues of toxicity, and the repeated appearance of drug resistance, scientists must broaden the arsenal of existing therapies beyond conventional medicinal chemistry. To curb this menace, a series of potential metal-based hybrids have been synthesized and screened. Ferrocene is one of the potent organometallic candidates and the hybridization of ferrocene with other pharmacophores results in compounds with enhanced biological activities. Many researchers have reported the ferrocene compounds as potent pharmacophores and useful as anticancer and antimalarial agents when hybridized with other pharmaceutical hybrids. Drug, such as Ferroquine (FQ, SSR97193), is currently the most advanced organometallic compound developed from the hybridization of ferrocene and chloroquine and has demonstrated great potency in clinical trials against both drug-sensitive and drug-resistant malaria. Not only ferroquine but its derivatives have shown significant activity as antimalarial agents. The present review focuses on the discovery of FQ, the hypothesis of its mode of action, and recent clinical trials of ferrocene compounds as a new class of antimalarial agents. The structure-activity relationship (SAR) of ferrocene derivatives is also discussed to provide insight into the rational design of more effective antimalarial candidates. Finally, efforts have been made to discuss the future expectations for ferrocene-based antimalarial drugs.

Topics: Antimalarials; Ferrous Compounds; Humans; Illusions; Malaria; Metallocenes; Plasmodium falciparum

Resistance to chemotherapy is a current clinical problem, especially in the treatment of microbial infections and cancer. One strategy to overcome this is to make new derivatives of existing drugs by conjugation to organometallic fragments, either by an appropriate linker, or by direct coordination of the drug to a metal. We illustrate this with examples of conjugated organometallic metallocene sandwich and half-sandwich complexes, Ru

Topics: Aminoquinolines; Antimalarials; Chloroquine; Coordination Complexes; Ferrous Compounds; Humans; Malaria; Metallocenes; Molecular Structure; Organometallic Compounds; Ruthenium Compounds

In the face of the recent pandemic and emergence of infectious diseases of viral origin, research on parasitic diseases such as malaria continues to remain critical and innovative methods are required to target the rising widespread resistance that renders conventional therapies unusable. The prolific use of auxiliary metallo-fragments has augmented the search for novel drug regimens in an attempt to combat rising resistance. The development of organometallic compounds (those containing metal-carbon bonds) as antimalarial drugs has been exemplified by the clinical development of ferroquine in the nascent field of Bioorganometallic Chemistry. With their inherent physicochemical properties, organometallic complexes can modulate the discipline of chemical biology by proffering different modes of action and targeting various enzymes. With the beneficiation of platinum group metals (PGMs) in mind, this review aims to describe recent studies on the antimalarial activity of PGM-based organometallic complexes. This review does not provide an exhaustive coverage of the literature but focusses on recent advances of bioorganometallic antimalarial drug leads, including a brief mention of recent trends comprising interactions with biomolecules such as heme and intracellular catalysis. This resource can be used in parallel with complementary reviews on metal-based complexes tested against malaria.

Topics: Amines; Aminoquinolines; Animals; Antimalarials; Benzimidazoles; Coordination Complexes; Ferrous Compounds; HEK293 Cells; Humans; Imidazoles; Iridium; Ligands; Malaria; Metallocenes; Molecular Structure; Organometallic Compounds; Osmium; Palladium; Platinum; Quinolines; Rhodium; Ruthenium; Salicylates; Silanes; Tamoxifen; Thiosemicarbazones

Malaria and cancer are chronic diseases. The challenge with drugs available for the treatment of these diseases is drug toxicity and resistance. Ferrocene is a potent organometallic which have been hybridized with other compounds resulting in compounds with enhanced biological activity such as antimalarial and anticancer. Drugs such as ferroquine were developed from ferrocene and chloroquine. It was tested in the 1990s as an antimalarial and is still an effective antimalarial. Many researchers have reported ferrocene compounds as potent compounds useful as anticancer and antimalarial agents when hybridized with other pharmaceutical scaffolds. This review will be focused on compounds with ferrocene moieties that exhibit either an anticancer or antimalarial activity.

