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Pueblo Africano , Inteligencia Artificial , Desarrollo de Medicamentos , Investigadores , África , Inteligencia Artificial/tendencias , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/tendencias , Investigación Biomédica/métodos , Investigación Biomédica/tendencias , Bases de Datos como Asunto , Investigadores/tendenciasRESUMEN
UCT594 is a 2-aminopyrazine carboxylic acid Plasmodium phosphatidylinositol 4-kinase inhibitor with potent asexual blood-stage activity, the potential for interrupting transmission, as well as liver-stage activities. Herein, we investigated pharmacokinetic/pharmacodynamic (PK/PD) relationships relative to blood-stage activity toward predicting the human dose. Dose-fractionation studies were conducted in the Plasmodium falciparum NSG mouse model to determine the PK/PD indices of UCT594, using the in vivo minimum parasiticidal concentration as a threshold. UCT594 demonstrated concentration-dependent killing in the P. falciparum-infected NSG mouse model. Using this data and the preclinical pharmacokinetic data led to a low predicted human dose of <50 mg. This makes UCT594 an attractive potential antimalarial drug.
RESUMEN
Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves Mg2+-independent stabilization of the DNA cleavage complex with DNA gyrase and is thereby not cross-resistant with other DNA gyrase-inhibiting antibacterials, including fluoroquinolones. Compound 22 from the series was profiled broadly and showed in vitro cidality as well as intracellular activity against M. tuberculosis in macrophages. Evidence for the DNA gyrase mode of action was supported by inhibition of the target in a DNA supercoiling assay and elicitation of an SOS response seen in a recA reporter strain of M. tuberculosis. Pharmacokinetic properties of 22 supported evaluation of efficacy in an acute model of M. tuberculosis infection, where modest reduction in CFU numbers was seen. This work offers promise for deriving a novel drug class of tuberculosis agent without preexisting clinical resistance.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Girasa de ADN/genética , Fluoroquinolonas/farmacología , Fluoroquinolonas/uso terapéutico , Humanos , Inhibidores de Topoisomerasa II/farmacología , Tuberculosis/tratamiento farmacológicoRESUMEN
A second generation of 4-aminoquinoline- and 8-aminoquinoline-based tetrazoles and lactams were synthesized via the Staudinger and Ugi multicomponent reactions. These compounds were subsequently evaluated in vitro for their potential antiplasmodium activity against a multidrug-resistant K1 strain and for their antitrypanosomal activity against a cultured T. b. rhodesiense STIB900 strain. Several of these compounds (4a-g) displayed good antiplasmodium activities (IC50 = 0.20-0.62 µM) that were comparable to the reference drugs, while their antitrypanosomal activity was moderate (<20 µM). Compound 4e was 2-fold more active than primaquine and was also the most active (IC50 = 7.01 µM) against T. b. rhodesiense and also exhibited excellent aqueous solubility (>200 µM) at pH 7.
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Aminoquinolinas/síntesis química , Aminoquinolinas/farmacología , Lactamas/química , Tetrazoles/química , Aminoquinolinas/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Técnicas de Química Sintética , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Trypanosoma brucei rhodesiense/efectos de los fármacosRESUMEN
The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human ß2 and ß5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.
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Artemisininas/farmacología , Plasmodium falciparum/enzimología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Artemisininas/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Inhibidores de Proteasoma/química , Relación Estructura-ActividadRESUMEN
The in vivo antimalarial efficacies of two phosphatidylinositol 4-kinase (PI4K) inhibitors, a 3,5-diaryl-2-aminopyrazine sulfoxide and its corresponding sulfone metabolite, were evaluated in the NOD-scid IL2Rγnull (NSG) murine malaria disease model of Plasmodium falciparum infection. We hypothesized that the sulfoxide would serve as a more soluble prodrug for the sulfone, which would lead to improved drug exposure with oral dosing. Both compounds had similar efficacy (90% effective dose [ED90], 0.1 mg kg-1 of body weight) across a quadruple-dose regimen. Pharmacokinetic profiling revealed rapid sulfoxide clearance via conversion to sulfone, with sulfone identified as the major active metabolite. When the sulfoxide was dosed, the exposure of the sulfone achieved was as much as 2.9-fold higher than when the sulfone was directly dosed, thereby demonstrating that the sulfoxide served as an effective prodrug for the treatment of malaria.
