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PubMed2003

Structure-activity relationships of antileishmanial and antimalarial chalcones.

A series of oxygenated chalcones which have been evaluated earlier for antimalarial activity (Plasmodium falciparum K1) were tested for antileishmanial activity against Leishmania donovani amastigotes. A comparison of structure-activity relationships reveal that different physicochemical and structural requirements exist for these two activities. Antileishmanial activity is associated with less lipophilic chalcones, in particular those with 4'-hydroxyl-substituted B rings and hetero/polyaromatic A rings. In contrast, chalcones with good antimalarial activity have alkoxylated B rings and electron-deficient A rings. Visualization of the steric and electrostatic fields generated from comparative molecular field analysis (CoMFA) indicate that the ring A of chalcones make a more significant contribution to antileishmanial activity while both rings A and B are important for antimalarial activity. Despite different requirements, two alkoxylated chalcones (8, 19) were identified which combined good antimalarial and antileishmanial activities.

Animals↗
PubMed2002

Solution structures of antimalarial drug-heme complexes.

Paramagnetic metal centers [such as Fe(III) found within ferriprotoporphyrin IX heme (FPIX)] exert through space effects on the relaxation rate of nearby proton spins that depend critically on the metal-proton distance. We have measured these effects for all protons of several antimalarial drugs that bind to FPIX by systematically varying the drug:heme molar ratio in high field NMR experiments. These measurements allow us to determine precise FPIX Fe-drug H distances for the solution structures of noncovalent complexes formed between FPIX mu-oxo dimers and the antimalarial drugs chloroquine (CQ), quinine (QN), and quinidine (QD). Using these distances, we then performed distance restraint calculations to determine the lowest-energy solution structures of these complexes. Structures were solved for neutral, monoprotic (+1), and diprotic (+2) forms of the drugs. Analysis of these structures allows us to visualize for the first time the stereospecific differences between QN and QD binding to FPIX and the differences in populations of QN and QD solution structures upon changes in digestive vacuolar pH for drug resistant malarial parasites [Dzekunov, S. M., et al. (2000) Mol. Biochem. Parasitol. 110, 107-124]. The data indicate a previously unrecognized key role for the CQ aliphatic chain in stabilizing FPIX-CQ complexes, and suggest how lengthening or shortening the chain might perturb stability. We also define FPIX:drug stoichiometries of 2:1 for the complexes formed at physiological FPIX concentrations, in contrast to the 4:1 and 5:1 stoichiometries previously determined at higher FPIX concentrations [Dorn, A., et al. (1998) Biochem. Pharmacol. 55, 727-736]. These atomic resolution antimalarial drug-heme structures should help elucidate how these drugs inhibit formation of hemozoin during metabolism of heme within the malarial parasite Plasmodium falciparum and assist ongoing development of strategies for circumventing antimalarial drug resistance.

Aminoquinolines↗
PubMed1992

Extraordinarily potent antimalarial compounds: new, structurally simple, easily synthesized, tricyclic 1,2,4-trioxanes.

New, racemic, tricyclic trioxane alcohol 3 was designed and synthesized as a structurally simple analog of clinically useful, tetracyclic, antimalarial artemisinin. A series of 20 ester and ether derivatives of alcohol 3 were prepared easily, without destruction of the essential trioxane system. Chemical structure-antimalarial activity for each derivative was evaluated in vitro against chloroquine-resistant and chloroquine-sensitive Plasmodium falciparum parasites. Many of these derivatives were highly efficacious; carboxylate ester 9f, carbamate ester 10a, and sulfonate ester 12a had antimalarial potency similar to that of artemisinin, and carboxylate esters 9b and 9d, carbamate esters 10b and 10c, and phosphate esters 11a-c had antimalarial potency up to 7 times higher than that of artemisinin. Several of these most active analogs (e.g., carboxylate 9b and carbamates 10a and 10c) are stable crystalline solids, a feature of considerable practical value for any new drug candidate.

