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At least 1,189 records · Page 66Linked to original sources
PubMed2003

Antimalarial activity of novel 1,2,5,6-tetraoxacycloalkanes and 1,2,5-trioxacycloalkanes.

Photooxygenation of 2-phenylnorbornene 1 in the presence of 30% aqueous hydrogen peroxide afforded 1,2-bishydroperoxide 3, which could be cycloalkylated on treatment with silver oxide and a 1,omega-diiodoalkane to provide the tricyclic peroxides 12. Trimethylsilylation of 3 followed by TMSOTf-catalyzed cyclocondensation with carbonyl compounds led to the formation of the tricyclic peroxides 14 containing a 1,2,4,5-tetroxepane structure. Photooxygenation of 1 in the presence of either unsaturated hydroperoxides or unsaturated alcohols followed by bis(collidine)iodine hexafluorophosphate promoted cyclization gave the corresponding cyclic peroxides 15-17. Several of these cyclic peroxides showed substantial antimalarial activity particularly in vitro.

Animals↗
PubMed2002

Mixed steroidal 1,2,4,5-tetraoxanes: antimalarial and antimycobacterial activity.

Mixed 1,2,4,5-tetraoxanes possessing simple spirocycloalkane and spirocholic acid-derived substituents were prepared and shown to have significantly higher in vitro antimalarial activity than bis-substituted tetraoxanes. Out of 41 synthesized tetraoxanes, 12 were in vitro more potent against Plasmodium falciparum chloroquine-resistant W2 clone than artemisinin, and the most potent one was 2.4 times as active as arteether. In addition, 9 compounds exhibit higher activity than chloroquine against P. falciparum chloroquine-susceptible D6 clone. Cytotoxicity was assessed for most active compounds against the Vero cell line, showing a cytotoxicity/antimalarial potency ratio of 1/(1400-9500). For the first time, tetraoxanes were screened against Mycobacterium tuberculosis with MICs as low as 4.73 microM against H37Rv strain. Mixed tetraoxanes were synthesized in a simple procedure from cholic acid methyl esters by direct coupling of steroidal gem-dihydroperoxide to simple ketones and further transformed into corresponding acids and amides.

Animals↗
PubMed2004

Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents.

In only four chemical steps from naturally occurring artemisinin (1), trioxane dimers 6 and 7 were prepared on a multigram scale in overall 32-44% yields. In mice, both isonicotinate N-oxide dimer 6 and isobutyric acid dimer 7 were considerably more antimalarially efficacious than clinically used sodium artesunate (2) via both oral and intravenous administration. In the transgenic adenocarcinoma of mouse prostate model, some of the trioxane dimers had potent anticancer activity.

Adenocarcinoma↗
PubMed2004

Orally active antimalarials: hydrolytically stable derivatives of 10-trifluoromethyl anhydrodihydroartemisinin.

New fluoroartemisinin derivatives containing polar or water-soluble functionalities at C-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10. The substitution reaction from 10 was more selective than that from the nonfluorinated parent bromide; the allylic bromide 10 underwent no allylic rearrangement and provided only nucleophilic substitution products in high yields with N-, O-, and C-nucleophiles. Among them, amines 11a-c appeared to be highly in vivo efficient antimalarials on mice infected with Plasmodium berghei, more than the reference sodium artesunate 1d. In particular, the most effective piperazinoethanol derivative 11b cured all mice after oral treatment at a dose lower than 10 mg/kg. Further pharmacokinetic studies showed that the bioavailability in rats following oral administration was 25 times greater for 11b than for artemether 1b.

Administration, Oral↗
PubMed2004

Synthesis, antimalarial activity, and molecular modeling of new pyrrolo[1,2-a]quinoxalines, bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines.

Three pyrrolo[1,2-a]quinoxalines, 15 bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines were synthesized from various substituted nitroanilines or nitropyridines and tested for their in vitro activity upon the erythrocytic development of Plasmodium falciparum strains with different chloroquine-resistance status. Bispyrrolo[1,2-a]quinoxalines showed superior antimalarial activity with respect to monopyrrolo[1,2-a]quinoxalines. The best activity was observed with bispyrrolo[1,2-a]quinoxalines linked by a bis(3-aminopropyl)piperazine. Moreover, it was observed that the presence of a methoxy group on the pyrrolo[1,2-a]quinoxaline nucleus increased the pharmacological activity. Drug effects upon beta-hematin formation were assayed and showed similar or higher inhibitory activities than CQ. A possible mechanism of interaction implicating binding of pyrroloquinoxalines to beta-hematin was supported by molecular modeling.

Animals↗
PubMed2005

Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes.

This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.

Adamantane↗
PubMed2005

Mono- and bis-thiazolium salts have potent antimalarial activity.

