ferroquine (SSR97193) / Sanofi - LARVOL DELTA

The non-artemisinin antimalarial drugs under development: a review. (PubMed, Clin Microbiol Infect) - "Although attrition remains a possibility, several promising candidate drugs with novel modes of action are advancing through clinical development. Many are expected to become available for treating uncomplicated and severe malaria within the next decade. These new antimalarials could significantly enhance malaria treatment, reduce resistance, and support global health effort toward malaria control, elimination, and, potentially, eradication."

Journal • Review • Infectious Disease • Malaria

A novel mutation in Plasmodium falciparumchloroquine resistance transporter mediates in vitro resistance to the antimalarial candidate drug ZY19489 (ASTMH 2024) - "One such molecule is ZY19489, a fast-killing triaminopyrimidine presently in Phase 2 trials in combination with ferroquine...Studies with purified PfCRT reconstituted in proteoliposomes provided evidence that ZY19489 can impede mutant PfCRT-mediated efflux of tritiated chloroquine, CQ, from the digestive vacuole, DV, in CQ-resistant lines, suggesting that ZY19489 can compete with CQ for mutant PfCRT-mediated drug transport. Notably, 72-hour parasite survival assays showed significant sensitization of Dd2 Dd2 N246H parasites to DV-acting drugs including CQ, piperaquine and desethylamodiaquine but not lumefantrine or atovaquone...This was confirmed by metabolomics, which revealed a reduction in levels of Hb-derived short peptides in ZY19489-treated parasites. These data strongly implicate inhibition of Hb degradation and a novel mutation in PfCRT as central to ZY19489 action and resistance."

Late-breaking abstract • Preclinical • Infectious Disease

A Study to Determine Safety, Tolerability, and Pharmacokinetics of Different Orally Administered Regimens of the Combination ZY19489-Ferroquine in Adult Asymptomatic Plasmodium Falciparum Carriers (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Zydus Lifesciences Limited | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Malaria

Ferrocenyl Azoles: Versatile N-Containing Heterocycles and their Anticancer Activities. (PubMed, Chem Rec) - "The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit...Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles."

Journal • Review • Oncology

Recent advances, challenges and updates on the development of therapeutics for malaria. (PubMed, EXCLI J) - "This review is primarily concerned with the description of newly synthesized antimalarial compounds, i.e. Tafenoquine, Cipargamin, Ferroquine, Artefenomel, DSM265, MMV390048 designed to improve the activity of pure antimalarial enantiomers. In this review, we selected the representative malarial drugs in clinical trials, classified them with detailed targets according to their action, discussed the relationship within the human trials, and generated a summative discussion with prospective expectations."

Journal • Review • Infectious Disease • Malaria

Exploring antimalarial potential: Conjugating organometallic moieties with organic fragments for enhanced efficacy. (PubMed, Bioorg Chem) - "The success of Ferroquine (FQ, SR97193), an effective chloroquine-ferrocene conjugate currently undergoing the patient-exploratory phase as a combination therapy with the novel triaminopyrimidine ZY-19489 for malaria, has sparked intense interest in organometallic compound drug discovery. Four main organometallic antimalarial compounds have been chosen based on conjugated organic moieties: existing antimalarial drugs, other clinical drugs, hybrid drugs, and promising scaffolds of thiosemicarbazones, benzimidazoles, and chalcones, in particular. The presented insights contribute to the ongoing discourse on organometallic compound drug development for malaria diseases."

Journal • Review • Infectious Disease • Malaria

Exploring the modulatory influence on the antimalarial activity of amodiaquine using scaffold hybridisation with ferrocene integration. (PubMed, Eur J Med Chem) - "Employing the organometallic hybridisation approach, which has been shown to restore the antimalarial activity of chloroquine in the form of an organometallic hybrid clinical candidate ferroquine (FQ), the present study utilises this strategy to modulate the biological performance of AQ by incorporating ferrocene. Moreover, representative compounds from this series show the potential to block malaria transmission by inhibiting the growth of stage II/III and V gametocytes in vitro. Preliminary mechanistic insights also revealed hemozoin inhibition as a potential mode of action."