Animals↗
PubMed2001

Inhibition of heme detoxification processes underlies the antimalarial activity of terpene isonitrile compounds from marine sponges.

A series of terpene isonitriles, isolated from marine sponges, have previously been shown to exhibit antimalarial activities. Molecular modeling studies employing 3D-QSAR with receptor modeling methodologies performed with these isonitriles showed that the modeled molecules could be used to generate a pharmacophore hypothesis consistent with the experimentally derived biological activities. It was also shown that one of the modeled compounds, diisocyanoadociane (4), as well as axisonitrile-3 (2), both of which have potent antimalarial activity, interacts with heme (FP) by forming a coordination complex with the FP iron. Furthermore, these compounds were shown to inhibit sequestration of FP into beta-hematin and to prevent both the peroxidative and glutathione-mediated destruction of FP under conditions designed to mimic the environment within the malaria parasite. By contrast, two of the modeled diterpene isonitriles, 7-isocyanoamphilecta-11(20),15-diene (12) and 7-isocyano-15-isothiocyanatoamphilecta-11(20)-ene (13), that displayed little antimalarial activity also showed little inhibitory activity in these FP detoxification assays. These studies suggest that the active isonitrile compounds, like the quinoline antimalarials, exert their antiplasmodial activity by preventing FP detoxification. Molecular dynamics simulations performed with diisocyanoadociane (4) and axisonitrile-3 (2) allowed their different binding to FP to be distinguished.

Animals↗
PubMed2002

Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.

The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot form dihydroartemisinin by P450-catalyzed oxidation, they represent useful leads that might prove to be superior to the currently used derivatives, artemether and artesunate.

Animals↗
PubMed2003

Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials.

Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC(50) = 6.01 nM +/- 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED(50) activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.

Aminoquinolines↗
PubMed2006

Endoperoxide derivatives from marine organisms: 1,2-dioxanes of the plakortin family as novel antimalarial agents.

Plakortin (1) is a remarkably simple 1,2-dioxane derivative, extracted from the marine sponge Plakortis simplex, showing a submicromolar activity against chloroquine-resistant strains of Plasmodium falciparum. Using plakortin as a novel antimalarial hit, we have prepared a series of semisynthetic derivatives in order to gain insights into the structural requirements of simple 1,2-dioxanes for exhibiting antimalarial activity. Their synthesis, spectroscopic and computational analysis, and in vitro antimalarial activity are herein reported. Results obtained, besides confirming the crucial role of the cycloperoxide functionality, revealed other structural features critical for antimalarial activity, namely the "Western" alkyl side chain, the dioxane ring conformation, and the absolute configuration of the stereogenic carbons on the 1,2-dioxane ring, when affecting the bioactive ring conformation.

Animals↗
PubMed1997

Antimalarial activity of new dihydroartemisinin derivatives. 7. 4-(p-substituted phenyl)-4(R or S)-[10(alpha or beta)-dihydroartemisininoxy]butyric acids.

To search for water soluble dihydroartemisinin derivatives with higher efficacy and longer plasma half-life than artesunic or artelinic acid, a series of new stereoisomers of 4-(p-substituted phenyl)-4(R or S)-[10(alpha or beta)-dihydroartemisininoxy]butyric acids were synthesized as new potential antimalarial agents. Two approaches were taken in the design of these new molecules in an attempt to (a) increase the lipophilicity of the molecule and (b) decrease the rate of oxidative dealkylation of the target compounds. The new compounds showed a 2-10-fold increase in in vitro antimalarial activity against D-6 and W-2 clones of Plasmodium falciparum than artemisinin or artelinic acid. R-diastereomers are, in general, more potent than the corresponding S-diastereomers. p-Chlorophenyl and p-bromophenyl derivatives showed in vivo oral antimalarial activity against P. berghei (with 3/8 cured) superior to that of artelinic acid (1/8 cured), whereas p-fluorophenyl and p-methoxyphenyl analogs demonstrated activity only comparable (1/8 cured) to that of artelinic acid at the same dosage level (64 mg/kg twice a day). The in vivo antimalarial activity of these new compounds correlates with their SD50 (50% parasitemia suppression dose). The biological results suggested that an electronic effect, besides the lipophylicity, may play a role in determining the efficacy of this class of compounds.

Animals↗
PubMed1997

Synthesis and antimalarial effects of phenothiazine inhibitors of a Plasmodium falciparum cysteine protease.

Acridinediones have previously been shown to have potent antimalarial activity. A series of sulfur isosteres of acridinediones have been synthesized and evaluated for their inhibition of the Plasmodium falciparum cysteine protease falcipain and for their antimalarial activity. A number of these phenothiazines inhibited falcipain and demonstrated activity against cultured P. falciparum parasites at low micromolar concentrations. We propose that the compounds exerted their antimalarial effects by two mechanisms, one of which involves the inhibition of falcipain and a consequent block in parasite degradation of hemoglobin. These compounds and related phenothiazines are worthy of further study as potential antimalarial agents.

Animals↗
PubMed1993

Cytotoxic and antimalarial alkaloids from the tubers of Stephania pierrei.

Biological evaluation of extracts prepared from the tubers of Stephania pierrei revealed cytotoxic and antimalarial activity. During the course of separation, two new aporphine alkaloids, (-)-asimilobine-2-O-beta-D-glucoside [2] and (-)-nordicentrine [8], in addition to twenty-one known isoquinoline alkaloids, were isolated. Each isolate was assessed for cytotoxic and antimalarial activities. It was found that the cytotoxicity of S. pierrei was mainly due to the presence of the aporphine alkaloids containing the 1,2-methylenedioxy group 3-10, whereas the antimalarial activity was attributed to the nonquaternary aporphine alkaloids 1, 3-10 and the tetrahydroprotoberberines possessing a phenolic functionality, 13-15, 18. None of the isolates showed a degree of selectivity comparable to that of antimalarial drugs such as chloroquine, quinine, mefloquine, and artemisinin. Comparison of the alkaloid content of S. pierrei and Stephania erecta strongly suggested separate identities for the two plants.

Animals↗
PubMed1998

Metabolism-dependent neutrophil cytotoxicity of amodiaquine: A comparison with pyronaridine and related antimalarial drugs.

Life-threatening agranulocytosis and hepatotoxicity during prophylactic administration of amodiaquine have led to its withdrawal. Agranulocytosis is thought to involve bioactivation to a protein-reactive quinoneimine metabolite. The toxicity of amodiaquine and the lack of cheap drugs have prompted a search for alternative antimalarial agents. The aim of this study was to determine the metabolism and neutrophil toxicity of amodiaquine, pyronaridine, and other related antimalarial agents. Horseradish peroxidase and hydrogen peroxide were used to activate drugs to their respective quinoneimine metabolites. Metabolites were trapped as stable glutathione conjugates, prior to analysis by LC/MS. Amodiaquine was metabolized to a polar metabolite (m/z 661), identified as a glutathione adduct. Tebuquine was converted to two polar metabolites. The principal metabolite (m/z 686) was derived from glutathione conjugation and side chain elimination, while the minor metabolite gave a protonated molecule (m/z 496). Only parent ions were identified when chloroquine, cycloquine, or pyronaridine was incubated with the activating system and glutathione. Calculation of the heat of formation of the drugs, however, demonstrated that amodiaquine, tebuquine, cycloquine, and pyronaridine readily undergo oxidation to their quinoneimine. None of the antimalarial compounds depleted the level of intracellular glutathione (1-300 microM) when incubated with neutrophils alone. Additionally, with the exception of tebuquine, no cytotoxicity below 100 microM was observed. In the presence of the full activating system, however, all compounds except chloroquine resulted in depletion of the level of glutathione and were cytotoxic. Pretreating the cells with glutathione and other antioxidants inhibited metabolism-dependent cytotoxicity. In summary, our data show that amodiaquine and related antimalarials containing a p-aminophenol moiety undergo bioactivation in vitro to chemically reactive and cytotoxic intermediates. In particular, pyronaridine, which is currently being investigated in humans, was metabolized to a compound which was toxic to neutrophils. Thus, the possibility that it will cause agranulocytosis in clinical practice cannot be excluded, and will require careful monitoring.

Adult↗
PubMed2001

Assessment of antimalarial effect of ICL670A on in vitro cultures of Plasmodium falciparum.

We tested in vitro the antimalarial properties of ICL670A, a newly developed iron chelator for the long-term oral treatment of iron overload. Ring-stage synchronized cultures of Plasmodium falciparum cultured in human erythrocytes were exposed to different concentrations of ICL670A and the conventional iron chelator, desferrioxamine B (DFO), for 48 h. Malarial growth was measured by incorporation of [3H]-hypoxanthine. ICL670A at 30 micromol/l had marked antimalarial activity that was observable by 6 h after beginning the exposure of ring-stage parasites to the agent. Over 48 h of culture, malarial growth was significantly lower with ICL670A than with DFO at concentrations of both 30 micromol/l (P = 0.008) and 60 micromol/l (P = 0.001). At 48 h, growth relative to control was 53% with ICL670A and 83% with DFO at concentrations of 30 micromol/l, and 20% with ICL670A and 26% with DFO at concentrations of 60 micromol/l. Standard 50% inhibitory concentrations (IC50s) were similar for ICL670A and DFO. Precomplexation with iron completely abolished the inhibitory effect of ICL670A, indicating that this new agent, like DFO, probably inhibits parasite growth via deprivation of iron from critical targets within the parasite. Further studies to address the question of the antimalarial potential of ICL670A in combination with classic antimalarials would be of interest.

Analysis of Variance↗
PubMed2002

Synthesis and antimalarial activity of substituted pyrazole derivatives.

The development of new antimalarial drugs is an urgent priority considering the increasing prevalence of drug-resistant Plasmodium falciparum parasites. A series of pyrazoles are described as part of efforts directed toward the synthesis of some potent antimalarial agents. The replacement of the ester group as a substituent in the pyrazole ring by nitrile group caused a precipitous loss of activity as antimalarial due to the lack of hydrogen-bond formation. Further modification of the heterocyclic ring to give substituted aryl derivatives afforded potent antimalarial derivatives: methyl 5-amino-3-anisidinepyrazole-4-carboxylic acid 3a (IC50: 0.149 mumol/l) and methyl 5-amino-3-(m anisidin)pyrazole-4-carboxylic acid 3c (IC50: 0.15 mumol/l). The synthesis, structure-activity relationships (SAR), X-ray crystallography and pharmacological activity associated with these series of compounds are discussed.

Animals↗
PubMed2004

Prodrugs of bisthiazolium salts are orally potent antimalarials.

We created neutral antimalarial prodrugs that deliver bisthiazolium compounds with antimalarial activity in the nanomolar range. These drugs primarily affect early intraerythrocytic stages through rapid, nonreversible cytotoxicity. The compounds are suitable for both parenteral and oral use and plasma promotes rapid conversion of the prodrug into the drug. We demonstrate that very low doses offer protection in a murine model of malaria. The drugs show great potential for curing high parasitemia with short-course treatments. Oral administration of the TE3 prodrug completely cures Plasmodium cynomolgi infection in rhesus monkeys. The drugs specifically accumulate inside infected erythrocytes, block phosphatidylcholine biosynthesis, and interact with hemozoin. To our knowledge, this class of compounds represents one of the most potent antimalarials tested to date. These unique properties signal a promising future for this class of antimalarial.

Administration, Oral↗
PubMed2006

Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity.

With >1 million deaths annually, mostly among children in sub-Saharan Africa, malaria poses one of the most critical challenges in medicine today. Although introduction of the artemisinin class of antimalarial drugs has offered a temporary solution to the problem of drug resistance, new antimalarial drugs are needed to ensure effective control of the disease in the future. Herein, we have investigated members of the methionine aminopeptidase family as potential antimalarial targets. The Plasmodium falciparum methionine aminopeptidase 1b (PfMetAP1b), one of four MetAP proteins encoded in the P. falciparum genome, was cloned, overexpressed, purified, and used to screen a 175,000-compound library for inhibitors. A family of structurally related inhibitors containing a 2-(2-pyridinyl)-pyrimidine core was identified. Structure/activity studies led to the identification of a potent PfMetAP1b inhibitor, XC11, with an IC(50) of 112 nM. XC11 was highly selective for PfMetAP1b and did not exhibit significant cytotoxicity against primary human fibroblasts. Most importantly, XC11 inhibited the proliferation of P. falciparum strains 3D7 [chloroquine (CQ)-sensitive] and Dd2 (multidrug-resistant) in vitro and is active in mouse malaria models for both CQ-sensitive and CQ-resistant strains. These results suggest that PfMetAP1b is a promising target and XC11 is an important lead compound for the development of novel antimalarial drugs.

Amino Acid Sequence↗
PubMed1994

A statistical analysis of the antimalarial activity of proguanil and cycloguanil in human volunteers.

Proguanil, an orally administered antimalarial drug, was given to 36 individuals (200 mg daily for 3 days). The antimalarial activity in plasma samples collected after the drug administration was then determined by bioassay. Concentrations of proguanil and cycloguanil (the principal active metabolite) in these samples were also measured by high performance liquid chromatography. A regression analysis was then performed on these variables to determine if the antimalarial activity of the samples was due to proguanil alone or to proguanil and cycloguanil together. The analysis indicated that cycloguanil is the main determinant of antimalarial activity after proguanil administration and that the activity of cycloguanil is not influenced by the presence of proguanil.

Adolescent↗
PubMed2004

Treatment with antimalarials adversely affects the oxidative energy metabolism in rat liver mitochondria.

Effects of in vivo treatment with the three antimalarials chloroquine, primaquine and quinine on rat liver mitochondrial energy transduction functions were examined. Treatment with all the three antimalarials decreased the state 3 and state 4 respiration rates drastically. The extent of inhibition was higher with pyruvate + malate as the substrate than with glutamate. The antimalarials also acted as uncouplers. The uncoupling effect was seen on site II and site III of phosphorylation; site I was unaffected. As a consequence the ADP phosphorylation rates also decreased significantly. Following antimalarials treatment the basal and Mg2+ stimulated ATPase activities increased while the DNP-stimulated ATPase activity was reduced by half. Treatment with chloroquine resulted in decreased contents of cytochromes aa3 and b; primaquine and quinine treatments increased the contents of the two cytochromes in 14 day treatment groups.

Adenosine Triphosphatases↗
PubMed2000

Influence of hemoglobin E trait on the antimalarial effect of artemisinin derivatives.

To determine whether hemoglobin E trait influences the antimalarial effect of artemisinin derivatives, we retrospectively compared 32 case patients with hemoglobin E trait to 32 control patients who did not have hemoglobin E, beta-thalassemia, glucose-6-phosphate dehydrogenase deficiency, or alpha-thalassemia trait on the basis of a mean corpuscular volume > or =78 femtoliters. All patients were admitted to the Hospital for Tropical Diseases in Bangkok, Thailand, with acute falciparum malaria. Control patients were matched to case patients with hemoglobin E trait by treatment with artemisinin derivatives versus other antimalarial drugs, by ethnic group, and by parasite count. Among 38 patients treated with artemisinin derivatives, the presence of hemoglobin E trait was associated with significantly faster parasite clearance (2.9-fold; 95% confidence interval [CI], 1.4-6.3; P=.006). Among 26 patients treated only with other antimalarial drugs, hemoglobin E trait did not significantly enhance parasite clearance (hazards ratio, 1.1; 95% CI, 0.5-2.5; P=. 8). Hemoglobin E trait may potentiate the antimalarial effect of artemisinin derivatives.

Adult↗