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PubMed2005

Unambiguous synthesis and prophylactic antimalarial activities of imidazolidinedione derivatives.

WR182393, a guanidinoimidazolidinedione derivatives with potent causal prophylactic antimalarial activity by intramuscular injection, was previously prepared by treatment of chloroproguanil and diethyl oxalate, yielding a mixture of two closely related isomers. Poor solubility of the mixture made the separation and purification impossible. To overcome the separation problem, new and facile unambiguous syntheses of the two active components were reported. The new synthetic methods facilitate the synthesis of not only the active components, but also their derivatives. To search for compounds with good oral efficacy, a series of carbamate derivatives of the active components were prepared by the new procedure, many of which showed profound causal prophylactic antimalarial activity against Plasmodium yoelii in mouse by oral administration.

Administration, Oral↗
PubMed2005

Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class of trypanothione reductase inhibitor, and of N-acyl derivatives of 2-amino-4-chlorophenyl phenyl sulfide.

Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition approximately 40-fold (3',4'-dichlorobenzyl-[5-chloro-2-phenylsulfanyl-phenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 +/- 0.2 microM). Molecular modelling explained docking orientations and energies by: (i) involvement of the Z-site hydrophobic pocket (roughly bounded by F396', P398', and L399'), (ii) ionic interactions for the cationic nitrogen with Glu-466' or -467'. A series of N-acyl-2-amino-4-chlorophenyl sulfides showed mixed inhibition (Ki, Ki' = 11.3-42.8 microM). The quaternized analogues of the 2-chlorophenyl phenyl sulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. brucei rhodesiense STIB900, T. cruzi Tulahuan, and Leishmania donovani HU3. The N-acyl-2-amino-4-chlorophenyl sulfides were active against Plasmodium falciparum. The phenothiazine and diaryl sulfide quaternary compounds were also powerful antimalarials, providing a new structural framework for antimalarial design.

Animals↗
PubMed2006

Tetraoxane antimalarials and their reaction with Fe(II).

Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4' ') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg.kg-1.day-1, and 2/5 mice at 50 mg.kg-1.day-1, showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO* radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO* radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.

Animals↗
PubMed2006

Orally active 1,2,4-trioxanes: synthesis and antimalarial assessment of a new series of 9-functionalized 3-(1-arylvinyl)-1,2,5-trioxaspiro[5.5]undecanes against multi-drug-resistant plasmodium yoelii nigeriensis in mice.

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.

Administration, Oral↗
PubMed2005

Synthesis and evaluation of new antimalarial phenylurenyl chalcone derivatives.

Phenylurenyl chalcone derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, activity of the cysteine protease falcipain-2, in vitro globin hydrolysis, beta-hematin formation, and murine Plasmodium berghei malaria. The most active antimalarial compound was 1-[3'-N-(N'-phenylurenyl)phenyl]-3(3,4,5-trimethoxyphenyl)-2-propen-1-one 49, with an IC(50) of 1.76 microM for inhibition of P. falciparum development. Results suggest that chalcones exert their antimalarial activity via multiple mechanisms.

Animals↗
PubMed2006

Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity.

In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 degrees C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.

Administration, Oral↗
PubMed2006

Similar structure-activity relationships of quinoline derivatives for antiprion and antimalarial effects.

Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrP(Sc), a pathogenic misfolded isoform of the normal cellular prion protein (PrP(C)). Until now, no pharmacological options exist for these novel pathogens. Here we describe the screening of a series of polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The most active molecule, named 42, had a half-effective concentration (EC50) for antiprion activity of 50 nM. In a library of quinoline derivatives we were able to identify several structure-activity relationships (SAR). Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria, particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion and antimalarial substances overlap.

Animals↗
PubMed2006

Synthesis and antimalarial efficacy of aza-fused rhodacyanines in vitro and in the P. berghei mouse model.

Several aza-fused rhodacyanines were synthesized and assessed for their in vitro and in vivo antimalarial activities against Plasmodium falciparum K1 and P. berghei. All synthetic compounds showed strong selective antimalarial in vitro activity. Class II azarhodacyanines, 3, consisting of four heterocyclic units, were found to display good parasitemia suppression and low acute toxicity in vivo. Among them, 3c appeared to be the most effective at a dose of 20-25 mg kg(-1) day(-1) (ip).

Animals↗
PubMed1997

Synthesis, antimalarial activity, and molecular modeling of tebuquine analogues.