Journal • Infectious Disease • Malaria

A Study to Determine Safety, Tolerability, and Pharmacokinetics of Different Orally Administered Regimens of the Combination ZY19489-Ferroquine in Adult Asymptomatic Plasmodium Falciparum Carriers (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: Zydus Lifesciences Limited | Trial completion date: May 2024 ➔ May 2025 | Initiation date: Jul 2023 ➔ Apr 2024 | Trial primary completion date: Feb 2024 ➔ Feb 2025

Trial completion date • Trial initiation date • Trial primary completion date • Infectious Disease • Malaria

Antifungal and Antiparasitic Activities of Metallocene-Containing Fluconazole Derivatives. (PubMed, ACS Infect Dis) - "Among the different options taken by researchers, the one involving the use of organometallic complexes is probably the most successful one with a compound, namely, ferroquine, already in clinical trials against malaria. Of high interest, the two most potent compounds of the study on T. cruzi that contain a ferrocene or cobaltocenium were found to be harmless for an invertebrate animal model, namely, Caenorhabditis elegans (C. elegans), without affecting motility, viability, or development."

Journal • Infectious Disease • Malaria

Insights into the Mode of Action and a Novel Mutant PfCRT-Mediated Mechanism of Resistance to the Antimalarial Clinical Candidate ZY-19489 (ASTMH 2023) - "One such molecule is ZY-19489, a fast-killing triaminopyrimidine currently in Phase II trial in combination with ferroquine (FQ)...This study aimed to leverage in vitro selection and whole genome analysis (IVSWGA), quantitative trait loci (QTL) analysis, stage-specificity experiments and transport studies using P. falciparum lines expressing wildtype (Dd2 Dd2 ) or mutant P. falciparum chloroquine resistance transporter (pfcrt) alleles to characterize the mechanisms of resistance to ZY-19489...No change in susceptibility was observed for lumefantrine or atovaquone...Stage-specificity tests showed that ZY-19489 is most potent against schizonts and rings, the latter recently shown to be the initial assembly stage of the parasite's Hb processing machinery. These data implicate Pf CRT N246H mutation in mediating ZY-19489 resistance."

Clinical • CNS Disorders • Infectious Disease • Psychiatry • Schizophrenia

Predicting optimal antimalarial drug combinations from a standardized Plasmodium falciparum humanized mouse model (ASTMH 2023) - "Then, using historical data on monotherapy and two small cohorts of Pfalc Hu Mice evaluated with ferroquine plus artefenomel or piperaquine plus artefenomel, we found that only measurements of parasite killing, (i.e., cure of mice) as a function of drug exposure in blood allowed direct estimation of the individual drug contribution to efficacy by using multivariate statistical modelling and intuitive graphic displays. Overall, the analysis of parasite killing in the Pfalc Hu Mouse model is a unique and robust experimental in vivo tool to inform the selection of optimal combinations by pharmacometric PK/PD modelling."

Preclinical • Infectious Disease • Malaria

Ferrocene-Based Drugs, Delivery Nanomaterials and Fenton Mechanism: State of the Art, Recent Developments and Prospects. (PubMed, Pharmaceutics) - "reported ferrocifens, ferrocene analogs of tamoxifen, the chemotherapeutic for hormone-dependent breast cancer...Independently, in 1997, ferroquine, an analog of the antimalarial drug chloroquine upon the introduction of a ferrocenyl substituent in the carbon chain, was reported by the Biot-Brocard group and found to be active against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum...In a majority of ferrocene-containing drugs, however, the production of reactive oxygen species (ROS), in particular the OH. radical, produced by Fenton catalysis, plays a key role and is scrutinized in this mini-review, together with the supramolecular approach utilizing drug delivery nanosystems, such as micelles, metal-organic frameworks (MOFs), polymers, and dendrimers."

