Multidrug-resistant Plasmodium Yoelii Nigeriensis Research Articles

Novel saturated 1,2,4-trioxanes and their antimalarial activity against multidrug resistant Plasmodium yoelii nigeriensis in Swiss mice model via oral route

Novel saturated 6-(4′-aryloxy phenyl) vinyl 1,2,4-trioxanes 12a(1–3)–12d(1–3) and 13a(1–3)–13d(1–3) have been designed and synthesized, in one single step from diimide reduction of 11a(1–3)–11d(1–3). All the newly synthesized trioxanes were evaluated for their antimalarial activity against multi-drug resistant Plasmodium yoelii nigeriensis via oral route. Cyclopentane-based trioxanes 12b1, 12c1 and 12d1, provided 100 % protection to the infected mice at 24 mg/kg × 4 days. The most active compound of the series, trioxane 12b1, provided 100 % protection even at 12 mg/kg × 4 days and 60 % protection at 6 mg/kg × 4 days. The currently used drug, β-arteether provides only 20 % protection at 24 mg/kg × 4 days.

Novel amino- and hydroxy-functionalized 1,2,4-trioxanes and their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via intramuscular and oral route

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.

Novel hydrazone derivatives of N-amino-11-azaartemisinin with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via intramuscular route

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.

Reduction of the Double Bond of 6-Arylvinyl-1,2,4-trioxanes Leads to a Remarkable Increase in Their Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii nigeriensis in a Swiss Mice Model.

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, β-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 β-arteether.

Novel naphthyl based 1,2,4-trioxanes: Synthesis and in vivo efficacy in the Plasmodium yoelii nigeriensis in Swiss mice

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.

Synthesis of novel 1,2,4-trioxanes and antimalarial evaluation against multidrug-resistant Plasmodium yoelii nigeriensis

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.

Synthesis and Biological Evaluation of 8-Quinolinamines and Their Amino Acid Conjugates as Broad-Spectrum Anti-infectives.

In the search of therapeutic agents for emerging drug-resistant parasites, the synthesis of newer classes of 8-quinolinamines has emerged as a successful chemotherapeutic approach. We report synthesis of 8-quinolinamines bearing 5-alkoxy, 4-methyl, and 2-tert-butyl groups in the quinoline framework and their amino acid conjugates as broad-spectrum anti-infectives. 8-Quinolinamines exhibited potent in vitro antimalarial activity [IC50 = 20–4760 ng/mL (drug-sensitive Plasmodium falciparum D6 strain) and IC50 = 22–4760 ng/mL (drug-resistant P. falciparum W2 strain)]. The most promising analogues have cured all animals at 25 mg/kg/day against drug-sensitive Plasmodium berghei and at 50 mg/kg/day against multidrug-resistant Plasmodium yoelii nigeriensis infections in Swiss mice. The in vitro antileishmanial activities (IC50 = 0.84–5.0 μg/mL and IC90 = 1.95–7.0 μg/mL) comparable to standard drug pentamidine were exhibited by several of the synthesized 8-quinolinamines. At the same time, very promising antifungal activities (Candida albicans—IC50 = 4.93–19.38 μg/mL; Candida glabrata—IC50 = 3.96–19.22 μg/mL; Candida krusei—IC50 = 2.89–18.95 μg/mL; Cryptococcus neoformans—IC50 = 0.67–18.64 μg/mL; and Aspergillus fumigatus—IC50 = 6.0–19.32 μg/mL) and antibacterial activities (Staphylococcus aureus—IC50 = 1.33–18.9 μg/mL; methicillin-resistant S. aureus—IC50 = 1.38–15.34 μg/mL; and Mycobacterium intracellulare—IC50 = 3.12–20 μg/mL) were also observed. None of the 8-quinolinamines exhibited cytotoxicity and therefore are a promising structural class of compounds as antiparasitic and antimicrobials.

New orally active diphenylmethyl-based ester analogues of dihydroartemisinin: Synthesis and antimalarial assessment against multidrug-resistant Plasmodium yoelii nigeriensis in mice.