Tebuquine (5) is a 4-aminoquinoline that is significantly more active than amodiaquine (2) and chloroquine (1) both in vitro and in vivo. We have developed a novel more efficient synthetic route to tebuquine analogues which involves the use of a palladium-catalyzed Suzuki reaction to introduce the 4-chlorophenyl moiety into the 4-hydroxyaniline side chain. Using similar methodology, novel synthetic routes to fluorinated (7a, b) and a dehydroxylated (7c) analogue of tebuquine have also been developed. The novel analogues were subjected to testing against the chloroquine sensitive HB3 strain and the chloroquine resistant K1 strain of Plasmodium falciparum. Tebuquine was the most active compound tested against both strains of Plasmodia. Replacement of the 4-hydroxy function with either fluorine or hydrogen led to a decrease in antimalarial activity. Molecular modeling of the tebuquine analogues alongside amodiaquine and chloroquine reveals that the inter-nitrogen separation in this class of drugs ranges between 9.36 and 9.86 A in their isolated diprotonated form and between 7.52 and 10.21 A in the heme-drug complex. Further modeling studies on the interaction of 4-aminoquinolines with the proposed cellular receptor heme revealed favorable interaction energies for chloroquine, amodiaquine, and tebuquine analogues. Tebuquine, the most potent antimalarial in the series, had the most favorable interaction energy calculated in both the in vacuo and solvent-based simulation studies. Although fluorotebuquine (7a) had a similar interaction energy to tebuquine, this compound had significantly reduced potency when compared with (5). This disparity is possibly the result of the reduced cellular accumulation (CAR) of fluorotebuquine when compared with tebuquine within the parasite. Measurement of the cellular accumulation of the tebuquine analogues and seven related 4-aminoquinolines shows a significant relationship (r = 0.98) between the CAR of 4-aminoquinoline drugs and the reciprocal of drugs IC50.

Aminoquinolines↗
PubMed1997

Correlation of antimalarial activity of artemisinin derivatives with binding affinity with ferroprotoporphyrin IX.

The antimalarial activity of a number of artemisinin derivatives, both newly synthesized and currently used as drugs, against Plasmodium falciparum in culture shows a correlation with their affinity of binding with ferroprotoporphyrin IX, as measured from the spectral change of the latter. The new C-16-functionalized artemisinin derivatives were obtained through a novel one-pot synthesis of artemisitene (2) from naturally abundant artemisinin (1), followed by Michael addition with nucleophiles. The correlation points to the biological significance of the interaction of these derivatives with ferroprotoporphyrin IX and may provide a basis for primary screening of peroxidic antimalarials of similar structures.

Animals↗
PubMed1997

Synthesis and antimalarial activity in vitro and in vivo of a new ferrocene-chloroquine analogue.

The antimalarial activities of ferrocenic compounds mimicking chloroquine and active upon chloroquine-resistant strains of Plasmodium falciparum were evaluated. Four 7-chloro-4-[[[2-[(N,N-substituted amino)methyl]ferrocenyl]methyl]amino]quinoline derivatives have been synthesized; one of them, 1a, showed high potent antimalarial activity in vivo on mice infected with Plasmodium berghei N. and Plasmodium yoelii NS. and was 22 times more potent against schizontocides than chloroquine in vitro against a drug-resistant strain of P. falciparum.

Animals↗
PubMed1998

Orally active antimalarial 3-substituted trioxanes: new synthetic methodology and biological evaluation.

On the basis of a mechanistic understanding of the mode of action of artemisinin-like antimalarials, a series of structurally simple 3-aryl-1,2,4-trioxanes 5 was designed and was prepared in three to five operations from commercial reactants. The 3-aryl group was attached in each case as a nucleophile. In an electronically complementary fashion, 3-(fluoroalkyl)-trioxanes 6 were prepared via attachment of electrophilic fluoroalkyl esters. Both in vitro and in vivo antimalarial evaluations of these new trioxanes showed 12 beta-methoxy-3-aryltrioxanes 5g, 5j, 5k, and 51 to be highly potent, with crystalline fluorobenzyl ether trioxane 5k especially potent even when administered to rodents orally. As shown by rearrangement of hexamethyl Dewar benzene into hexamethylbenzene, iron-induced degradation of some of these 3-aryltrioxanes 5 involves generation of high-valent iron oxo species that might kill malaria parasites.

Administration, Oral↗
PubMed1999

Orally active, hydrolytically stable, semisynthetic, antimalarial trioxanes in the artemisinin family.

In only three chemical operations, natural trioxane lactone artemisinin (1) was converted into a series of C-10 carbon-substituted 10-deoxoartemisinin compounds 4-9. The three steps involved lactone reduction, replacement of the anomeric lactol OH by F using diethylaminosulfur trifluoride, and finally boron trifluoride-promoted substitution of F by aryl, heteroaryl, and acetylide nucleophiles. All of these C-10 nonacetal, chemically robust, enantiomerically pure compounds 4-9 have high antimalarial potencies in vitro against Plasmodium falciparum malaria parasites, and furans 5a and 5b and pyrrole 7a are antimalarially potent also in vivo even when administered to rodents orally.

