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PubMed1994

Roles of peptidyl-prolyl cis-trans isomerase and calcineurin in the mechanisms of antimalarial action of cyclosporin A, FK506, and rapamycin.

The immunosuppressive peptide cyclosporin A inhibits the growth of malaria parasites in vitro and in vivo, but little is known about its mechanism of antimalarial action. The immunosuppressive action of cyclosporin A is believed to result from binding of the drug to cyclophilins (intracellular peptidyl-prolyl cis-trans isomerases), and inhibition of the protein phosphatase calcineurin by the cyclosporin A-cyclophilin complex. Two immunosuppressive macrolides, FK506 and rapamycin, bind to a distinct isomerase, FKBP12, and the FK506-FKBP complex also inhibits calcineurin. Calcineurin itself is apparently involved in signal transduction between the T-cell membrane and nucleus, and its inhibition blocks T-cell activation. Rapamycin inhibits a later step in T-cell proliferation. Peptidyl-propyl cis-trans isomerase activity was detected in extracts of Plasmodium falciparum. It was completely inhibited by concentrations of cyclosporin A above 0.1 microM, but not by FK506 or rapamycin, and probably represented one or more cyclophilins. Comparison of the antimalarial and anti-isomerase activities of a series of cyclosporin analogues failed to reveal a correlation between the two properties. Cyclosporin A and its more active 8'-oxymethyl-dihydro-derivative, in combination with the cyclophilin-containing P. falciparum extract, inhibited the protein phosphatase activity of bovine calcineurin. Therefore inhibition of a putative P. falciparum calcineurin by a complex of CsA and cyclophilin might be responsible for the antimalarial action of the drug. The most active cyclosporin, however, was a 3'-keto-derivative of cyclosporin D (SDZ PSC-833) which inhibited P. falciparum growth with a 50% inhibitory concentration (IC50) of 0.032 microM (compared with 0.30 microM for cyclosporin A), but was a poor inhibitor of the parasite isomerase. 3'-Keto-cyclosporin D has negligible immunosuppressive activity, but it strongly inhibits the P-glycoprotein of multi-drug resistant mammalian tumour cells. FK506 and rapamycin were also active antimalarials (IC50 of 1.9 and 2.6 microM, respectively) but in the absence of detectable FKBP in P. falciparum extracts, their mechanisms of antimalarial action remain unclear.

Amino Acid Isomerases↗
PubMed1988

Detection and determination of antimalarial drugs and their metabolites in body fluids.

This review of methods for determining antimalarial drugs in biological fluids has focused on the various analytical techniques for the assay of chloroquine, quinine, amodiaquine, mefloquine, proguanil, pyrimethamine, sulphadoxine, primaquine and some of their metabolites. The methods for determining antimalarials and their metabolites in biological samples have changed rapidly during the last eight to ten years with the increased use of chromatographic techniques. Chloroquine is still the most used antimalarial drug, and various methods of different complexity exist for the determination of chloroquine and its metabolites in biological fluids. The pharmacokinetics of chloroquine and other antimalarials have been updated using these new methods. The various analytical techniques have been discussed, from simple colorimetric methods of intermediate selectivity and sensitivity to highly sophisticated, selective and sensitive chromatographic methods applied in a modern analytical laboratory. Knowledge concerning the method for a particular study is determined by the type of application and the facilities, equipment and personnel available. Often is it useful to apply various methods when conducting a clinical study in malaria-endemic areas. Field-adapted methods for the analysis of urine samples can be applied at the study site for screening, and corresponding blood samples can be preserved for subsequent analysis in the laboratory. Selecting samples for laboratory analysis is based on clinical, parasitological and field-assay data. The wide array of methods available for chloroquine permit carefully tailored approaches to acquire the necessary analytical information in clinical field studies concerning the use of this drug. The development of additional field-adapted and field-interfaced methods for other commonly used antimalarials will provide similar flexibility in field studies of these drugs.

Antimalarials↗
PubMed2006

Non-stochastic quadratic fingerprints and LDA-based QSAR models in hit and lead generation through virtual screening: theoretical and experimental assessment of a promising method for the discovery of new antimalarial compounds.

