arterolane and Malaria

Malaria is a prevalent fatal disease in tropical and subtropical regions around the world. Combinations of Artemisinin, folate antagonists, quinolines, and antibiotics are major choices in clinics. Currently, wide range of parasite's resistance necessitates the search for chemical compounds with new structures and novel antimalarial targets. The literature review was performed covering the relevant literatures published from 1966 to 2021. On the basis of structural classification (spiro-peroxides, spiroindolones, spirocyclohexadienones et al.), different types of molecules were summarized with resources, anti-malarial activities, structure-activity relationship, target introductions, resistance, development progress, and synthetic strategies, for the purpose of providing comprehensive information for developing antimalarial drugs to overcome drug resistance and highlighting the importance of the spiral structure in medicinal chemistry.

Topics: Antimalarials; Drug Resistance; Folic Acid Antagonists; Humans; Malaria; Plasmodium falciparum; Quinolines

Natural products have played a pivotal role in malaria chemotherapy progressing from quinine and artemisinin to ozonide-based compounds. Many of these natural products have served as template for the design and development of antimalarial drugs currently in the clinic or in the development phase. In this review, we will detail those privileged scaffolds that have guided medicinal chemistry efforts yielding molecules that have reached the clinic.

Topics: Antimalarials; Biological Products; Chemistry, Pharmaceutical; Humans; Malaria; Molecular Structure

This digest covers some of the most relevant progress in malaria drug discovery published between 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug discovery efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria.

Topics: Animals; Antimalarials; Drug Discovery; Humans; Liver; Liver Transplantation; Malaria; Molecular Structure

Chloroquine has been the treatment of choice for acute vivax malaria for more than 60 years. Malaria caused by Plasmodium vivax has recently shown resistance to chloroquine in some places. This study compared the efficacy and safety of fixed dose combination (FDC) of arterolane maleate and piperaquine phosphate (PQP) with chloroquine in the treatment of uncomplicated vivax malaria.. Patients aged 13-65 years with confirmed mono-infection of P. vivax along with fever or fever in the previous 48 h were included. The 317 eligible patients were randomly assigned to receive FDC of arterolane maleate and PQP (n = 159) or chloroquine (n = 158) for 3 days. Primaquine was given as an anti-relapse measure on day 3 and continued for 14 consecutive days. Primary efficacy analysis included assessment of the proportion of aparasitaemic and afebrile patients at 72 h. Safety endpoints were analysis of adverse events, vital signs, laboratory data, and abnormalities on electrocardiograph. Patients participated in the study for at least 42 days.. In per protocol population, the proportion of aparasitaemic and afebrile patients at 72 h was 100% (140/140) in the FDC of arterolane maleate and PQP group, and 99.3% (145/146) in the chloroquine group (Fisher, p > 0.9999). In intent to treat population, the corresponding value was reported to be 96.9% (154/159) in the FDC of arterolane maleate and PQP group and 98.7 % (156/158) in the chloroquine group (Fisher, p = 0.4479). The median parasite clearance time was 24 h in FDC of arterolane maleate and PQP group and 26 h in chloroquine group (Log-rank, p = 0.2264). Similarly, median fever clearance time was 24 h in both the groups (Log-rank, p = 0.7750). In PP population, day 28 cure rates were 100 % in both the groups (95% CI (96.52, 100.0 for FDC of arterolane maleate and PQP and 96.73, 100.0 in chloroquine group)). Incidence of adverse events was 82.4% in the FDC of arterolane maleate and PQP group and 85.4% in the chloroquine group. Most of the adverse events were mild to moderate in intensity. The commonly reported clinical adverse events in the FDC of arterolane maleate and PQP versus chloroquine group were vomiting (5.0 vs 5.1%), headache (1.3 vs 3.2%) and prolonged QT (1.9 vs 3.2%). No deaths were reported. The pharmacokinetic analysis indicates that arterolane maleate is well absorbed and has a relatively short t1/2 of 3.2 h. Piperaquine is also well absorbed after oral administration with a t1/2 of about 228.33 h.. The study showed that FDC of arterolane maleate and PQP effectively cured vivax malaria and attained acceptable level of cure up to day 28. Both the groups showed similar safety profile. Trial Registration Clinical Trial Registry India: CTRI/2011/11/002129.

Topics: Adolescent; Adult; Aged; Antimalarials; Chloroquine; Drug Therapy, Combination; Female; Heterocyclic Compounds, 1-Ring; Humans; Malaria; Malaria, Vivax; Male; Maleates; Middle Aged; Peroxides; Quinolines; Spiro Compounds; Young Adult

The World Health Organization (WHO) recommends artemisinin combination therapy (ACT) for the treatment of uncomplicated Plasmodium falciparum malaria. The present study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate 37.5 mg and piperaquine phosphate (PQP) 187.5 mg dispersible tablets in paediatric patients aged 6 months to 12 years.. Male and female patients aged 6 months to 12 years who were confirmed cases of P. falciparum mono-infection with fever or documented history of fever in the previous 24 h were included. The patients were administered FDC of arterolane maleate and PQP as single daily doses for three consecutive days based on their age. The primary efficacy outcome was proportion of patients with polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) on day 28. Safety was analysed based on adverse events (AE), laboratory abnormalities and abnormalities on electrocardiograph.. A total of 141 eligible paediatric patients received FDC of arterolane maleate and PQP in a 42-day follow-up study. All the enrolled patients (141) were included in intention to treat (ITT) and safety analyses, and 126 patients were considered in per protocol (PP) population. The PCR-corrected ACPR on day 28 was achieved in all patients (100 %; 95 % CI 97.11-100) included in PP population. The median parasite clearance time (PCT) and fever clearance time (FCT) were 24 h (95 % CI 18.0-24.0) and 10 h (95 % CI 4.0-18.0), respectively. The most frequently reported clinical AE was vomiting. Majority of the AEs were mild to moderate in severity and resolved without sequelae. No patient was discontinued for any QTc (corrected QT interval) prolongation. No deaths or serious AEs were reported during the study.. The findings from this study showed that FDC of arterolane maleate and PQP effectively cures P. falciparum malaria and attains acceptable level of cure by day 28 in paediatric patients. The efficacy and safety results observed in children warrants further studies on FDC of arterolane maleate and PQP dispersible tablets.. Clinical Trial Registry India: CTRI/2009/091/000531.

Topics: Antimalarials; Child; Child, Preschool; Cote d'Ivoire; Drug Combinations; Female; Heterocyclic Compounds, 1-Ring; Humans; India; Infant; Infant, Newborn; Malaria; Malaria, Falciparum; Male; Peroxides; Plasmodium falciparum; Quinolines; Rwanda; Spiro Compounds; Tablets

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.

Topics: Administration, Oral; Animals; Antimalarials; Disease Models, Animal; Drug Stability; Humans; Inhibitory Concentration 50; Malaria; Mice; Morpholines; Plasmodium falciparum; Rats; Tetraoxanes

Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pK

Topics: Adamantane; Animals; Antimalarials; Female; Malaria; Male; Mice; Peroxides; Plasmodium berghei; Plasmodium falciparum; Rats; Structure-Activity Relationship

We describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane. Conformational analysis suggested that trans-3″-substituted trioxolanes would exhibit Fe(II) reactivity and antiparasitic activity similar to that achieved with canonical cis-4″ substitution. The chiral 3″ analogues were prepared as single stereoisomers and evaluated alongside their 4″ congeners against cultured malaria parasites and in a murine malaria model. As predicted, the trans-3″ analogues exhibited in vitro antiplasmodial activity remarkably similar to that of their cis-4″ comparators. In contrast, efficacy in the Plasmodium berghei mouse model differed dramatically for some of the congeneric pairs. The best of the novel 3″ analogues (e.g., 12i) outperformed arterolane itself, producing cures in mice after a single oral exposure. Overall, this study suggests new avenues for modulating Fe(II) reactivity and the pharmacokinetic and pharmacodynamic properties of 1,2,4-trioxolane antimalarials.

Topics: Animals; Antimalarials; Female; Ferrous Compounds; Heterocyclic Compounds, 1-Ring; Malaria; Mice; Peroxides; Plasmodium berghei; Plasmodium falciparum; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship

Topics: Animals; Antimalarials; Carbamates; Cathepsin C; Drug Carriers; Heterocyclic Compounds, 1-Ring; Iron; Malaria; Peroxides; Protease Inhibitors; Spiro Compounds

A new series of 6 dimeric trioxane sulfones has been prepared from the natural trioxane artemisinin in five or six chemical steps. One of these thermally and hydrolytically stable new chemical entities (4c) completely cured malaria-infected mice via a single oral dose of 144 mg/kg. At a much lower single oral dose of only 54 mg/kg combined with 13 mg/kg of mefloquine hydrochloride, this trioxane dimer 4c as well as its parent trioxane dimer 4b also completely cured malaria-infected mice. Both dimers 4c and 4b were potently and selectively cytotoxic toward five cancer cell lines.

Topics: Administration, Oral; Animals; Antimalarials; Antineoplastic Agents; Artemisinins; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drug Stability; Drug Therapy, Combination; Humans; Malaria; Mefloquine; Mice; Sulfones

RBx11160 (OZ277) is a promising antimalarial drug candidate that Ranbaxy Laboratories Limited and Medicines for Malaria Venture (MMV) are currently developing as a fixed combination with piperaquine. Here, we describe the in vitro (Plasmodium falciparum) and in vivo (Plasmodium berghei) activities of piperaquine in combination with RBx11160 and artemether. In vitro, both combinations demonstrated a slight tendency towards antagonism with mean sums of fractional inhibitory concentrations (mean Sigma FICs) of 1.5. In vivo, piperaquine and artemether were borderline antagonistic (mean Sigma FIC of 1.4). However, an additive in vivo interaction of piperaquine and RBx11160 (mean Sigma FIC of 1.1) was identified, suggesting that a RBx11160-piperaquine combination therapy in humans should allow each molecule to exert its full antimalarial effect.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Atovaquone; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Erythrocytes; Female; Heterocyclic Compounds, 1-Ring; Humans; Malaria; Mice; Parasitemia; Parasitic Sensitivity Tests; Peroxides; Plasmodium berghei; Plasmodium falciparum; Pyrimethamine; Quinolines; Spiro Compounds

Topics: Africa; Animals; Antimalarials; Artemisinins; Clinical Trials as Topic; Drug Costs; Drug Design; Drug Evaluation, Preclinical; Drug Resistance; Drug Therapy, Combination; Drug Utilization; Genetic Engineering; Heterocyclic Compounds, 1-Ring; Humans; Malaria; Peroxides; Plasmodium falciparum; Spiro Compounds; World Health Organization

Topics: Animals; Antimalarials; Artemisinins; Heterocyclic Compounds, 1-Ring; Humans; Malaria; Peroxides; Sesquiterpenes; Spiro Compounds

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)--may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.

Topics: Animals; Antimalarials; Artemisinins; Biological Availability; Drug Design; Drug Evaluation, Preclinical; Half-Life; Heterocyclic Compounds, 1-Ring; Humans; Inhibitory Concentration 50; Malaria; Mice; Oxidation-Reduction; Peroxides; Plasmodium berghei; Plasmodium falciparum; Rats; Rats, Wistar; Sesquiterpenes; Solubility; Spiro Compounds; Tissue Distribution

Topics: Antimalarials; Artemisinins; Clinical Trials as Topic; Drug Costs; Drug Design; Drug Therapy, Combination; Heterocyclic Compounds, 1-Ring; Humans; Malaria; Peroxides; Research Support as Topic; Sesquiterpenes; Spiro Compounds; Thailand