ABSTRACT
Following the economic and social state of humanity, Malaria is categorized as one of the life-threatening illness epidemics in under developed countries. For the eradication of the same, 1,2,4-trioxanes 17a1-a2, 17b1-b2, 17c1-c2 15a-c, 18 and 19 have been synthesized continuing the creation of a novel series. Additionally, these novel compounds were tested for their effectiveness against the multidrug-resistant Plasmodium yoelii nigeriensis in mice model using both oral and intramuscular (im) administration routes. The two most potent compounds of the series, 17a1 and 17a2, demonstrated 100 % protection at 48 mg/kg x 4 days via oral route, which is twice as potent as artemisinin. In this model artemisinin provided 100 % protection at a dose of 48 mg/kg × 4 days and 80 % protection at 24 mg/kg × 4 days via im route.
Subject(s)
Antimalarials , Artemisinins , Plasmodium yoelii , Animals , Mice , Antimalarials/pharmacology , Structure-Activity Relationship , Drug Resistance, Multiple , Artemisinins/pharmacologyABSTRACT
A mechanistic approach to understand the course of metabolism for synthetic 1,2,4-trioxanes, potent antimalarial compounds, to evaluate their bioavailability for antimalarial action has been studied in the present work. It is an important parameter to study the course of metabolism of a drug candidate molecule when administered via oral route during its journey from oral intake to its target site. From the pharmacokinetics point of view, it determines the bioavailability of an active drug or a prodrug at the target point. In this work, synthetic arylvinyl-1,2,4-trioxanes 1a-u have been evaluated under various acidic conditions to mimic the milieu of the stomach (pH between 1.5 and 3.5) through which they have to pass when administered orally. The effect of acid on trioxanes led to their degradation into corresponding ketones and glyoxal. Under such acidic conditions glyoxal polymerized to form a nonisolable condensate product. The study indicates that the actual bioavailability of the drug is far less than the administered dose.
ABSTRACT
Novel hydrazone derivatives 10a-m were prepared from N-Amino-11-azaartemisinin (9) and screened for their antimalarial activity by oral and intramuscular (i.m.) routes against multidrug-resistant Plasmodium yoelii in Swiss mice model. Several of the hydrazone derivatives showed higher order of antimalarial activity. Compounds 10b, 10g, 10m provided 100% protection to the infected mice at the dose of 24 mg/kg × 4 days via oral route. Fluorenone based hydrazone 10m the most active compound of the series, provided 100% protection at the dose of 6 mg/kg × 4 days via intramuscular route and also provided 100% protection at the dose of 12 mg/kg × 4 days via oral route. While artemisinin gave 100% protection at 48 mg/kg × 4 days and only 60% protection at 24 mg/kg × 4 days via intramuscular (i.m.) route. Compound 10m found to be four-fold more active than artemisinin via intramuscular route.
Subject(s)
Antimalarials/pharmacology , Artemisinins/pharmacology , Hydrazones/pharmacology , Malaria/drug therapy , Plasmodium yoelii/drug effects , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Artemisinins/chemistry , Dose-Response Relationship, Drug , Drug Resistance, Multiple/drug effects , Hydrazones/chemical synthesis , Hydrazones/chemistry , Malaria/parasitology , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
Novel 6-arylethyl-1,2,4-trioxanes6a-i and 7a-i are easily accessible in one step from the diimide reduction of 6-arylvinyl-1,2,4-trioxanes 5a-i. All of these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in a Swiss mice model. Most of the saturated trioxanes 6c, 6f, 6g, 6h, and 6i, the active compounds of the series, provided 100% protection to the malaria-infected mice at a dose of 24 mg/kg × 4 days. Further, trioxane 6i, the most active compound of the series, also showed 100% protection even at a dose of 12 mg/kg × 4 days and 20% protection at a dose of 6 mg/kg × 4 days. In this model, ß-arteether provided 100% protection at a dose of 48 mg/kg × 4 days and only 20% protection at a dose of 24 mg/kg × 4 days via the oral route, which was found to exhibit 4-fold antimalarial activity compared with the currently used drug ß-arteether.
ABSTRACT
By use of artemisinin 1 as the starting material, two new amino- and hydroxy-functionalized 11-azaartemisinins 9 and 11 and their derivatives 12a-g, 13a-g, 14a-g, and 15a-c have been prepared and screened for antimalarial activity by oral route against multidrug-resistant Plasmodium yoelii in Swiss mice. While azaartemisinins 9 and 11 showed only modest activity, several of their derivatives showed high order of antimalarial activity. Biphenyl-based compound 13f, the most active compound of the series, provided 100% and 80% protection to the infected mice at 12 mg/kg × 4 days and 6 mg/kg × 4 days, respectively. Compounds 12f, 13b, 13e, 13g, and 14f showed 100% protection at 12 mg/kg × 4 days, while compounds 12a-c, 14a, 14c-e, 14g, and 15a-c showed similar levels of protection at 24 mg/kg × 4 days. Clinically useful drug ß-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days in this model.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Artemisinins/chemical synthesis , Artemisinins/pharmacology , Plasmodium yoelii/drug effects , Administration, Oral , Animals , Antimalarials/administration & dosage , Artemisinins/administration & dosage , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Drug Resistance, Multiple/drug effects , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mice , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
Keto-trioxanes 7a-d, easily accessible in two steps from allylic alcohols 5a-d, underwent reductive amination with substituted anilines to furnish amino-functionalized trioxanes 8a-i, 9a-i, 10a-i, and 11a-i. All these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice. 2-Naphthalene-based trioxanes 9c and 9i, the most active compounds of the series, provided 100% protection to the malaria-infected mice at 24 mg/kg × 4 days, while the related trioxane 9b and phenanthrene-based trioxane 11e provided a similar level of protection at 48 mg/kg × 4 days. All other trioxanes, except 10c, 10d, and 10g, provided 100% protection at 96 mg/kg × 4 days. In this model, ß-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days.
Subject(s)
Aniline Compounds/chemical synthesis , Antimalarials/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Ketones/chemical synthesis , Naphthalenes/chemical synthesis , Spiro Compounds/chemical synthesis , Administration, Oral , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Drug Resistance , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Ketones/chemistry , Ketones/pharmacology , Malaria/prevention & control , Mice , Naphthalenes/chemistry , Naphthalenes/pharmacology , Parasitic Sensitivity Tests , Plasmodium yoelii/drug effects , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
A new series of 6-(4'-aryloxy-phenyl)vinyl-1,2,4-trioxanes 10a-d, 11a-d, and 12a-d have been synthesized and evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. Trioxanes 10b and 10c, the two most active compounds of the series, provided 100% protection to the infected mice at 48 mg/kg x 4 days. Clinically useful drug beta-arteether provided 100% and 20% protection at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively, in this model.
Subject(s)
Antimalarials/chemistry , Heterocyclic Compounds/chemistry , Plasmodium yoelii/drug effects , Vinyl Compounds/chemistry , Administration, Oral , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Drug Resistance, Multiple , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Mice , Structure-Activity Relationship , Vinyl Compounds/chemical synthesis , Vinyl Compounds/pharmacologyABSTRACT
A new series of bis-1,2,4-trioxanes 12a-h, 13a-h, and 14a-h and tris-1,2,4-trioxanes 12i-14i were prepared and evaluated against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. Cyclopentane-based bis-trioxanes 12a, 12b, 12f-h and cyclohexane-based bis-trioxanes 13a, 13f, and 13g showed promising activity. All the tris-1,2,4-trioxanes were found to be inactive. Bis-trioxane 12a, the most active compound of the series, provided 100% and 80% protection to infected mice at 48 and 24 mg/kg x 4 days, respectively. Clinically useful drug beta-arteether provided 100% and 20% protection at similar doses.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Drug Resistance, Multiple/drug effects , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Plasmodium yoelii/drug effects , Animals , Antimalarials/chemistry , Dose-Response Relationship, Drug , Drug Design , Heterocyclic Compounds/chemistry , Mice , Molecular Structure , Parasitic Diseases, Animal/drug therapy , Parasitic Sensitivity Tests , Stereoisomerism , Structure-Activity RelationshipABSTRACT
An efficient conversion of artemisinin 1 into three new amino- and hydroxy-functionalized 11-aza prototypes 9, 11, and 12 has been achieved on a multigram scale by reaction with hydrazine, hydroxylamine, and 2-amino ethanol, respectively. Of these, 9 has been further diversified into a wide range of derivatives including imines, amines, amides, and linker based dimers. Prototypes 11 and 12 have been converted into the corresponding ethers in high yields. Some of these compounds have shown a high order of activity against multidrug-resistant malaria in mice by oral route.