In order to explore the ability of non-stochastic quadratic indices to encode chemical information in antimalarials, four quantitative models for the discrimination of compounds having this property were generated and statistically compared. Accuracies of 90.2% and 83.3% for the training and test sets, respectively, were observed for the best of all the models, which included non-stochastic quadratic fingerprints weighted with Pauling electronegativities. With a comparative purpose and as a second validation experiment, an exercise of virtual screening of 65 already-reported antimalarials was carried out. Finally, 17 new compounds were classified as either active/inactive ones and experimentally evaluated for their potential antimalarial properties on the ferriprotoporphyrin (FP) IX biocrystallization inhibition test (FBIT). The theoretical predictions were in agreement with the experimental results. In the assayed test compound C5 resulted more active than chloroquine. The current result illustrates the usefulness of the TOMOCOMD-CARDD strategy in rational antimalarial-drug design, at the time that it introduces a new family of organic compounds as starting point for the development of promising antimalarials.

Algorithms↗
PubMed2003

In vitro antimalarial activity of retinoids and the influence of selective retinoic acid receptor antagonists.

Retinol (vitamin A alcohol) may have a beneficial role in the host response to malaria in humans and previously published data have suggested that it has a direct inhibitory effect on the growth of Plasmodium falciparum in vitro. To further investigate the role of retinoids as potential antimalarial agents, we assessed the effect of all-trans-retinoic acid (RA), 9-cis-RA and 13-cis-RA, as well as retinol itself and its ester, retinyl palmitate, on 3H-hypoxanthine uptake by the laboratory-adapted strains of P. falciparum 3D7 and K1. In addition, we examined the influence of three specific RA receptor antagonists, ER 27191, Ro 415253 and AGN 194301, on retinoid-induced growth inhibition of 3D7. All-trans-RA, 9-cis-RA and 13-cis-RA in concentrations ranging from 1 x 10(-4) to 5 x 10(-10) M each had antimalarial activity, but at IC50 values (5.9 x 10(-5) to 7.9 x 10(-5) M) that were less than those of retinol (2.5 x 10(-5) to 3.2 x 10(-5) M). Retinyl palmitate had minimal effect on 3H-hypoxanthine uptake. Each of the three specific antagonists inhibited growth of 3D7 (IC50 range 1.2 x 10(-5) to 3.0 x 10(-5) M) but, in isobolographic analysis, were antagonistic to retinol (dose factor potentiation, DFP 0.46-0.79) and, in the case of Ro 415253, to all-trans-RA (DFP=0.39). Although we did not attempt to quantify losses of retinoids from the system, these data suggest that retinol has greater antimalarial activity than its RA metabolites and especially retinyl palmitate. The specific RA receptor antagonists showed paradoxical antimalarial activity but consistently antagonised the effect of retinol and all-trans-RA in isobolographic experiments. We conclude that RA metabolites may be less suitable than retinol per se as antimalarial agents and that P. falciparum might possess or acquire a RA receptor-like moiety.

Animals↗
PubMed1996

Mode of antimalarial effect of methylene blue and some of its analogues on Plasmodium falciparum in culture and their inhibition of P. vinckei petteri and P. yoelii nigeriensis in vivo.

The antimalarial action of methylene blue (MB) was first noted by Paul Ehrlich in the late 19th century. Although it has only sporadically been adopted as a serviceable drug, the resolution of its antimalarial action seems warranted, as it is currently used for the treatment of various methemoglobinemias. In this work we have used MB, and its analogues Azures A (AZA), B (AZB), C (AZC), and thionin (TH), as well as the oxazine Celestine blue (CB) and azine Phenosaphranin (PS). All MB analogues inhibit the growth of various strains of Plasmodium falciparum in culture with IC50s in the 2 x 10(-9)-1 x 10(-7) M range, with the rank order MB approximately AZA > AZB > AZC > TH > PS > CB. The IC50s for a mammalian cell line were in the 3 x 10(-6)-4 x 10(-5) M range, and the rank order was TH approximately AZB > AZA approximately PS > AZC approximately CB > MB. As MB could affect cell growth through the oxidation of NADPH, we tested the action of the various compounds on the hexose-monophosphate shunt activity. Appreciable activation of the shunt was observed at 1 x 10(-5) M in both cell types, thus accounting for inhibition of growth of mammalian cells but not of parasites. All compounds were found to complex with heme in a rank order similar to their antimalarial effect. It is therefore suggested that MB and its congeners act by preventing the polymerization of heme, which is produced during the digestion of host cell cytosol in the parasite food vacuole, into hemozoin. In this respect, these compounds seem to act similarly to the 4-aminoquinoline antimalarials. All compounds effectively suppressed the growth of P. vinckei petteri in vivo with IC50 in the 1.2-5.2 mg/kg range, and MB and AZB suppressed P. yoelii nigeriensis in the 9-11 mg/kg range (i.e. at doses similar to those of chloroquine). The potential toxicity of these compounds may restrict their clinical use, but their impressive antimalarial activities suggest that the phenothiazine structure could serve as a lead compound for further drug development.