A new series of ester analogues of artemisinin 8a-f, incorporating diphenylmethyl as pharmacologically privileged substructure, and 8g-j have been prepared and evaluated for their antimalarial activity against multidrug-resistant (MDR) Plasmodium yoelii nigeriensis in Swiss mice via oral route. These diphenylmethyl-based ester analogues 8a-f were found to be 2-4 folds more active than the antimalarial drugs β-arteether 4 and artesunic acid 5. Ester 8a, the most active compound of the series, provided complete protection to the infected mice at 24 mg/kg × 4 days as well as 12 mg/kg × 4 days, respectively. In this model β-arteether provided 100% and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively.

Ketoconazole, a cytochrome P450 inhibitor can potentiate the antimalarial action of α/β arteether against MDR Plasmodium yoelii nigeriensis

The emergence of multidrug resistant (MDR) strains of Plasmodium falciparum in South East Asia and other tropical countries, is posing serious challenge for the international efforts to eradicate malaria. New drug target/ACT/non-ACT combinations need to be discovered to control the spread of MDR malaria. The present communication deals with antimalarial potential of a new combination comprising of ketoconazole (KTZ) (an antifungal/inhibitor of CYP3A4) and artemisinin derivative α/β arteether (ART). In vitro interactions of these drugs against chloroquine sensitive/resistant P. falciparum (Pf3D7/K1) have shown an overall additive interaction with mean sum fractional inhibitory concentrations (∑FICs) of 1.1±0.33 against 3D7 and 1.51±0.42 against K1 strains.Sub-curative doses of KTZ (150mg/kg×7 days) combined with ART (6.25–12.5mg/kg×5 days) both administered orally have shown 100% curative action against MDR P. yoelii nigeriensis in Swiss mice. Besides lower dose of KTZ (75mg/kg) which is non-curative itself, in combination with 12.5mg/kg×5 days of ART treatment, was also 100% curative. Further studies on mechanism of action of KTZ (150mg/kg single dose) have shown that significant inhibitory action of the antifungal drug is through very high level of suppression of CYP (nearly 90%) compared to that of healthy mice liver. The companion drug therapy comprising of KTZ together with ART (25mg/kg×1 dose) also produced more than 50% inhibitory effect on the CYP enzyme level. Since the ART is known to be rapidly metabolized by the liver cytochrome P450 (CYP) 3A4 to Dihydroquinghasu, the combined therapy with KTZ (a strong CYP 3A4 inhibitor) may influence the pharmacokinetics of ART and consequently slow down the drug metabolism and prolong the plasma life of the active drug, which would contribute to enhanced antimalarial action of ART against MDR P. yoelii nigeriensis.

Synthesis and antimalarial activity of 3,3-spiroanellated 5,6-disubstituted 1,2,4-trioxanes.

Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound of the series (compound 25) provided 100% protection at 24 mg/kg × 4 days, and other 1,2,4-trioxanes 22, 26, 27, and 30 also showed promising activity. In this model, β-arteether provided 100 and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively, by oral route. Compound 25 displayed a similar in vitro pharmacokinetic profile to that of reference drug β-arteether. The activity results demonstrated the importance of an aryl moiety at the C-5 position on the 1,2,4-trioxane pharmacophore.

Linker-Based Hemisuccinate Derivatives of Artemisinin: Synthesis and Antimalarial Assessment against Multidrug-Resistant Plasmodium yoelii nigeriensis in Mice

Artesunic acid 5, the hemisuccinate derivative of dihydroartemisinin 2, is the only clinically useful water-soluble derivative of artemisinin 1. However, being a lactol ester, it is rapidly hydrolyzed back to dihydroartemisinin in aqueous alkaline solution, a reaction that seriously limits its utility. A new series of potentially more stable linker-based hemisuccinate derivatives 12a-i and 14a-c have been prepared. The process involved acid-catalyzed reaction of dihydroartemisinin with various diols and polyethylene glycols to give hydroxy-functionalized ethers 7a-i and 10a-c and their further derivatization to hemisuccinate esters 12a-i and 14a-c. Both the hydroxy-functionalized ethers 7a-i and 10a-c and their hemisuccinate derivatives 12a-i and 14a-c have been assessed for antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice. Several of these hemisuccinate derivatives have shown very promising activity. Hemisuccinate derivatives 12f and 12i, the two most active compounds of the series, provided 100% protection to malaria-infected mice at 24 mg/kg × 4 days and therefore are twice as potent as artesunic acid, which provides a similar level of protection at 48 mg/kg × 4 days.

