1-2-4-trioxane and Malaria

According to WHO "World health statistics 2018", malaria alongside acute respiratory infections and diarrhoea, is one of the major infectious disease causing children's death in between the age of 1-5 years. Similarly, according to another report (2016) malaria accounts for approximately 3.14% of the total disease burden worldwide. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise due to the rapid spread of malaria parasites that are resistant to antimalarial drugs. Artemisinin (8), a major breakthrough in the antimalarial chemotherapy was isolated from the plant Artemisia annua in 1972. Its semi-synthetic derivatives such as artemether (9), arteether (10), and artesunic acid (11) are quite effective against multi-drug resistant malaria strains and are currently the drug of choice for the treatment of malaria. Inspite of exhibiting excellent antimalarial activity by artemisinin (8) and its derivatives, parallel programmes for the discovery of novel natural and synthetic peroxides were also the area of investigation of medicinal chemists all over the world. In these continuous efforts of extensive research, natural ozonide (1,2,4- trioxolane) was isolated from Adiantum monochlamys (Pteridaceae) and Oleandra wallichii (Davalliaceae) in 1976. These naturally occurring stable ozonides inspired chemists to investigate this novel class for antimalarial chemotherapy. The first identification of unusually stable synthetic antimalarial 1,2,4-trioxolanes was reported in 1992. Thus, an unusual entry of ozonides in the field of antimalarial chemotherapy had occurred in the early nineties. This review highlights the recent advancements and historical developments observed during the past 42 years (1976-2018) focusing mainly on important ventures of the antimalarial 1,2,4-trioxolanes (ozonides).

Topics: Animals; Antimalarials; Biological Products; Heterocyclic Compounds; Humans; Malaria; Parasitic Sensitivity Tests; Plasmodium falciparum

The ozonides are one of the most advanced drug classes in the antimalarial development pipeline and were designed to improve on limitations associated with current front-line artemisinin-based therapies. Like the artemisinins, the pharmacophoric peroxide bond of ozonides is essential for activity, and it appears that these antimalarials share a similar mode of action, raising the possibility of cross-resistance. Resistance to artemisinins is associated with Plasmodium falciparum mutations that allow resistant parasites to escape short-term artemisinin-mediated damage (elimination half-life ~1 h). Importantly, some ozonides (e.g., OZ439) have a sustained in vivo drug exposure profile, providing a major pharmacokinetic advantage over the artemisinin derivatives. Here, we describe recent progress made towards understanding ozonide antimalarial activity and discuss ozonide utility within the context of artemisinin resistance.

Topics: Artemisinins; Drug Resistance; Heterocyclic Compounds; Humans; Malaria; Plasmodium falciparum

The development of new efficient therapeutics for the treatment of malaria and cancer is an important endeavor. Over the past 15 years, much attention has been paid to the synthesis of dimeric structures, which combine two units of artemisinin, as lead compounds of interest. A wide variety of atemisinin-derived dimers containing different linkers demonstrate improved properties compared to their parent compounds (e.g., circumventing multidrug resistance), making the dimerization concept highly compelling for development of efficient antimalarial and anticancer drugs. The present Perspective highlights recent developments on different types of artemisinin-derived dimers and their structural and functional features. Particular emphasis is put on the respective in vitro and in vivo studies, exploring the role of the length and nature of linkers on the activities of the dimers, and considering the future prospects of the dimerization concept for drug discovery.

Topics: Animals; Antimalarials; Antineoplastic Agents, Phytogenic; Artemisinins; Dimerization; Heterocyclic Compounds; Humans; Malaria; Molecular Conformation; Neoplasms

Trioxane based compounds such as artemisinin and its synthetic and semi-synthetic analogues constitute promising class of antimalarial agents. The pharmaceutical development of artemisinin was started in 1971 after the isolation from Chinese medicinal plant Artemisia annua and this compound has drawn much attention from medical chemist and pharmacologist worldwide. Researchers from across the globe have independently and collaboratively conducted various studies on the artemisinin system in an attempt to identify lead molecules for malaria chemotherapy. This systematic study led to the discovery of artemether, arteether, dihydroartemisinin, and sodium artesunate which are being used as antimalarial drug for the treatment of Plasmodium falciparum related infections. These studies also revealed that the trioxane bridge is essential for the antimalarial activity of this class of compounds. Another class of structurally simple peroxides that emerged from these studies was the 1,2,4,5-tetraoxanes. Some of the tetraoxane based compounds have shown promising antimalarial potential, and much of work has been done on this type of compound in recent years. Apart from their antimalarial activity, these classes of compounds have also shown promising anticancer and antibacterial activity. To this end, an attempt has been made to describe the medicinal potential of trioxane and tetraoxane-based compounds. Literature from 1999 has been critically reviewed and an attempt has been made to discuss structure activity relationship study among the series of trioxane and tetraoxane based compounds.

Topics: Animals; Antimalarials; Antineoplastic Agents; Artemisia; Artemisinins; Heterocyclic Compounds; Humans; Malaria; Neoplasms; Plasmodium; Tetraoxanes

Malaria is a global health problem that needs attention of drug discovery scientists to investigate novel compounds with high drug efficacy, safety and low cost to counter the malaria parasites that are resistant to existing drug molecules. This is an overview of past to present status of antimalarial drugs including newly researched candidates and also the alternative approaches for the complete control of malaria.

Topics: Aminoquinolines; Antimalarials; Biological Products; Coordination Complexes; Drug Therapy, Combination; Folic Acid Antagonists; Heterocyclic Compounds; Humans; Malaria; Malaria Vaccines; Peroxides; Tetraoxanes

A new series of 1,2,4-trioxanes 9a1-a4, 9b1-b4, 10-13 and 9c1-c4 were synthesized and evaluated against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via oral and intramuscular (i.m.) routes. Adamantane-based trioxane 9b4, the most active compound of the series, provided 100% protection to the infected mice at the dose 48 mg/kg × 4 days and 100% clearance of parasitemia at the dose 24 mg/kg × 4 days via oral route. Adamantane-based trioxane 9b4, is twice active than artemisinin. We have also studied the photooxygenation behaviour of allylic alcohols 6a-b (3-(4-alkoxynaphthyl)-but-2-ene-1-ols) and 6c (3-[4-(tert-butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-but-2-en-1-ol). Being behaving as dienes, they furnished corresponding endoperoxides, while behaving as allylic alcohols, they yielded β-hydroxyhydroperoxides. All the endoperoxides (7a-c) and β-hydroxyhydroperoxides (8a-c) have been separately elaborated to the corresponding 1,2,4-trioxanes, except from endoperoxide 7c. It is worthy to note that TBDMS protected naphthoyl endoperoxide 7c unable to deliver 1,2,4-trioxane, which demonstrated the strength of the O-Si bond is not easy to cleave under acidic condition.

Topics: Animals; Antimalarials; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Heterocyclic Compounds; Malaria; Mice; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium yoelii; Structure-Activity Relationship

Malaria epidemics represent one of the life-threatening diseases to low-income lying countries which subsequently affect the economic and social condition of mankind. In continuation in the development of a novel series of 1,2,4-trioxanes 13a1-c1, 13a2-c2, and 13a3-c3 have been prepared and further converted into their hemisuccinate derivatives 14a1-c1, 14a2-c2, and 14a3-c3 respectively. All these new compounds were evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular (im) routes. Hydroxy-functionalized trioxane 13a1 showed 80% protection and its hemisuccinate derivative 14a1 showed 100% protection at a dose of 48 mg/kg × 4 days by both routes, which is twice active than artemisinin by oral route.

Topics: Administration, Oral; Animals; Antimalarials; Drug Resistance, Microbial; Drug Resistance, Multiple; Heterocyclic Compounds; Injections, Intramuscular; Malaria; Mice; Parasitic Sensitivity Tests; Plasmodium yoelii

Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC

Topics: Antimalarials; Dose-Response Relationship, Drug; Heterocyclic Compounds; Malaria; Molecular Docking Simulation; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship

The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (Fe(II)) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe(II)-sensitive "trigger," making drug release contingent on Fe(II)-promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the Fe(II)-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe(II)-targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron.

Topics: Animals; Delayed-Action Preparations; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Delivery Systems; Drug Therapy, Combination; Electrophoresis, Polyacrylamide Gel; Ferrous Compounds; Heterocyclic Compounds; Malaria; Mice; Photochemotherapy; Plasmodium berghei

Four 5-carbon-linked trioxane dimer orthoesters (6a-6d) have been prepared in 4 or 5 chemical steps from the natural trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally.

Topics: Administration, Oral; Animals; Antimalarials; Artemisinins; Crystallography, X-Ray; Drug Therapy, Combination; Esters; Heterocyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Malaria; Mefloquine; Mice; Molecular Structure; Plasmodium berghei

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.

Topics: Adamantane; Animals; Antimalarials; Artemisinins; Dose-Response Relationship, Drug; Drug Stability; Heterocyclic Compounds; Iron; Malaria; Male; Mice; Peroxides; Plasmodium berghei; Rats; Rats, Sprague-Dawley; Time Factors; Treatment Outcome

Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria.

Topics: Alkenes; Amides; Animals; Antimalarials; Crystallography, X-Ray; Disease Models, Animal; Heterocyclic Compounds; Malaria; Mice; Models, Molecular; Molecular Structure; Oxidation-Reduction; Oxygen; Parasitic Sensitivity Tests; Plasmodium berghei; Propanols; Stereoisomerism; Sulfhydryl Compounds; Sulfides; Sulfones

The synthesis, characterization, and antimalarial evaluation of a new series of potential antimalarial molecules, named trioxaferroquines, are reported. Trioxaferroquines are hybrid antimalarial drugs containing a 1,2,4-trioxane covalently linked to ferroquine (Fq), a synthetic ferrocenylquinoline derivative currently under clinical development. The aim was to combine, within a single structure, an iron(II) species, a 1,2,4-trioxane, as in artemisinin, and a substituted quinoline, as in chloroquine.

Topics: Aminoquinolines; Animals; Antimalarials; Crystallography, X-Ray; Drug Resistance; Drug Stability; Female; Ferrous Compounds; Heterocyclic Compounds; Humans; Malaria; Metallocenes; Mice; Models, Molecular; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship

A new series of 8-(1-aryl-vinyl)-6,7,10-trioxaspiro [4.5] decanes 7a-e and 3-(1-aryl-vinyl)-l,2,5-trioxaspiro [5.5] undecanes 8a-e have been prepared and screened against multi-drug resistant Plasmodium yoelii in mice. 8-(1-Naphthalen-2-yl-vinyl)-6,7,10-trioxaspiro [4.5] decane 7b, the most active trioxane of the series, has also shown promising activity against Plasmodium cynomolgi in rhesus monkeys.

Topics: Animals; Antimalarials; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Haplorhini; Heterocyclic Compounds; Malaria; Mice; Naphthalenes; Plasmodium cynomolgi; Plasmodium yoelii; Spiro Compounds

Using easily accessible keto-trioxanes 7a-g as the starting materials, a series of new variously functionalized 1,2,4-trioxanes 10-36 have been prepared and evaluated for antimalarial activity against multi-drug-resistant Plasmodium yoelii nigeriensis in mice in the dose range of 24 mg/kg x 4 days to 96 mg/kg x 4 days by oral route. Trioxanes 10, 12, 14, 16, 18, 20, and 22 have shown promising antimalarial activity. Trioxanes 14 and 18, the two most active compounds of the series, provide 100% and 60% protection at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively. In this model beta-arteether provides 100% and 20% protection at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively.

Topics: Administration, Oral; Amination; Animals; Antimalarials; Artemisinins; Drug Resistance, Multiple; Heterocyclic Compounds; Malaria; Mice; Molecular Structure; Plasmodium yoelii; Structure-Activity Relationship; Survival Rate