Animals↗
PubMed1999

Bisquinoline antimalarials: their role in malaria chemotherapy.

Quinoline compounds, such as chloroquine, are used widely to treat malaria; however, the malarial parasite is rapidly becoming resistant to the drugs currently available. Presently, rational drug design is hindered considerably due to the mode of action of chloroquine being poorly understood. We rely on serendipity, rather than solid structural evidence, to generate new antimalarials. Hence any insight into the possible modes of action of quinoline antimalarials, including the bisquinolines, would greatly aid rational drug design. The quinoline antimalarial drugs, chloroquine, quinine and mefloquine, are thought to act by interfering with the digestion of haemoglobin in the blood stages of the malaria life-cycle. These quinoline antimalarials traverse down the pH gradient to accumulate to millimolar concentrations in the acidic vacuole of the parasite. It has been suggested that this high intravacuolar concentration prevents haem sequestration, causing a build up of the toxic haem moiety and the death of the parasite by its own toxic waste. The actual mechanism by which the parasite sequesters haem and the drug target(s) during this process, however, still remains elusive. As a consequence, haem polymerisation and the efficiency of quinoline antimalarials, including the bisquinolines, as inhibitors of this process has been investigated. In this paper, the potential role of the bisquinolines in the fight against chloroquine-resistant malaria is addressed.

Animals↗
PubMed1982

Antimalarials and ophthalmologic safety.

Antimalarial drugs were shown to be useful agents in the treatment of discoid and systemic lupus erythematosus in 1951. However, by 1966, fear of retinal toxicity and the availability of alternative therapies had led to limited use of antimalarials. Continued experience with these alternative therapies has made their intrinsic, sometimes devastating toxicities more evident and has contributed to the renewed interest in antimalarial agents evident in the number of comprehensive reviews appearing recently in the dermatology literature. Many of these reviews, while generally excellent, have propagated some apparent misconceptions by disregarding or de-emphasizing data suggesting that irreversible retinal toxicity due to antimalarials can be easily avoided by judicious daily dosage and regular ophthalmologic follow-up. This article will discuss the historical basis of these misconceptions and the subsequent studies which suggest that antimalarial retinal toxicity can be avoided without sacrificing the therapeutic efficacy of these agents.

Antimalarials↗
PubMed2000

The search for natural bioactive compounds through a multidisciplinary approach in Bolivia. Part II. Antimalarial activity of some plants used by Mosetene indians.

Forty-six different species collected in the Mosetene ethnia, dwelling in the Andean Piedmont of Bolivia, were screened for antimalarial properties. Thirty-three extracts were screened for antimalarial activity in vitro on Plasmodium falciparum chloroquine resistant strain (Indo), and forty-seven extracts were evaluated in vivo on the rodent malaria P. vinckei petteri 279BY. Only two plants are specifically used in combination by the Mosetene against malaria attack (Hymenachne donacifolia and Tesseria integrifolia), but they did not display any activity in vivo at 1000 mg/kg. The in vivo most active extracts were Swietenia macrophylla bark, Trema micrantha bark and Triplaris americana bark, not all of them were used for antimalarial purposes by the Mosetene. The following extracts were moderately active: Jacaratia digitata inner bark and Momordica charantia aerial part (both traditionally used as febrifuge), Kalanchoe pinnate aerial part (used in inflammatory processes), Lunania parviflora twigs and leaves, Phyllanthus acuminatus (used as piscicide), Tynanthus schumannianus fruit (used against diarrhoea), Triumfetta semitrilobata (used as febrifuge, to alleviate kidney and gynecological pain) and finally Solanum mammosum fruit (used against scabies). We present here the results of this screening, emphazing on the in vivo antimalarial activity of the selected plants. The antimalarial in vivo activity of the selected species, in relation with their traditional Mosetene use is then discussed.

Animals↗
PubMed1999

Stereoelectronic features of the cinchona alkaloids determine their differential antimalarial activity.