Topics: Aminoquinolines; Antimalarials; Antineoplastic Agents; Chloroquine; Drug Resistance, Neoplasm; Drug Therapy, Combination; Ferrous Compounds; Humans; Malaria; Metallocenes; Neoplasms; Plasmodium falciparum

The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency. There are at least 13 agents in clinical development. Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations. Leading candidates progressing through the pipeline are artefenomel-ferroquine and lumefantrine-KAF156, both in Phase 2b. Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy. Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years. Latest predictions are that the malaria burden will continue to be high in the coming decades. This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come. Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration.

Topics: Aminoquinolines; Antimalarials; Artemisinins; Drug Discovery; Drug Resistance, Multiple; Ferrous Compounds; Humans; Imidazoles; Lumefantrine; Malaria; Metallocenes; Piperazines; Signal Transduction; Treatment Outcome

Malaria is a major public health problem all over the world, particularly in tropical and subtropical countries due to the development of resistance and most deadly infection is caused by Plasmodium falciparum. There is a direct need for the discovery of new drugs with unique structures and mechanism of action to treat sensitive and drug-resistant strains of various plasmodia for radical cure of this disease. Traditional compounds such as quinine and related derivatives represent a major source for the development of new drugs. This review presents recent modifications of 4-aminoquinoline and 8-aminoquinolone rings as leads to novel active molecules which are under clinical trials. The review also encompasses the other heterocyclic compounds emerged as potential antimalarial agents with promising results such as acridinediones and acridinone analogues, pyridines and quinolones as antimalarials. Miscellaneous heterocyclics such as tetroxane derivatives, indole derivatives, imidazolopiperazine derivatives, biscationic choline-based compounds and polymer-linked combined antimalarial drugs are also discussed. At last brief introduction to heterocyclics in natural products is also reviewed. Most of them have been under clinical trials and found to be promising in the treatment of drug-resistant strains of Plasmodium and others can be explored for the same purpose.

Topics: Acridines; Aminoquinolines; Antimalarials; Biological Products; Clinical Trials as Topic; Drug Resistance, Microbial; Ferrous Compounds; Heterocyclic Compounds; Humans; Malaria; Metallocenes; Pyridones; Pyrimidines

Malaria has been teasing human populations from a long time. Presently, several classes of antimalarial drugs are available in market, but the issues of toxicity, lower efficacy and the resistance by malarial parasites have decreased their overall therapeutic indices. Thus, the search for new promising antimalarials continues, however, the battle against malaria is far from over. Ferroquine is a derivative of chloroquine with antimalarial properties. It is the most successful of the chloroquine derivatives. Not only ferroquine, but also its derivatives have shown promising potential as antimalarials of clinical interest. Presently, much research is dedicated to the development of ferroquine derivatives as safe alternatives to antimalarial chemotherapy. The present article describes the structural, chemical and biological features of ferroquine. Several classes of ferroquine derivatives including hydroxyferroquines, trioxaferroquines, chloroquine-bridged ferrocenophanes, thiosemicarbazone derivatives, ferrocene dual conjugates, 4-N-substituted derivatives, and others have been discussed. Besides, the mechanism of action of ferroquine has been discussed. A careful observation has been made into pharmacologically significant ferroquine derivatives with better or equal therapeutic effects to that of chloroquine and ferroquine. A brief discussion of the toxicities of ferroquine derivatives has been made. Finally, efforts have been made to discuss the current challenges and future perspectives of ferroquine-based antimalarial drug development.

