Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5 – 2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage). Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.

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The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside

Pharmaceutics ◽

10.3390/pharmaceutics13122066 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2066

Author(s):

Liezl Gibhard ◽

Dina Coertzen ◽

Janette Reader ◽

Mariëtte E. van der Watt ◽

Lyn-Marie Birkholtz ◽

...

Keyword(s):

Late Stage ◽

Early Stage ◽

Blood Stage ◽

Combination Therapies ◽

Prolonged Incubation ◽

Model Following ◽

Synthetic Accessibility ◽

Artemisinin Combination Therapies

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5–2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.

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Half- Sandwich cyclopentadienylruthenium(II) Complexes: A New Antimalarial Chemotype

10.26434/chemrxiv.12155178.v1 ◽

2020 ◽

Author(s):

Sofia Alexandra Milheiro ◽

Joana Gonçalves ◽

Ricardo Lopes ◽

Margarida Madureira ◽

Lis Lobo ◽

...

Keyword(s):

Mammalian Cells ◽

Blood Stage ◽

Nuclear Accumulation ◽

Selective Absorption ◽

Asexual Parasite ◽

Single Digit ◽

Liver Stage ◽

Dual Stage ◽

Fluorescent Compounds ◽

Half Sandwich

<a>A small library of “half-sandwich” cyclopentadienylruthenium(II) compounds of general formula [(</a>η5-C5R5)Ru(PPh3)(N-N)][PF6], a scaffold hitherto unfeatured in the toolbox of antiplasmodials, was screened for activity against the blood stage of CQ-sensitive 3D7-GFP, CQ-resistant Dd2 and artemisinin-resistant IPC5202 Plasmodium falciparum strains, and the liver stage of P. berghei. The best performing compounds displayed dual-stage activity, with single-digit nM IC50 values against blood stage malaria parasites, nM activity against liver stage parasites, and residual cytotoxicity against mammalian cells (HepG2, Huh7). Parasitic absorption/distribution of 7-nitrobenzoxadiazole-appended fluorescent compounds Ru4 and Ru5 was investigated by confocal fluorescence microscopy, revealing parasite-selective absorption in infected erythrocytes and nuclear accumulation of both compounds. The lead compound Ru2 impaired asexual parasite differentiation, exhibiting fast parasiticidal activity against both ring and trophozoite stages of a synchronized P. falciparum 3D7 strain. These results point to cyclopentadienylruthenium(II) complexes as a highly promising chemotype for the development of dual-stage antiplasmodials.

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A Study by the Development of Triple Artemisinin Combination Therapies (DeTACT) Collaboration (Africa)

Case Medical Research ◽

10.31525/ct1-nct03923725 ◽

2019 ◽

Author(s):

Keyword(s):

Combination Therapies ◽

Artemisinin Combination Therapies

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Small Molecules Effective Against Liver and Blood Stage Malarial Infection

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666181129143623 ◽

2019 ◽

Vol 18 (23) ◽

pp. 2008-2021 ◽

Cited By ~ 3

Author(s):

Snigdha Singh ◽

Neha Sharma ◽

Charu Upadhyay ◽

Sumit Kumar ◽

Brijesh Rathi ◽

...

Keyword(s):

Drug Targets ◽

Malaria Parasite ◽

Blood Stage ◽

Culture Methods ◽

Liver Stage ◽

Malarial Infection ◽

Dual Stage ◽

New Treatment ◽

Global Threat

Malaria is a lethal disease causing devastating global impact by killing more than 8,00,000 individuals yearly. A noticeable decline in malaria related deaths can be attributed to the most reliable treatment, ACTs against P. falciparum. However, the cumulative resistance of the malaria parasite against ACTs is a global threat to control the disease and, therefore the new effective therapeutics are urgently needed, including new treatment approaches. Majority of the antimalarial drugs target BS malarial infection. Currently, scientists are eager to explore the drugs with potency against not only BS but other life stages such as sexual and asexual stages of the malaria parasite. Liver Stage is considered as one of the important drug targets as it always leads to BS and the infection can be cured at this stage before it enters into the Blood Stage. However, a limited number of compounds are reported effective against LS malaria infection probably due to scarcity of in vitro LS culture methods and clinical possibilities. This mini review covers a range of chemical compounds showing efficacy against BS and LS of the malaria parasite’s life cycle collectively (i.e. dual stage activity). These scaffolds targeting dual stages are essential for the eradication of malaria and to evade resistance.

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Comparative Efficacies of Artemisinin Combination Therapies in Plasmodium falciparum Malaria and Polymorphism ofpfATPase6,pfcrt,pfdhfr, andpfdhpsGenes in Tea Gardens of Jalpaiguri District, India

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05388-11 ◽

2012 ◽

Vol 56 (5) ◽

pp. 2511-2517 ◽

Cited By ~ 25

Author(s):

Pabitra Saha ◽

Subhasish K. Guha ◽

Sonali Das ◽

Shrabanee Mullick ◽

Swagata Ganguly ◽

...

Keyword(s):

Plasmodium Falciparum Malaria ◽

Study Groups ◽

Combination Therapies ◽

Antimalarial Drug Resistance ◽

Content Type ◽

Private Practitioners ◽

Mutational Pattern ◽

Sequencing Method ◽

Periodic Monitoring ◽

Artemisinin Combination Therapies

ABSTRACTIn India, chloroquine has been replaced by a combination of artesunate and sulfadoxine-pyrimethamine (AS-SP) for uncomplicatedP. falciparummalaria. Other available combinations, artemether-lumefantrine (AM-LF) and artesunate-mefloquine (AS-MQ), not included in the national program, are widely used by private practitioners. Little is known about the therapeutic efficacy of these artemisinin combinations and the prevalence of molecular markers associated with antimalarial drug resistance. A total of 157 patients withP. falciparummonoinfection were recruited and randomized into three study groups (AS-SP, AM-LF, and AS-MQ). All patients were followed up for 42 days to study the clinical and parasitological responses according to the WHO protocol (2009). We assessed the polymorphism of thepfATPase6,pfcrt,pfdhfr, andpfdhpsgenes by the DNA-sequencing method. The PCR-corrected therapeutic efficacies of AS-SP, AM-LF, and AS-MQ were 90.6% (95% confidence interval [CI], 0.793 to 0.969), 95.9% (95% CI, 0.860 to 0.995), and 100% (95% CI, 0.927 to 1.00), respectively. No specific mutational pattern was observed in thepfATPase6gene. All isolates had a K76T mutation in thepfcrtgene. In thepfdhfr-pfdhpsgenotype, quadruple mutation was frequent, and quintuple mutation was documented in 6.3% ofP. falciparumisolates. The significant failure rate of AS-SP (9.5%), although within the limit (10%) for drug policy change, was due to SP failure because of prevailing mutations inpfdhfr, I51R59N108, withpfdhps, G437and/or E540. The efficacy of this ACT needs periodic monitoring. Artemether-lumefantrine and artesunate-mefloquine are effective alternatives to the artesunate-sulfadoxine-pyrimethamine combination.

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Combined Transcriptome and Proteome Profiling for Role of pfEMP1 in Antimalarial Mechanism of Action of Dihydroartemisinin

Microbiology Spectrum ◽

10.1128/spectrum.01278-21 ◽

2021 ◽

Author(s):

Lina Chen ◽

Zhongyuan Zheng ◽

Hui Liu ◽

Xi Wang ◽

Shuiqing Qu ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Mechanism Of Action ◽

Blood Cells ◽

Artemisinin Derivative ◽

Combination Therapies ◽

Proteomic Profiling ◽

First Line ◽

Content Type ◽

Artemisinin Combination Therapies

Malaria parasites induce morphological and biochemical changes in the membranes of parasite-infected red blood cells (iRBCs) for propagation, with artemisinin combination therapies as the first-line treatments. To understand whether artemisinin targets or interacts with iRBC membrane proteins, this study investigated the molecular changes caused by dihydroartemisinin (DHA), an artemisinin derivative, in Plasmodium falciparum 3D7 using a combined transcriptomic and membrane proteomic profiling approach.

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