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Antimaláricos/farmacología , Malaria Falciparum/tratamiento farmacológico , Parasitemia/tratamiento farmacológico , Profármacos/farmacología , Pirazinas/farmacología , Sulfonas/farmacología , Sulfóxidos/farmacología , 1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , 1-Fosfatidilinositol 4-Quinasa/genética , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Animales , Antimaláricos/sangre , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Biotransformación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Eritrocitos/parasitología , Expresión Génica , Humanos , Malaria Falciparum/metabolismo , Malaria Falciparum/parasitología , Malaria Falciparum/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Parasitemia/patología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Plasmodium falciparum/crecimiento & desarrollo , Profármacos/síntesis química , Profármacos/farmacocinética , Pirazinas/sangre , Pirazinas/síntesis química , Pirazinas/farmacocinética , Sulfonas/sangre , Sulfonas/síntesis química , Sulfonas/farmacocinética , Sulfóxidos/sangre , Sulfóxidos/síntesis química , Sulfóxidos/farmacocinética , Resultado del TratamientoRESUMEN
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.
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A series of novel fusidic acid (FA) derivatives was synthesized by replacing the carboxylic acid group with various ester and amide groups and evaluated in vitro for their antiplasmodial activity against the chloroquine-sensitive NF54 and multidrug-resistant K1 strains of the malarial parasite Plasmodium falciparum. Most of these derivatives showed a 4-49 and 5-17-fold increase in activity against NF54 and KI strains, respectively, as compared to FA and had a good selectivity index. These derivatives are stable over the incubation period and do not appear to be prodrugs of fusidic acid.
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Amidas/química , Ésteres/química , Ácido Fusídico/química , Ácido Fusídico/farmacología , Plasmodium falciparum/efectos de los fármacos , Amidas/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Cloroquina/farmacología , Resistencia a Medicamentos/efectos de los fármacos , Ésteres/farmacología , Ácido Fusídico/síntesis química , Relación Estructura-ActividadRESUMEN
Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer) tested at 1-150 µM had an apparent rate of permeability (Papp) typical of poorly absorbed compounds (1.73 × 10-6 cm/s). Major glucose transporters, sodium glucose linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), and efflux protein (P-glycoprotein, PgP) (1.84 × 10-6 cm/s; efflux ratio: 1.1) were excluded as primary transporters, since the Papp of aspalathin was not affected by the presence of specific inhibitors. The Papp of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM), which decreased the Papp value to 2.9 × 10-7 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated) were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly.
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Aspalathus/química , Chalconas/farmacocinética , Absorción Intestinal , Intestinos/química , Animales , Disponibilidad Biológica , Transporte Biológico , Células CACO-2 , Chalconas/administración & dosificación , Humanos , Ratones , Permeabilidad , Extractos Vegetales/química , Orina/químicaRESUMEN
A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively.
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Aminoquinolinas/química , Aminoquinolinas/uso terapéutico , Antimaláricos/química , Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacología , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Derivados del Benceno/química , Derivados del Benceno/farmacocinética , Derivados del Benceno/farmacología , Derivados del Benceno/uso terapéutico , Humanos , Malaria Falciparum/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Relación Estructura-ActividadRESUMEN
A series of compounds derived from the 2-amino-4-(2-pyridyl) thiazole scaffold was synthesized and tested for in vitro antimycobacterial activity against the Mycobacterium tuberculosis H37Rv strain, antiplasmodial activity against the chloroquine sensitive NF54 Plasmodium falciparum strain and cytotoxicity on a mammalian cell line. Optimal antimycobacterial activity was found with compounds with a 2-pyridyl ring at position 4 of the thiazole scaffold, a substituted phenyl ring at the 2-amino position, and an amide linker between the scaffold and the substituted phenyl. The antiplasmodial activity was best with compounds that had the phenyl ring substituted with hydrophobic electron withdrawing groups.
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Antibacterianos/síntesis química , Antibacterianos/farmacología , Antimaláricos/síntesis química , Antimaláricos/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos/métodos , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/fisiología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/fisiologíaRESUMEN
Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 µM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 µM; hERG IC50 = 0.63 µM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 µM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 µM, and liver-stage PbHepG2 IC50 = 2.30 µM), good microsomal metabolic stability (MLM CLint < 11 µL·min-1·mg-1, EH < 0.33), and solubility (150 µM). It shows a â¼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg-1 resulting from poor permeability (logâ¯D7.4 = -0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.
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Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.
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Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase ß (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.
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1-Fosfatidilinositol 4-Quinasa , Antimaláricos , Hemoproteínas , Naftiridinas , Plasmodium falciparum , Pez Cebra , Plasmodium falciparum/efectos de los fármacos , Animales , Naftiridinas/farmacología , Naftiridinas/química , Naftiridinas/síntesis química , Naftiridinas/uso terapéutico , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/síntesis química , 1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Humanos , Relación Estructura-Actividad , Hemoproteínas/antagonistas & inhibidores , Hemoproteínas/metabolismo , Ratones , Ratas , Malaria Falciparum/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis químicaRESUMEN
A series of new deoxyamodiaquine-based compounds was synthesized via the modified TMSN3-Ugi multi-component reaction and evaluated in vitro for antiplasmodial activity. The most potent compounds, 6b, 6c and 6j, showed IC50 values in the range of 6-77nM against chloroquine-resistant K1- and W2-strains of Plasmodium falciparum. In vitro ADME characterization of frontrunner compounds 6b and 6c indicates that these two compounds are rapidly metabolized and have a high clearance rate in human and rat liver microsomes. This result correlated well with an in vivo pharmacokinetics study, which showed low bioavailability of 6c in rats. Tentative metabolite identification was determined by LC-MS and suggested metabolic lability of groups attached to the tertiary nitrogen. Preliminary studies on 6b and 6c suggested strong inhibitory activity against the major CYP450 enzymes. In silico docking studies were used to rationalize strong inhibition of CYP3A4 by 6c. Full characterization and biological evaluation of the metabolites is currently underway in our laboratories.
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Aminoquinolinas/síntesis química , Amodiaquina/análogos & derivados , Antimaláricos/síntesis química , Tetrazoles/química , Tetrazoles/síntesis química , Aminoquinolinas/farmacocinética , Aminoquinolinas/toxicidad , Amodiaquina/farmacocinética , Amodiaquina/toxicidad , Animales , Antimaláricos/farmacocinética , Antimaláricos/toxicidad , Sitios de Unión , Células CHO , Supervivencia Celular/efectos de los fármacos , Cricetinae , Cricetulus , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Resistencia a Medicamentos/efectos de los fármacos , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Plasmodium falciparum/efectos de los fármacos , Estructura Terciaria de Proteína , Ratas , Relación Estructura-Actividad , Tetrazoles/farmacocinética , Tetrazoles/toxicidadRESUMEN
We previously identified a novel class of antimalarial benzimidazoles incorporating an intramolecular hydrogen bonding motif. The frontrunner of the series, analogue A, showed nanomolar activity against the chloroquine-sensitive NF54 and multi-drug-resistant K1 strains of Plasmodium falciparum (PfNF54 IC50 = 0.079 µM; PfK1 IC50 = 0.335 µM). Here, we describe a cell-based medicinal chemistry structure-activity relationship study using compound A as a basis. This effort led to the identification of novel antimalarial imidazopyridines with activities of <1 µM, favorable cytotoxicity profiles, and good physicochemical properties. Analogue 14 ( PfNF54 IC50 = 0.08 µM; PfK1 IC50 = 0.10 µM) was identified as the frontrunner of the series. Preliminary mode of action studies employing molecular docking, live-cell confocal microscopy, and a cellular heme fractionation assay revealed that 14 does not directly inhibit the conversion of heme to hemozoin, although it could be involved in other processes in the parasite's digestive vacuole.