Topics: Aminoquinolines; Animals; Antimalarials; Dose-Response Relationship, Drug; Ferrous Compounds; Humans; Malaria; Metallocenes; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium; Structure-Activity Relationship

Urogenital schistosomiasis is prevalent in many malaria endemic regions of sub-Saharan Africa and can lead to long-term health consequences if untreated. Antimalarial drugs used to treat uncomplicated malaria have shown to exert some activity against Schistosoma haematobium. Here, we explore the efficacy on concomitant urogenital schistosomiasis of first-line recommended artemisinin-based combination therapies (ACTs) and investigational second-generation ACTs when administered for the treatment of uncomplicated malaria in Gabon.. Microscopic determination of urogenital schistosomiasis was performed from urine samples collected from patients with confirmed uncomplicated malaria. Egg excretion reduction rate and cure rate were determined at 4-weeks and 6-weeks post-treatment with either artesunate-pyronaridine, artemether-lumefantrine, artesunate-amodiaquine or artefenomel-ferroquine.. Fifty-two (16%) out of 322 malaria patients were co-infected with urogenital schistosomiasis and were treated with antimalarial drug combinations. Schistosoma haematobium egg excretion rates showed a median reduction of 100% (interquartile range (IQR), 17% to 100%) and 65% (IQR, -133% to 100%) at 4-weeks and 6-weeks post-treatment, respectively, in the artesunate-pyronaridine group (n = 20) compared to 35% (IQR, -250% to 70%) and 65% (IQR, -65% to 79%) in the artemether-lumefantrine group (n = 18). Artesunate-amodiaquine (n = 2) and artefenomel-ferroquine combination (n = 3) were not able to reduce the rate of eggs excreted in this limited number of patients. In addition, cure rates were 56% and 37% at 4- and 6-weeks post-treatment, respectively, with artesunate-pyronaridine and no cases of cure were observed for the other antimalarial combinations.. Antimalarial treatments with artesunate-pyronaridine and artemether-lumefantrine reduced the excretion of S. haematobium eggs, comforting the hypothesis that antimalarial drugs could play a role in the control of schistosomiasis.. This trial is registered with clinicaltrials.gov, under the Identifier NCT04264130.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artesunate; Drug Combinations; Ethanolamines; Gabon; Humans; Malaria; Malaria, Falciparum; Schistosomiasis haematobia

Recent studies have shown that the solubilization of two antimalarial drug candidates, artefenomel (OZ439) and ferroquine (FQ), designed to provide a single-dose combination therapy for uncomplicated malaria can be enhanced using milk as a lipid-based formulation. However, milk as an excipient faces significant quality and regulatory hurdles. We therefore have investigated infant formula as a potential alternative formulation approach. The significance of the lipid species present in a formula with different lipid compositions upon the solubilization of OZ439 and FQ during digestion has been investigated. Synchrotron small-angle X-ray scattering was used to measure the diffraction from a dispersed drug during digestion and thereby determine the extent of drug solubilization. High-performance liquid chromatography was used to quantify the amount of drug partitioned into the digested lipid phases. Our results show that both the lipid species and the amount of lipids administered were key determinants for the solubilization of OZ439, while the solubilization of FQ was independent of the lipid composition. Infant formulas could therefore be designed and used as milk substitutes to tailor the desired level of drug solubilization while circumventing the variability of components in naturally derived milk. The enhanced solubilization of OZ439 was achieved during the digestion of medium-chain triacylglycerols (MCT), indicating the potential applicability of MCT-fortified infant formula powder as a lipid-based formulation for the oral delivery of OZ439 and FQ.

Topics: Adamantane; Administration, Oral; Aminoquinolines; Animals; Antimalarials; Chromatography, High Pressure Liquid; Digestion; Excipients; Fatty Acids; Ferrous Compounds; Humans; Infant; Infant Formula; Lipids; Malaria; Mass Spectrometry; Metallocenes; Milk; Peroxides; Scattering, Small Angle; Solubility; Triglycerides

Milk is an attractive lipid-based formulation for the delivery of poorly water-soluble drugs to pediatric populations. We recently observed that solubilization of artefenomel (OZ439) during in vitro intestinal lipolysis was driven by digestion of triglycerides in full-cream bovine milk, reflecting the ability of milk to act as an enabling formulation in the clinic. However, when OZ439 was co-administered with a second antimalarial drug, ferroquine (FQ) the exposure of OZ439 was reduced. The current study therefore aimed to understand the impact of the presence of FQ on the solubilization of OZ439 in milk during in vitro intestinal digestion. Synchrotron small-angle X-ray scattering was used for in situ monitoring of drug solubilization (inferred via decreases in the intensity of drug diffraction peaks) and polymorphic transformations that occurred during the course of digestion. Quantification of the amount of each drug solubilized over time and analysis of their distributions across the separated phases of digested milk were determined using high-performance liquid chromatography. The results show that FQ reduced the solubilization of OZ439 during milk digestion, which may be due to competitive binding of FQ to the digested milk products. Interactions between the protonated FQ-H