Journal • Review • Breast Cancer • Infectious Disease • Oncology • Solid Tumor

A Study to Determine Safety, Tolerability, and Pharmacokinetics of Different Orally Administered Regimens of the Combination ZY19489-Ferroquine in Adult Asymptomatic Plasmodium Falciparum Carriers (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: Zydus Lifesciences Limited

New P1 trial • Infectious Disease • Malaria

Investigations on the Novel Antimalarial Ferroquine in Biomimetic Solutions Using Deep UV Resonance Raman Spectroscopy and Density Functional Theory. (PubMed, Anal Chem) - "By applying the resonant laser line at λ = 257 nm, a minimal FQ concentration of 3.1 μM was detected, whereas the pre-resonant excitation wavelength 244 nm provides an LoD of 6.9 μM. These values were all up to one order of magnitude lower than the concentration found for the food vacuole of a parasitized erythrocyte."

Journal • Infectious Disease • Malaria

Predicting Optimal Antimalarial Drug Combinations from a Standardized Plasmodium falciparum Humanized Mouse Model. (PubMed, Antimicrob Agents Chemother) - "Then, using historical data on monotherapy and two small cohorts of PfalcHuMice evaluated with ferroquine plus artefenomel or piperaquine plus artefenomel, we found that only measurements of parasite killing (i.e., cure of mice) as a function of drug exposure in blood allowed direct estimation of the individual drug contribution to efficacy by using multivariate statistical modeling and intuitive graphic displays. Overall, the analysis of parasite killing in the PfalcHuMouse model is a unique and robust experimental in vivo tool to inform the selection of optimal combinations by pharmacometric pharmacokinetic and pharmacodynamic (PK/PD) modeling."

Journal • Preclinical • Infectious Disease • Malaria

Ferrocene Derivatives as New Generation of Antimalarial Agents: Opportunity or Illusion? (PubMed, Curr Top Med Chem) - "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. 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."

Journal • Infectious Disease • Malaria • Oncology

Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria. (PubMed, Malar J) - P2a | "The contribution of artefenomel exposure to the clinical and parasitological activity of ferroquine/artefenomel could not be demonstrated in this study. Parasite clearance was faster with ferroquine/artefenomel versus ferroquine alone. All treatments were well tolerated."

Journal • P2a data • Infectious Disease • Malaria

Effectiveness of antimalarial drug combinations in treating concomitant urogenital schistosomiasis in malaria patients in Lambaréné, Gabon: A non-randomised event-monitoring study. (PubMed, PLoS Negl Trop Dis) - P2 | "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."

Journal • Infectious Disease • Malaria

New In Vitro Interaction-Parasite Reduction Ratio Assay for Early Derisk in Clinical Development of Antimalarial Combinations. (PubMed, Antimicrob Agents Chemother) - "Last, our more informative in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g., a concentration-dependent change in the maximum killing effect (E) and the concentration producing 50% of the killing maximum effect (EC) of piperaquine or artefenomel or a directional reduction of the EC of ferroquine by artefenomel and a directional reduction of E of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations for malaria and potentially also in other therapeutic areas."

Journal • Preclinical • Infectious Disease • Malaria

Evaluation of ferrocenyl-containing γ-hydroxy-γ-lactam-derived tetramates as potential antiplasmodials. (PubMed, Eur J Med Chem) - "The compounds were screened in vitro for their antiplasmodial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) clones of P. falciparum, displaying activity in the range of 0.12-100 μM, with generally good resistance index. The low cytotoxicity of the ferrocenyl-containing γ-hydroxy-γ-lactam tetramates against Human Umbilical Vein Endothelial (HUVEC) cell line demonstrated selective antiparasitic activity. The redox properties of these ferrocene-derived tetramates were studied and physico-biochemical studies evidenced that these derivatives can exert potent antimalarial activities via a mechanism distinct from ferroquine."