Three new series comprising 24 novel cationic choline analogues and consisting of mono- or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC(50) values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED(50) </= 0.22 mg/kg), and low toxicity in mice infected by Plasmodium vinckei.

Animals↗
PubMed2005

Imidazolidin-4-one derivatives of primaquine as novel transmission-blocking antimalarials.

Imidazolidin-4-one derivatives of primaquine were synthesized as potential double prodrugs of the parent drug. The title compounds inhibit the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The imidazolidin-4-ones are very stable, both in human plasma and in pH 7.4 buffer, indicating that they are active per se. Thus, imidazolidin-4-ones derived from 8-aminoquinolines represent a new entry in antimalarial structure-activity relationships.

Animals↗
PubMed2004

5-substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials.

Plasmodium parasites are exposed to elevated fluxes of reactive oxygen species during intraerythrocytic life. The most important antioxidative systems are based on the glutathione reductases of the malarial parasite Plasmodium falciparum and the host erythrocyte. The development of menadione chemistry has led to the selection of the carboxylic acid 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl] hexanoic acid M(5) as an inhibitor of the parasitic enzyme. As reported here, revisiting the mechanism of M(5) action revealed an uncompetitive inhibition type with respect to both NADPH and glutathione disulfide. Masking the polarity of the acidic function of M(5) by ester or amide bonds improved antiplasmodial activity. Bioisosteric replacement of the carboxylic function by tetrazole to increase bioavailability and to maintain comparable acidity led to improved antimalarial properties as well, but only with the cyanoethyl-protected tetrazoles. Using computed ab initio quantum methods, detailed analyses of the electronic profiles and the molecular properties evidenced the similarity of M(5) and the bioisoteric tetrazole T(4). The potential binding site of these molecules is discussed in light of the recently solved crystallographic structure of P. falciparum enzyme.

Animals↗
PubMed2006

Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities.

Three ferroquine (FQ) derivatives, closely mimicking the antimalarial drug hydroxychloroquine (HCQ), have been prepared. Whereas these organometallic compounds provide the expected reduced cytotoxic effects compared to FQ, they inhibit in vitro growth of Plasmodium falciparum far better than chloroquine (CQ). Moreover, this new class of bioorganometallic compounds exert antiviral effects with some selectivity toward SARS-CoV infection. These new drugs may offer an interesting alternative for Asia where SARS originated and malaria has remained endemic.

Animals↗
PubMed2006

Lead compounds for antimalarial chemotherapy: purine base analogs discriminate between human and P. falciparum 6-oxopurine phosphoribosyltransferases.

The malarial parasite Plasmodium falciparum depends on the purine salvage enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) to convert purine bases from the host to nucleotides needed for DNA and RNA synthesis. An approach to developing antimalarial drugs is to use HGXPRT to convert introduced purine base analogs to nucleotides that are toxic to the parasite. This strategy requires that these compounds be good substrates for the parasite enzyme but poor substrates for the human counterpart, HGPRT. Bases with a chlorine atom in the 6-position or a nitrogen in the 8-position exhibited strong discrimination between P. falciparum HGXPRT and human HGPRT. The k(cat)/K(m) values for the Plasmodium enzyme using 6-chloroguanine and 8-azaguanine as substrates were 50 - 80-fold and 336-fold higher than for the human enzyme, respectively. These and other bases were effective in inhibiting the growth of the parasite in vitro, giving IC(50) values as low as 1 microM.

Animals↗
PubMed1996

Ionophore properties of monensin derivatives studied on human erythrocytes by 23Na NMR and K+ and H+ potentiometry: relationship with antimicrobial and antimalarial activities.

Eight derivatives of monensin with a modified C25-C26 moiety were synthesized. Their ionophore properties were studied on human erythrocytes by measuring Na+ influx with 23Na NMR and concomitant K+ and H+ efflux by potentiometry. Modification of OH-26 led to inversion of selectivity of transport in favor of K+/Na+ in comparison with monensin. This selectivity disappeared by suppression of the C26-OH moiety. Finally the ionophore ability was lost if the head-to-tail chelation of the monensin skeleton was prevented by blocking the terminal OH-25 and -26 functions. All the compounds were inactive on Gram-negative bacteria and fungi. MIC measured on Bacillus cereus showed that derivatives with increased K+/Na+ selectivity were clearly the most active against Bacillus growth. Most of the compounds showed potential antimalarial properties in the nanomolar range when tested in vitro against Plasmodium falciparum. The IC50S measured were correlated with the whole Na+ and K+ transport efficiency rather than with the ionic selectivity. In both cases determination of initial fluxes of transport for both cations (Na+ and K+) was necessary to investigate the relationship between biological and ionophore properties.

Adult↗
PubMed1996

Structure-activity relationships of the antimalarial agent artemisinin. 4. Effect of substitution at C-3.

Novel antimalarial artemisinin analogs, 3-alkylartemisinins as well as 3-(arylalkyl)- and 3-(carboxyalkyl)artemisinins, were prepared via the synthetic intermediate 2. Formation of the N,N-dimethylhydrazones 5 and 24 and then regio- and chemoselective deprotonation followed by alkylation provided initially alkylated hydrazones that upon chromatography gave ketones 6-13 and 25-30. Direct ozonolysis of the ketones followed by in situ acidification lead directly to the formation of title compounds 14-21 and 31-36. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found to be in some cases much more active than the natural product (+)-artemisinin. The results were included in structure-activity relationship (CoMFA) studies for further analog design.

Animals↗
PubMed1996

Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of benzylamino and alkylamino ether analogues of artemisinin.

Several artemisinin derivatives linked to benzylamino and alkylamino groups were synthesized in order to enhance accumulation within the malaria parasite. The in vitro antimalarial activity was assessed against the chloroquine sensitive HB3 strain and the chloroquine resistant K1 strain of Plasmodium falciparum. In general the incorporation of amino functionality enhances the activity relative to artemisinin. The most potent analogue in the series was compound 6 which was severalfold more active than artemisinin against both strains of P. falciparum used in the study.

Animals↗
PubMed1997

Antimalarial activity of molecules interfering with Plasmodium falciparum phospholipid metabolism. Structure-activity relationship analysis.

A series of 80 compounds, primary, secondary, and tertiary amines and quaternary ammonium and bisammonium salts, most of them synthesized as potential choline or ethanolamine analogs, were tested against the in vitro growth of Plasmodium falciparum, the human malaria parasite. They were active over the 10(-3)-10(-8) M concentration range. A structure-activity relationship study was carried out using autocorrelation vectors as structural descriptors, and multidimensional analysis. Principal component analysis, ascending hierarchical classification, and stepwise discriminant analysis showed that both the size and shape of the molecule were essential for antimalarial potency, making the lipophilicity and electronegativity distribution in the molecular space essential. Using the autocorrelogram describing the molecular shape and the electronegativity distribution on the molecular graph, 98% of the molecules were correctly classified either as poorly active or active with only three explanatory variables. The most active compounds were quaternary ammoniums salts whose nitrogen atom had only one long lipophilic chain of 11 or 12 methylene groups (E5, E6, E10, E13, E20, E21, E22, E23, F4, F8), or the bisammoniums whose polar heads were linked by linear alkyl chains of 10 to 12 carbon atoms (G4, G23). The hydroxyethyl group of choline was not very beneficial, whereas the charge and substitutions of nitrogen (aimed at increasing lipophilicity) were essential for optimal interactions. A crude topographic model of the ligand (choline) binding site was thus drawn up.

Animals↗
PubMed1998

Antimalarial cyclic peroxy ketals.

Over 20 new, cyclic, peroxy ketals have been prepared via a two-step protocol starting with readily available aryl methyl ketones. Structure-activity correlations using in vitro antimalarial data as a guide for optimization of potency have led to the design and synthesis of seven new peroxides that have IC50 values of 31-85 nM (artemisinin IC50 = 8.4 nM). Some SAR generalizations are discussed.

Animals↗
PubMed1998

Synthesis and antimalarial activities of fluoroalkyl derivatives of dihydroartemisinin.

Fluoroalkyl ethers (4) of dihydroartemisinin (2) have been prepared by reaction of fluoroalkyl alcohols with dihydroartemisinin by different methods (BF3,Et2O or TMSCl catalysis or Mitsunobu reaction). Ethers 4a-d derived from primary fluoroalkyl alcohols were obtained in moderate to good yields by these methods. Ethers 4e-j have been prepared from fluoroalkyl secondary and tertiary alcohols and phenol using the Mitsunobu reaction. Although in vitro antimalarial activities of ethers toward Plasmodium falciparum W-2 asiatic strain are moderate, in vivo activities against Plasmodium berghei (NT 173) are excellent.

Animals↗
PubMed1999

Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether.

Ten novel, second-generation, fluorinated ether and ester analogues of the potent first-generation analogues artemether (4a) and arteether (4b) have been designed and synthesized. All of the compounds demonstrate high antimalarial potency in vitro against the chloroquine-sensitive HB3 and -resistant K1 strains of Plasmodium falciparum. The most potent derivative 8 was 15 times more potent than artemisinin (2) against the HB3 strain of P. falciparum. In vivo, versus Plasmodium berghei in the mouse, selected derivatives were generally less potent than dihydroartemisinin with ED(50) values of between 5 and 8 mg/kg. On the basis of the products obtained from the in vitro biomimetic Fe(II)-mediated decomposition of 8, the radical mediator of biological activity of this series may be different from that of the parent drug, artemisinin (2).

Animals↗