Topics: Adamantane; Administration, Oral; Aminoquinolines; Animals; Antimalarials; Biological Availability; Drug Delivery Systems; Ferrous Compounds; Humans; In Vitro Techniques; Lipolysis; Malaria; Metallocenes; Milk; Peroxides; Solubility

A ferrocene-quinoline conjugate named ferroquine (FQ or SSR97193) is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. FQ was shown to be efficient for the treatment of uncomplicated malaria in humans (phase IIb of clinical trials). However, the molecular basis of FQ's mechanism of action is still unknown because few approaches (such as radioactive labelling or immunofluorescence) are available for that purpose. Previous reports from our laboratory suggest that the intramolecular hydrogen bond in the lateral side chain plays a crucial role in the antimalarial activity of the drug. We used two ruthenocenic bioprobes of FQ (with and without an intramolecular hydrogen bond) to study their localization and quantification in Plasmodium falciparum-infected erythrocytes. We first used Inductively Coupled Plasma Mass Spectroscopy (ICP-MS) analysis to trace ruthenoquine (RQ, with an intramolecular hydrogen bond) and methylruthenoquine (Me-RQ, without an intramolecular hydrogen bond) in the infected red blood cells (iRBCs). We showed that RQ accumulates faster in the digestive vacuole of the iRBCs than Me-RQ. We next examined the ruthenium distribution at the ultrastructural level by transmission electron microscopy (TEM). We showed that RQ accumulates faster in the parasitic digestive vacuole (DV) close to its membranes than Me-RQ.

Topics: Aminoquinolines; Antimalarials; Erythrocytes; Ferrous Compounds; Humans; Malaria; Metallocenes; Parasitic Sensitivity Tests; Plasmodium falciparum; Ruthenium

The direct antimalarial activity of ferroquine (FQ, SSR97193), a chloroquine (CQ) derivative, is well established. To determine whether the FQ anti-parasite activity affects the host immune properties, we have investigated its effect on several immunological parameters in young rats infected with Plasmodium berghei and compared it with that of CQ. In uninfected young rats, treatment with either drug did not show any impairment in the cellular distribution of spleen cells in their response to mitogens and did not induce the production of IL-10 in vivo. After infection, rats treated with CQ or FQ showed no parasitemia and survived with no recrudescence, in comparison with placebo. Nevertheless, FQ cured young rats more rapidly than its parent drug. Analysis of cellular distribution including CD4+TCR+, CD8+TCR+, NK and NKT cells in blood and spleen and the production of specific antibodies did not reveal any alteration of these parameters in infected young rats treated either with CQ or FQ. However, we observed a persistence of CD4+CD25+T-cells in infected CQ-treated rats when compared with infected FQ-treated rats, very likely related to the delay of blood parasite clearance by CQ-treatment. Another significant difference is that the CQ treatment dramatically inhibited the lymphoproliferative response of young infected rats when compared with FQ. Collectively, the absence of any observable immunotoxic effects due to FQ in naïve and infected young rats, together with previous results indicating the susceptibility to FQ of all Plasmodium falciparum field isolates and CQ-resistant strains make it a promising drug for malarial treatment.

Topics: Aminoquinolines; Animals; Antibodies, Protozoan; Antimalarials; Cell Proliferation; Cells, Cultured; Chloroquine; Enzyme-Linked Immunosorbent Assay; Ferrous Compounds; Flow Cytometry; Immunoglobulin G; Interferon-gamma; Interleukin-10; Malaria; Metallocenes; Plasmodium berghei; Rats; Rats, Inbred F344; Spleen