Journal • Infectious Disease

Separation of planar chiral ferrocenes by capillary electrokinetic chromatography and liquid chromatography. (PubMed, J Chromatogr A) - "In normal-phase mode liquid chromatography, the use of n-heptane, ethanol or isopropanol with 1% n-butylamine as mobile phase on six polysaccharide-based columns, allowed to fully separate the enantiomers of three compounds out of the six (i.e 7-chloro-N-(2-((dimethylamino)methyl)ferrocenyl)quinolin-4-amine (ferroquine) (compound 1), 1-[(1S)-(1-Aminoethyl)]-2-(diphenylphosphino)ferrocene (compound 5) and 1-[(1R)-1-(Dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene (compound 6)...This system allowed the improved separation of two ferrocene derivatives with an unusual resolution value equal to 41.5 in long-end mode. Overall, CEKC showed better enantioseparating power of the six chiral ferrocenes studied than liquid chromatography."

Journal

Structural activity relationship of metallo-aminoquines as a next generation antimalarials. (PubMed, Curr Top Med Chem) - "ferroquine (FQ or 1), Ruthenoquine (RQ or 2) and other related potent metal-analogues. It observed that some metal containing analogues (Fe-, Rh-, Ru-, Re-, Au-, Zn-, Cr-, Pd-, Sn-, Cd-, Ir-, Co-, Cu-, and Mn-aminoquines) were more potent; however, some were equally potent as Chloroquine (CQ) and 1. This is probably due to the intertion of metals in the CQ via various approaches, which might be a very attractive strategy to develop a SAR of novel metal containing antimalarials. Thus, this review aims to summarize the SAR of metal containing aminoquines towards the discovery of potent antimalarial hybrids to provide an insight for rational designs of more effective and less toxic metal containing amoniquines."

Journal • Infectious Disease • Malaria

Has Ferrocene Really Delivered Its Role in Accentuating the Bioactivity of Organic Scaffolds? (PubMed, J Med Chem) - "Ferroquine and ferrocifen are two of the most notable contributions of ferrocene to medicinal chemistry with remarkable antimalarial and anticancer properties...In this Perspective, we investigate the scope and limitations of ferrocene incorporation into organic compounds/natural products on their mode of action and biological activities. We have also discussed the detailed role of ferrocene modifications in influencing the anticancer, antimalarial, and antimicrobial properties of various bioactive moieties to design safer and promising ferrocene-based drugs."

Journal • Infectious Disease • Oncology

Drug susceptibility of Plasmodium falciparum in eastern Uganda: a longitudinal phenotypic and genotypic study. (PubMed, Lancet Microbe) - "Of 440 total isolates, 392 (89%) successfully grew in culture and showed excellent drug susceptibility for chloroquine (median half-maximal inhibitory concentration [IC] 20·0 nM [IQR 12·0-26·0]), monodesethylamodiaquine (7·1 nM [4·3-8·9]), pyronaridine (1·1 nM [0·7-2·3]), piperaquine (5·6 nM [3·3-8·6]), ferroquine (1·8 nM [1·5-3·3]), AQ-13 (24·0 nM [17·0-32·0]), lumefantrine (5·1 nM [3·2-7·7]), mefloquine (9·5 nM [6·6-13·0]), dihydroartemisinin (1·5 nM [1·0-2·0]), and atovaquone (0·3 nM [0·2-0·4]). These results suggest that additional changes will be seen over time and continued surveillance of susceptibility to key ACT components is warranted. National Institutes of Health and Medicines for Malaria Venture."

Journal • Infectious Disease • Malaria • ABCB1 • ABCC1

Computational Studies of Selected Transition Metal Complexes as Potential Drug Candidates against the SARS-CoV-2 Virus. (PubMed, ChemistrySelect) - "The molecular docking studies revealed that the iron-porphyrin complex (1) and antimalarial drug, ferroquine (2) could be the potential inhibitors of Main protease (M) and spike proteins respectively of SARS-CoV-2 virus...The complex 5 also exhibited good binding constants values of -7.67, -8.68 and -7.82 kcal/mol with the spike protein, M and RNA dependent RNA polymerase (RdRp) proteins respectively. Overall, transition metal complexes could provide an alternative and viable therapeutic solution for COVID-19."

Journal • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases