Antimalarial Pyrido[1,2-a]benzimidazoles Exert Strong Parasiticidal Effects by Achieving High Cellular Uptake and Suppressing Heme Detoxification

Editorial Material Chemistry, Multidisciplinary

Quinine fever

John G. Woodland et al.

Summary: This article traces the history of quinine from being a medicine used for colonialism to its roles as a chemical target, fluorescence standard, and key ingredient in popular drinks.

NATURE CHEMISTRY (2022)

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Article Chemistry, Medicinal

Peroxide Antimalarial Drugs Target Redox Homeostasis in Plasmodium falciparum Infected Red Blood Cells

Ghizal Siddiqui et al.

Summary: This study used chemoproteomics to investigate the protein alkylation targets of peroxide antimalarials and found a significant alkylation of proteins involved in redox homeostasis. Disrupted redox processes were confirmed and changes in cellular thiol levels were observed. These findings reveal the mechanism of action of peroxide antimalarials.

ACS INFECTIOUS DISEASES (2022)

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Review Cell Biology

The fight against malaria: Diminishing gains and growing challenges

Justin M. Cohen et al.

Summary: Since 2000, significant progress has been made in reducing the incidence and mortality of malaria through the widespread distribution of prevention and treatment tools. However, the future outlook is uncertain due to population growth in high-endemic areas and the emergence of drug and insecticide resistance.

SCIENCE TRANSLATIONAL MEDICINE (2022)

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Article Chemistry, Medicinal

Expanding the Activity Profile of Pyrido[1,2-a]benzimidazoles: Synthesis and Evaluation of Novel N1-1-Phenylethanamine Derivatives against Schistosoma mansoni

Alexandra Probst et al.

Summary: Praziquantel is currently the main drug for treating schistosomiasis, but there is a need for new antischistosomal drugs. The novel antischistosomal PBIs show potential efficacy and good hepatic microsomal stability, but exhibit some toxicity in vivo.

ACS INFECTIOUS DISEASES (2021)

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Article Multidisciplinary Sciences

Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Janette Reader et al.

Summary: This study screened the Medicines for Malaria Venture Pandemic Response Box against different life cycle stages of Plasmodium, identifying unique compounds with multistage or stage-specific activity, including potent transmission-blocking drugs. Mechanistic investigations revealed that ML324 inhibits histone demethylation, leading to aberrant gene expression and death in gametocytes, while parasites resistant to SQ109 implicate the V-type H+-ATPase as a druggable target.

NATURE COMMUNICATIONS (2021)

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Article Chemistry, Medicinal

A Diverse Range of Hemozoin Inhibiting Scaffolds Act on Plasmodium falciparum as Heme Complexes

Roxanne Openshaw et al.

Summary: A diverse range of hemozoin-inhibiting compounds have been found to lead to varying levels of exchangeable heme, with less active compounds often exhibiting higher levels. The presence of heme-inhibitor complexes in the parasite was confirmed through various imaging techniques. These findings suggest that hemozoin inhibitors act as complexes with free heme, each with its own unique activity.

ACS INFECTIOUS DISEASES (2021)

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Review Chemistry, Medicinal

Malaria Pigment Crystals: The Achilles′ Heel of the Malaria Parasite

Sergey Kapishnikov et al.

Summary: This article focuses on the biogenic formation of hemozoin crystals as a crucial process in heme detoxification by the malaria parasite. It details the in-vivo formation of hemozoin, presenting a model based on native-contrast 3D imaging. The process involves nucleation at the inner membrane leaflet of the parasitic digestive vacuole and growth in the adjacent aqueous medium, with heme liberation from hemoglobin and hemozoin formation being described as an assembly-line process, followed by the review of antimalarial drugs binding onto hemozoin surfaces, and the description of the drug bromoquine's actions within the vacuole.

CHEMMEDCHEM (2021)

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Article Chemistry, Medicinal

Benzimidazole Derivatives Are Potent against Multiple Life Cycle Stages of Plasmodium falciparum Malaria Parasites

Meta Leshabane et al.

Summary: This study identified benzimidazole derivatives with activity against various developmental stages of Plasmodium parasites, showing potential for the development of novel antimalarial drugs.

ACS INFECTIOUS DISEASES (2021)

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Review Chemistry, Multidisciplinary

Heme Detoxification in the Malaria Parasite: A Target for Antimalarial Drug Development

Katherine A. de Villiers et al.

Summary: During the past century, malaria deaths have significantly decreased, but there were still 405,000 deaths in 2018. Advances in the 21st century have largely been due to insecticide-treated bed nets and artemisinin combination therapy. Parasites with delayed artemisinin clearance phenotypes in Southeast Asia pose a threat to further progress.

ACCOUNTS OF CHEMICAL RESEARCH (2021)

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Review Pharmacology & Pharmacy

Malaria PK/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations

Emma Hughes et al.

Summary: Pharmacokinetic/pharmacodynamic models can optimize antimalarial dosing recommendations for vulnerable populations like children and pregnant women. Integrating PK data into clinical studies and incorporating drug resistance and host immunity data into PK/PD models can further improve malaria treatment outcomes.

CLINICAL PHARMACOLOGY & THERAPEUTICS (2021)

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Article Biochemistry & Molecular Biology

A second mechanism employed by artemisinins to suppress Plasmodium falciparum hinges on inhibition of hematin crystallization

Wenchuan Ma et al.

Summary: The study reveals a new mechanism employed by artemisinin-class drugs in subduing the erythrocytic phase of the malaria parasite life cycle, involving heme-drug adducts produced after artemisinin activation, which potently kills Plasmodium falciparum at low concentrations.