Synthesis and Antimalarial Assessment of a New Series of Orally Active Amino-Functionalized Spiro 1,2,4-Trioxanes

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, β-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days.

Search for new pharmacophores for antimalarial activity. Part III: Synthesis and bioevaluation of new 6-thioureido-4-anilinoquinazolines

Syntheses and in vitro antimalarial evaluation of 42 new thioureidoquinazolines have been carried out. Several analogs showed promising antimalarial effect in the in vitro investigation against chloroquine-sensitive 3D7 strain of Plasmodium falciparum whereas one of the compounds shows 50% curative effect in the mouse model at an oral dose of 100 mg/kg × 4 days against multidrug resistant Plasmodium yoelii nigeriensis.

Aromatic amino analogues of artemisinin: synthesis and in vivo antimalarial activity

Nine orally active novel artemisinin derivatives were prepared from artemisinin by four-step synthesis, and the compounds were evaluated in the rodent model using multidrug resistant Plasmodium yoelii nigeriensis. All of the compounds exhibited antimalarial activities with the ED50 ranging from 5.41 mg/kg–12.4 mg/kg. Among them, artemisinin derivative bearing N-(4-hydroxy-3-((4-phenylpiperazin-1-yl)methyl)phenyl) moiety (5f) was found to be the most active compound and was found to be three times more potent than artemisinin (ED50 16.4 mg/kg).

Orally active 1,2,4-trioxepanes: Synthesis and antimalarial activity of a series of 7-arylvinyl-1,2,4-trioxepanes against multidrug-resistant Plasmodium yoelii in Swiss mice

7-Arylvinyl-1,2,4-trioxepanes 7a– d, 8a– d, 9a– d, 10a– d, 11a– c, and 12a– c, prepared by photooxygenation of homoallylic alcohols 5a– d, were evaluated against multi-drug resistant Plasmodium yoelii nigeriensis in Swiss mice by oral and intramuscular routes. Trioxepane 11c, the most active compound of the series, showed more than 98% suppression of parsitaemia at 96 mg/kg by both oral and intramuscular routes. This is the first report on in vivo active 1,2,4-trioxepanes.

New Adamantane-Based Spiro 1,2,4-Trioxanes Orally Effective against Rodent and Simian Malaria

New 6-arylvinyl- and 6-adamantylvinyl-substituted 1,2,4-trioxanes (13a-g and 14a,b) have been prepared and evaluated for antimalarial activity against multidrug resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular routes. While all the 6-arylvinyl-substituted trioxanes, 13a-f, showed promising activity, none of the 6-adamantylvinyl-substituted trioxanes, 13g and 14a,b, exhibited significant activity. Trioxane, 13f, the most active compound of the series, provided 100% and 80% protection to malaria-infected mice at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively, by oral route. In this model, beta-arteether (3) provided 100% protection at 48 mg/kg x 4 days and only 20% protection at 24 mg/kg x 4 days. Trioxane 13f also showed complete suppression of parasitaemia at 10 mg/kg x 4 days by oral route in rhesus monkeys infected with P. cynomolgi. None of these trioxanes, except 13f, showed significant activity by the intramuscular route.

New Orally Active Derivatives of Artemisinin with High Efficacy against Multidrug-Resistant Malaria in Mice

A new series of ether derivatives of dihydroartemisinin have been prepared and evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by oral route. These new derivatives 7-17 are highly lipophilic (log P in the range of 5.51 to 7.19) as compared with beta-arteether (log P 3.84), and several of them are two- to four-fold more active than beta-arteether. Among the ether derivatives, alpha-isomers are more active than the beta-isomers. The ether derivatives 12alpha and 14alpha, the most active compounds of the series, provided 100% protection to infected mice at 12 mg/kgx4 days. In this model beta-arteether provides 100% and 20% protection at 48 mg/kgx4 days and 24 mg/kgx4 days, respectively.