For most potent antimalarial activity, the cinchona alkaloids appear to require certain electronic features, particularly a sufficiently acidic hydroxyl proton and an electric field direction pointing from the aliphatic nitrogen atom towards the quinoline ring. These observations are the result of an analysis of molecular electronic properties of eight cinchona alkaloids and an in vivo metabolite calculated using ab initio 3-21G quantum chemical methods in relation to their in vitro IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. The purpose is to provide a profile of the electronic characteristics necessary for potent antimalarial activity for use in the design of new antimalarial agents and to gain insight into the mechanistic path for antimalarial activity. Distinguishing features of the weakly active epiquinine and epiquinidine include a higher dipole moment, a different direction of the electric field, a greater intrinsic nucleophilicity, lower acidity of the hydroxyl proton, a lesser electron affinity of the lowest unoccupied molecular orbitals, and a higher proton affinity than the active cinchona alkaloids. A moderately potent quinine metabolite possesses some, but not all, of the same electronic features as the most potent cinchona alkaloids. Both the positioning of the hydroxyl and aliphatic amine groups and their electronic features appear to play a crucial role for antimalarial potency of the cinchona alkaloids, most likely by controlling the ability of these groups to form effective intermolecular hydrogen bonds.

Animals↗
PubMed1998

Photosensitizing properties of quinine and synthetic antimalarials.

Quinine, an alkaloid that occurs in the bark of trees of the genus Cinchona, has been used for the treatment of malaria in humans for over 150 years. In 1888 it was reported that quinine was more toxic to plant tissues and frog eggs in the light than in the dark; thus it is probably one of the first pure compounds shown to be a photosensitizer for biological systems. During this century, because of the toxic side effects of quinine and the appearance of quinine-resistant malarial strains, a search was begun to identify synthetic antimalarial compounds with improved properties. A number have been identified and are now in widespread use; but like quinine, most of these are also photosensitizers. Because of the very large numbers of patients receiving antimalarials, many studies have been made of the photophysical, photochemical and photosensitizing properties of quinine and several of the most commonly used synthetic antimalarials (chloroquine, primaquine, quinacrine and mefloquine). The results of these studies are summarized in this review. Most antimalarials photosensitize in part by the generation of singlet oxygen, although free radical pathways may also be involved. The carcinogenic and photocarcinogenic properties of antimalarials and related compounds are briefly surveyed.

Animals↗
PubMed1995

Antimalarial activity of new dihydroartemisinin derivatives. 6. alpha-Alkylbenzylic ethers.

A series of diastereomeric dihydroartemisinin alpha-alkylbenzylic ethers was synthesized in search for analogs with higher antimalarial efficacy and longer plasma half-life than the existing artemisinin derivatives. Artelinic acid was used as the model molecule for the design of new analogs. Two approaches were taken in an attempt to (a) increase the lipophilicity of the molecule and (b) decrease the rate of oxidative dealkylation of the target compounds. All compounds in this study showed at least equal or better in vitro antimalarial activity against Plasmodium falciparum than artelinic acid. The most active compounds of this series showed 10-, 20-, and 40-fold better inhibitory activity than artemether, artemisinin, and artelinic acid, respectively. Compounds which have a small methyl group substituted at the alpha-methylene group showed weaker activity than compounds with a larger carbethoxyalkyl substituent, indicating that the lipophilicity and the steric effect of the molecules play important roles in their antimalarial activity. This fact is further substantiated by the significantly weaker antimalarial activity of the carboxylic acids than their corresponding esters. Compounds with electron-withdrawing function (NO2) substantially increase the antimalarial activity. The S-diastereomers, in general, are severalfold more potent than the corresponding R-isomer.

Animals↗
PubMed2002

Potent antimalarial febrifugine analogues against the plasmodium malaria parasite.

Although febrifugine (1) and isofebrifugine (2), alkaloids isolated from roots of the Dichroa febrifuga plant, show powerful antimalarial activity against Plasmodium falciparum, strong side effects such as the emetic effect have precluded their clinical use against malaria. However, their antimalarial potency makes them attractive substances as leads for developing new types of chemotherapeutic antimalarial drugs. Thus, we have evaluated the in vitro antimalarial activity of the analogues of febrifugine (1) and isofebrifugine (2). The activities of the analogues derived from Df-1 (3) and Df-2 (4), condensation products of 1 and 2 with acetone, respectively, were also obtained. The 3' '-keto derivative (7, EC(50) = 2.0 x 10(-8) M) of 1 was found to exhibit potential antimalarial activity with high selectivity against P. falciparum in vitro. The in vitro activities of the reduction product (8, EC(50) = 2.0 x 10(-8) M) of 1 at C-2' and its cyclic derivatives 9 and 10 (EC(50) = 3.7 x 10(-9) and 8.6 x 10(-9) M, respectively) were found to be strongly active and selective. Additionally, the Dess-Martin oxidation product of 3 was found to be strongly active with high selectivity against P. falciparum. A structure-activity relationship study (SAR) demonstrates that the essential role played by the 4-quinazolinone ring in the appearance of activity and the presence of a 1' '-amino group and C-2', C-3' ' O-functionalities are crucial in the activity of 1. For 7, 8, and 9, prepared as racemic forms, an in vivo study has also been conducted.