JOURNAL OF BIOLOGICAL CHEMISTRY (2021)

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Article Biochemistry & Molecular Biology

Combining Stage Specificity and Metabolomic Profiling to Advance Antimalarial Drug Discovery

James M. Murithi et al.

CELL CHEMICAL BIOLOGY (2020)

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Article Multidisciplinary Sciences

Antimalarial activity of primaquine operates via a two-step biochemical relay

Grazia Camarda et al.

NATURE COMMUNICATIONS (2019)

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Article Chemistry, Medicinal

Ozonide Antimalarials Alkylate Heme in the Malaria Parasite Plasmodium falciparum

Carlo Giannangelo et al.

ACS INFECTIOUS DISEASES (2019)

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Article Chemistry, Medicinal

Structure-Activity Relationship Studies and Plasmodium Life Cycle Profiling Identifies Pan-Active N-Aryl-3-trifluoromethyl Pyrido[1,2-a]benzimidazoles Which Are Efficacious in an in Vivo Mouse Model of Malaria

Godfrey Mayoka et al.

JOURNAL OF MEDICINAL CHEMISTRY (2019)

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Article Cell Biology

Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay

Jerzy M. Dziekan et al.

SCIENCE TRANSLATIONAL MEDICINE (2019)

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Article Chemistry, Medicinal

Antimalarial Pyrido[1,2-a]benzimidazole Derivatives with Mannich Base Side Chains: Synthesis, Pharmacological Evaluation, and Reactive Metabolite Trapping Studies

John Okombo et al.

ACS INFECTIOUS DISEASES (2019)

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Article Chemistry, Medicinal

Structure-Activity Relationship and in Vitro Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Studies of N-aryl 3-Trifluoromethyl Pyrido[1,2-a]benzimidazoles That Are Efficacious in a Mouse Model of Schistosomiasis

Godfrey Mayoka et al.

ACS INFECTIOUS DISEASES (2019)

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Review Biotechnology & Applied Microbiology

The genomic architecture of antimalarial drug resistance

Annie N. Cowell et al.

BRIEFINGS IN FUNCTIONAL GENOMICS (2019)

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Review Chemistry, Medicinal

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

Poonam et al.

MEDICINAL RESEARCH REVIEWS (2018)

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Article Biochemistry & Molecular Biology

Dihydroartemisinin-Ferriprotoporphyrin IX Adduct Abundance in Plasmodium falciparum Malarial Parasites and the Relationship to Emerging Artemisinin Resistance

Laura E. Heller et al.

BIOCHEMISTRY (2018)

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Article Chemistry, Medicinal

Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model

Kawaljit Singh et al.

JOURNAL OF MEDICINAL CHEMISTRY (2017)

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Review Biochemistry & Molecular Biology

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

Benjamin Blasco et al.

NATURE MEDICINE (2017)

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Article Multidisciplinary Sciences

Quantification of labile heme in live malaria parasites using a genetically encoded biosensor

James R. Abshire et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2017)

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Article Infectious Diseases

Optimization of a multi-well colorimetric assay to determine haem species in Plasmodium falciparum in the presence of anti-malarials

Jill M. Combrinck et al.

MALARIA JOURNAL (2015)

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Review Pharmacology & Pharmacy

How do antimalarial drugs reach their intracellular targets?

Katherine Basore et al.

FRONTIERS IN PHARMACOLOGY (2015)

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Article Microbiology

Relative to Quinine and Quinidine, Their 9-Epimers Exhibit Decreased Cytostatic Activity and Altered Heme Binding but Similar Cytocidal Activity versus Plasmodium falciparum

Alexander P. Gorka et al.

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY (2013)

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Article Microbiology

Cytostatic versus Cytocidal Activities of Chloroquine Analogues and Inhibition of Hemozoin Crystal Growth

Alexander P. Gorka et al.

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY (2013)

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Article Biochemistry & Molecular Biology

Interactions of the Antimalarial Drug Methylene Blue with Methemoglobin and Heme Targets in Plasmodium falciparum: A Physico-Biochemical Study

Olga Blank et al.

ANTIOXIDANTS & REDOX SIGNALING (2012)

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Article Microbiology

Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model

Brioni R. Moore et al.

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY (2011)

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Article Chemistry, Medicinal

Antimalarial Pyrido[1,2-a]benzimidazoles

Albert J. Ndakala et al.

JOURNAL OF MEDICINAL CHEMISTRY (2011)

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Article Biochemistry & Molecular Biology

Plasmodium falciparum resistance to cytocidal versus cytostatic effects of chloroquine

Michelle F. Paguio et al.

MOLECULAR AND BIOCHEMICAL PARASITOLOGY (2011)

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Review Infectious Diseases

Haemozoin:: from melatonin pigment to drug target, diagnostic tool, and immune modulator

Thomas Haenscheid et al.

LANCET INFECTIOUS DISEASES (2007)

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Article Pharmacology & Pharmacy

Activity of piperaquine and other 4-aminoquinoline antiplasmodial drugs against chloroquine -sensitive and resistant blood-stages of Plasmodium falciparum -: Role of β-haematin inhibition and drug concentration in vacuolar water- and lipid-phases

David C. Warhurst et al.

BIOCHEMICAL PHARMACOLOGY (2007)

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Antimalarial Pyrido[1,2-a]benzimidazoles Exert Strong Parasiticidal Effects by Achieving High Cellular Uptake and Suppressing Heme Detoxification

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