Blood schizontocidal activity of selected 1,2,4-trioxanes (Fenozans) against the multidrug-resistant strain of Plasmodium yoelii nigeriensis (MDR) in vivo

Blood schizontocidal activity of 10 selected cis-fused cyclopenteno-1,2,4-trioxanes (namely Fenozan compound nos 6, 7, 11, 27, 32, 39, 44, 45, 48 and 51) have been re-investigated to establish their curative doses against the multidrug-resistant Plasmodium yoelii nigeriensis strain, which is lethal in Swiss mice. Freshly prepared formulations of these compounds prepared either in neutral groundnut (peanut) oil or in dimethyl sulfoxide (DMSO)-Tween-water, were compared for their antimalarial activity. Only 2 compounds, namely Fenozan derivatives 11 and 45, formulated in neutral groundnut oil for oral administration, showed highest activity with 100% cure rate in MDR P. yoelii nigeriensis-infected mice, while the DMSO-Tween-water formulations were inactive. Fenozan-48 produced 72.2% cure, when administered orally in groundnut oil (formulation) while its DMSO-Tween formulation was inactive. In the case of Fenozan 7, the oil and DMSO-Tween formulations produced 92.3 and 76.0% cures respectively. Fenozan derivatives nos 6, 27, 32, 39, 44 and 51 were not protective either in groundnut oil or DMSO-Tween oral formulations. The present study has applied more rigorous criteria for selection of active compounds, and has identified the 3,3-spirocyclopentane derivative Fenozan 11, and the 3,3-spirohydropyran derivative Fenozan 45, as potential blood schizontocides which can completely eliminate multidrug-resistant malaria infection in mice. Both these compounds are candidates for pre-clinical development. The present study advocates the preferred use of an oil vehicle for oral evaluation of potential antimalarial trioxanes/fenozans instead of the DMSO formulation, which gives inferior curative efficacy.

Blood schizontocidal activity of azithromycin and its combination with α/β arteether against multi-drug resistantPlasmodium yoelii nigeriensis, a novel MDR parasite model for antimalarial screening

Many different drug-resistant lines of rodent malaria are available as screening models. It is obligatory to screen new compounds for antimalarial activity against a series of resistant lines in order to identify a compound with potential for the treatment of multi-drug resistant (MDR) malaria infections. Instead of using a battery of resistant lines, a single MDR Plasmodium yoelii nigeriensis strain that shows a wide spectrum of drug resistance to high doses of chloroquine, mepacrine, amodiaquine, mefloquine, quinine, quinidine, halofantrine as well as tetracyclines, fluoroquinolines and erythromycin, was used to assess the blood schizontocidal efficacy of a new macrolide azithromycin and other antibiotics. The present study shows that only azithromycin has the potential to control an MDR P. y. nigeriensis infection in Swiss mice, provided the treatment with a dose of 50-100 mg/kg/day by oral route is continued for a period of 7 days. Tetracycline, oxytetracycline, doxycyline, erythromycin, ciprofloxacin and norfloxacin, although active in vitro, failed to protect the mice. Tetracycline, ciprofloxacin and norfloxacin combinations with chloroquine did not control the infection. Additionally, the antimalarial efficacy of azithromycin can be potentiated with the addition of arteether, which is an ethyl ether derivative of artemisinin. A total (100%) curative effect has been obtained with a shorter regimen of 4 days only.

Pyronaridine: An effective antimalarial against multidrug-resistant malaria

Pyronaridine, administered intramuscularly (im) to Swiss mice infected with the lethal multidrug-resistant Plasmodium yoelii nigeriensis, was found to exert high blood schizontocidal activity. The efficacy of doses of pyronaridine ranging from 0.625 to 30 mg (base/kg) was evaluated using a 4 day treatment schedule (drug was administered at 0, 24, 48 and 72 hrs). It was found that doses of 2.5mg/kg and higher protected animals completely from the lethal effects of the parasite. The same degree of protection was found when the treatment duration was reduced to 3 days. This study shows that pyronaridine is a potentially useful antimalarial drug that could be exploited for the control of multidrug-resistant malaria infection.