Animals↗
PubMed2005

Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine.

Resistant strains of Plasmodium falciparum and the unavailability of useful antimalarial vaccines reinforce the need to develop new efficacious antimalarials. This study details a pharmacophore model that has been used to identify a potent, soluble, orally bioavailable antimalarial bisquinoline, metaquine (N,N'-bis(7-chloroquinolin-4-yl)benzene-1,3-diamine) (dihydrochloride), which is active against Plasmodium berghei in vivo (oral ID(50) of 25 micromol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 microM). Metaquine shows strong affinity for the putative antimalarial receptor, heme at pH 7.4 in aqueous DMSO. Both crystallographic analyses and quantum mechanical calculations (HF/6-31+G) reveal important regions of protonation and bonding thought to persist at parasitic vacuolar pH concordant with our receptor model. Formation of drug-heme adduct in solution was confirmed using high-resolution positive ion electrospray mass spectrometry. Metaquine showed strong binding with the receptor in a 1:1 ratio (log K = 5.7 +/- 0.1) that was predicted by molecular mechanics calculations. This study illustrates a rational multidisciplinary approach for the development of new 4-aminoquinoline antimalarials, with efficacy superior to chloroquine, based on the use of a pharmacophore model.

Aminoquinolines↗
PubMed1996

Structure-activity relationships of the antimalarial agent artemisinin. 3. Total synthesis of (+)-13-carbaartemisinin and related tetra- and tricyclic structures.

Provided by total synthesis, endoperoxides 18, 20, and 22 underwent intramolecular oxymercuration-demercuration leading respectively to formation of an isomeric tetracycle, (1aS, 3S, 5aS, 6R, 8aS, 9R, 12S)-10-deoxo-13-carbaartemisinin (19), (+)-10-deoxo-13-carbaartemisinin (21), and (+)-13-carbaartemisinin (4). Structure assignment to 19 and 21 was based on single-crystal X-ray crystallographic analysis. Tricyclic endoperoxide 20 was converted to methyl and benzyl ethers 23 and 24 and reduced to saturated analog 25 which was also converted to ethers 26 and 27. In vitro antimalarial screening of both tri- and tetracyclic analogs was conducted using the W-2 and D-6 clones of Plasmodium falciparum. Neither target 4 nor 21 displayed substantial antimalarial potency in vitro against P. falciparum, but the diastereomeric peroxide 19 possessed good antimalarial potency in vitro. Tricyclic analogs were uniformly impotent. Iron(II) bromide-promoted rearrangement of 21 gave, in 79% yield, the unique tetracyclic alcohol 35, while 19 provided ring-opened cyclohexanone 41 (39%) along with the tricyclic epoxide 42 (20%). Neither 41 nor 42 possessed in vitro antimalarial activity, suggesting that epoxide-like intermediates are not responsible for the mode of action of this subclass of antimalarials. Rearrangement of 10-deoxoartemisinin (43) with FeBr2 gave a major product (79%) not encountered in the rearrangement of artemisinin that resulted from unraveling of the tetracyclic system cyclohexanone 46. Minor amounts of 1,10-dideoxoartemisinin (49) (8%) were also produced in this reaction.

Animals↗
PubMed1996

Molecular electronic properties of a series of 4-quinolinecarbinolamines define antimalarial activity profile.

A detailed computational study on a series of 4-quinolinecarbinolamine antimalarials was performed using the semiempirical Austin model 1 (AM1) quantum chemical method to correlate the electronic features with antimalarial activity and to illuminate more completely the fundamental molecular level forces that affect the function and utility of the compounds. Ab initio (3-21G level) calculations were performed on mefloquine, the lead compound in this series, to check the reliability of the AM1 method. Electron density in specific regions of the molecules appears to play the pivotal role toward activity. A large laterally extended negative potential in the frontal portion of the nitrogen atom of the quinoline ring and the absence of negative potential over the molecular plane are crucial for the potent antimalarials. These electrostatic features are likely to be the modulator of hydrophobicity or lipophilicity of the compounds and, hence, determine their activities. The magnitude of the positive potential located by the hydroxyl hydrogen atom also correlates with potent antimalarial activity. Two negative potential regions occur near the hydroxyl oxygen and piperidyl nitrogen atoms. The two negative potential regions and the positive potential located by the hydroxyl hydrogen atom are consistent with intermolecular hydrogen bonding with the cellular effectors. The present modeling study should aid in efficient designing of this class of antimalarial agents.