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Antimaláricos , Antagonistas del Ácido Fólico , Antimaláricos/farmacología , Antimaláricos/química , Enlace de Hidrógeno , Simulación del Acoplamiento Molecular , Química Farmacéutica , Plasmodium falciparum , HemoRESUMEN
RATIONALE: Artemisinin-based drugs and their metabolites are prone to in-source fragmentation under atmospheric pressure ionisation mass spectrometry (API-MS) conditions. To facilitate correct and efficient identification of all possible drug metabolites using full scan MS analyzer methods, stable [M + NH(4) ](+) ions should be produced in the MS source. METHODS: Using a high-performance liquid chromatography (HPLC) hybrid triple quadrupole linear ion trap MS system, electrospray ionisation (ESI), atmospheric pressure chemical ionisation (APCI) and atmospheric pressure photoionisation (APPI) methods were developed for the detection of [M + NH(4) ](+) ions of the test compounds dihydroartemisinin, artemisinin, artemether and artesunic acid. The optimised methods employed ammonium formate buffered HPLC mobile phase in combination with moderate source temperatures (100-200 °C) and showed satisfactorily reduced in-source fragmentation. RESULTS: With a full scan MS analyser method for the detection of the in vitro metabolites of the test compounds, the respective performance of the ESI and APCI methods was found to be comparable. ESI generally resulted in less in-source fragmentation. Incorrect assignment of metabolites resulted from strong in-source fragmentation of artemether using the APPI method. The most number of metabolites could be detected using ESI in combination with a selective MS analyser method. CONCLUSIONS: ESI and APCI full scan methods proved to be capable of detecting any drug metabolites present in reasonable concentrations, and are useful when employed in addition to selective scan methods that target low level expected metabolites. APPI can be a valuable alternative for detecting expected metabolites due to good signal-to-noise (S/N) ratio.
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Antimaláricos/metabolismo , Artemisininas/metabolismo , Espectrometría de Masas/métodos , Antimaláricos/análisis , Artemisininas/análisis , Cromatografía Líquida de Alta Presión/métodos , Femenino , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization's (WHO) goal to end the global TB pandemic by the year 2035. During the past 50 years, very few new drugs have been approved by medical agencies to treat drug-resistant TB. Therefore, the development of novel antimycobacterial drug candidates to combat the threat of drug-resistant TB is urgent. In this work, we developed and optimized a total synthesis of the antimycobacterial natural flavonoid chlorflavonin by selective ruthenium(II)-catalyzed ortho-C(sp2)-H-hydroxylation of a substituted 3'-methoxyflavonoid skeleton. We extended our methodology to synthesize a small compound library of 14 structural analogs. The new analogs were tested for their antimycobacterial in vitro activity against Mycobacterium tuberculosis (Mtb) and their cytotoxicity against various human cell lines. The most promising new analog bromflavonin exhibited improved antimycobacterial in vitro activity against the virulent H37Rv strain of Mtb (Minimal Inhibitory Concentrations (MIC90) = 0.78 µm). In addition, we determined the chemical and metabolic stability as well as the pKa values of chlorflavonin and bromflavonin. Furthermore, we established a quantitative structure-activity relationship model using a thermodynamic integration approach. Our computations may be used for suggesting further structural changes to develop improved derivatives.
RESUMEN
Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue 1 with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue 23 (PfNF54 IC50 = 0.012 µM; PfK1 IC50 = 0.040 µM) displaying high microsomal metabolic stability (HLM CLint < 11.6 µL·min-1·mg-1) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates in vivo efficacy in Plasmodium berghei-infected mice at 4 × 50 mg·kg-1 oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that 23 could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.