Administration, Oral↗
PubMed2000

Phenyl beta-methoxyacrylates: a new antimalarial pharmacophore.

Phenyl beta-methoxyacrylates, linked to an aromatic ring via an olefinic bridge, have been identified as novel, potentially inexpensive, antimalarial agents. The compounds are believed to exert their activity by inhibition of mitochondrial electron transport at the cytochrome bc(1) complex. A series of compounds have been synthesized to define structure-activity relationships affecting antimalarial activity. It was found that the beta-methoxyacrylate was required ortho to the linker and the optimal bridge was (E,E)-butadiene. Compounds in which the second aromatic ring was ortho-substituted or ortho,para-disubstituted gave optimal potency. Several compounds were identified with potency that is superior to that of chloroquine both in culture and in a murine malaria model.

Acrylates↗
PubMed1999

Synthesis and antimalarial activity of cyclic peroxides, 1,2,4,5, 7-pentoxocanes and 1,2,4,5-tetroxanes.

A variety of 1,2,4,5,7-pentoxocane and 1,2,4,5-tetroxane derivatives were prepared as potential peroxide antimalarial agents. In both series of cyclic peroxides, the steric and electronic effects of the substituents attached to the peroxide ring exert a remarkable influence on the antimalarial activity. For some cyclic peroxides, which were found to be highly effective in vitro, the study in vivo has been also conducted.

Animals↗
PubMed2001

Iron(II)-induced degradation of antimalarial beta-sulfonyl endoperoxides: evidence for the generation of potentially cytotoxic carbocations.

Reactions of antimalarial beta-sulfonyl endoperoxides 9 and 10, which, like yingzhaosu A (2), derive from the 2,3-dioxabicyclo[3.3.1]nonane system 3, with iron(II) salts were studied. Product analysis of the iron(II)-induced degradations provided evidence for the intermediacy of carbon-centered cyclohexyl radicals 20 and 31 and their possible oxidation to the corresponding carbocations 21 and 32. It is conceivable that the antimalarial activity of beta-sulfonyl endoperoxides of type 5 may derive from alkylation of vital intraparasitic biomolecules by free radicals and/or carbocations, generated within the malaria parasite through a similar iron(II)-induced degradation process.

Antimalarials↗
PubMed2002

Alkylating capacity and reaction products of antimalarial trioxanes after activation by a heme model.

The reactivity of 1,2,4-trioxane molecules 2-5, structurally related to the antimalarial drug artemisinin, with a heme model, manganese(II) tetraphenylporphyrin, is reported. With the pharmacologically active drugs 2-4, covalent adducts were obtained by addition of a drug-derived radical onto the porphyrin macrocycle, whereas no reaction was obtained with the nonactive compound 5. This confirms that alkylation is probably one of the key factors of the pharmacological activity of endoperoxide-based antimalarial drugs.

Alkylation↗
PubMed2005

Total syntheses of Yingzhaosu A and of its C(14)-epimer including the first evaluation of their antimalarial and cytotoxic activities.

[reaction: see text] The molecular structure of the naturally occurring antimalarial agent yingzhaosu A (1) is characterized by a 2,3-dioxabicyclo[3.3.1]nonane system (3a), an allylic alcohol, a homoallylic alcohol, and five stereogenic centers. Herein we report on the total synthesis of yingzhaosu A (1) in eight steps and 7.3% overall yield starting from (S)-limonene (12). To maximize efficacy, the bridged bicyclic endoperoxide molecular core was constructed by a multicomponent free-radical domino reaction in which five bonds are formed in a single operation. In addition, reaction protocols that are compatible with the sensitivity of the peroxide function to strong basic and nucleophilic reagents as well as to reducing agents were employed. An intriguing step involved the selective hydrogenation of a carbon-carbon double bond in the presence of a peroxide and an aldehyde function to give aldehyde peroxide 7. The two major synthons (aldehydoperoxide 7 and its complementary five-carbon atom unit 35) were linked through a Mukaiyama aldol reaction followed by in situ dehydration under mild buffered basic conditions. The carbonyl group in the resulting peroxidic enone 39 was stereoselectively reduced with either R-CBS catalyst (42b) to give, after in situ desilylation, yingzhaosu A (1) or with S-CBS catalyst (42a) its C(14)-epimer 40. The first quantitative in vitro and in vivo data for the antimalarial activity of yingzhaosu A (1) and its C(14)-epimer 40 are reported. The C(14)-epiyingzhaosu A (40) exhibits potent cytotoxic activity against the KB nasal-pharyngeal cancer cell line in vitro.

Antimalarials↗