Animals↗
PubMed2000

Antimalarial activity of compounds interfering with Plasmodium falciparum phospholipid metabolism: comparison between mono- and bisquaternary ammonium salts.

On the basis of a previous structure-activity relationship study, we identified some essential parameters, e.g. electronegativity and lipophilicity, required for polar head analogues to inhibit Plasmodium falciparum phospholipid metabolism, leading to parasite death. To improve the in vitro antimalarial activity, 36 cationic choline analogues consisting of mono-, bis-, and triquaternary ammonium salts with distinct substituents of increasing lipophilicity were synthesized. For monoquaternary ammonium salts, an increase in the lipophilicity around nitrogen was beneficial for antimalarial activity: IC(50) decreased by 1 order of magnitude from trimethyl to tripropyl substituents. Irrespective of the polar head substitution (methyl, ethyl, hydroxyethyl, pyrrolidinium), increasing the alkyl chain length from 6 to 12 methylene groups always led to increased activity. The highest activity was obtained for the N,N,N-tripropyl-N-dodecyl substitution of nitrogen (IC(50) 33 nM). Beyond 12 methylene groups, the antimalarial activities of the compounds decreased slightly. The structural requirements for bisquaternary ammonium salts in antimalarial activity were very similar to those of monoquaternary ammonium salts, i.e. polar head steric hindrance and lipophilicity around nitrogen (methyl, hydroxyethyl, ethyl, pyrrolidinium, etc.). In contrast, with bisquaternary ammonium salts, increasing the lipophilicity of the alkyl chain between the two nitrogen atoms (from 5 to 21 methylene groups) constantly and dramatically increased the activity. Most of these duplicated molecules had activity around 1 nM, and the most lipophilic compound synthesized exhibited an IC(50) as low as 3 pM (21 methylene groups). Globally, this oriented synthesis produced 28 compounds out of 36 with an IC(50) lower than 1 microM, and 9 of them had an IC(50) in the nanomolar range, with 1 compound in the picomolar range. This indicates that developing a pharmacological model for antimalarial compounds through choline analogues is a promising strategy.

Animals↗
PubMed2005

Antimalarials inhibit human erythrocyte membrane acetylcholinesterase.

The current study examined the ability of antimalarials chloroquine (CQ), primaquine (PQ), and quinine (Q) to inhibit human erythrocyte membrane acetylcholinesterase (AChE) and the mechanisms underlying their inhibitory action. CQ was found to be the most effective inhibitor of the enzyme followed by PQ and Q. The concentrations required to obtain 33% inhibition (IC(33)) for CQ and PQ were 22 and 38 microM, respectively, whereas that for Q was 3.2 mM. The concentrations required to obtain 67% inhibition (IC(67)) were about 9 and 7 times higher for CQ and PQ, whereas that for Q was only about 2.5 times higher. Hill plot analysis revealed that CQ shows de-binding above 40 microM. The two kinetic components of AChE were inhibited by the three antimalarials, and the inhibition was of mixed type. Increasing concentrations of antimalarials caused progressive decrease in the V(max) of both components. IC(33) concentrations resulted in 1.6- to 6-fold increase in K(m) of both the components while IC(67) concentration caused 2.8- to 13-fold increases in K(m) with maximum effect being seen with Q. The K(i) values were lowest for CQ suggesting that it was the most potent inhibitor; these values were 3.3 and 60 times higher for PQ and Q. Antimalarials represent the bifunctional compounds that possess anti-inflammatory properties and also inhibit cholinesterases. The results of our studies suggest that 4-aminoquinoline-based antimalarials like CQ and hydroxychloroquine, which are both potent anti-inflammatory agents and inhibitors of cholinesterases, may have potential use as the most effective neuroprotective agents against amyloid-beta-peptide (Abeta) neurotoxicity in Alzheimer's disease.

Acetylcholinesterase↗
PubMed1997

Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697.

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.

Animals↗