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A series of 6-alkyl-2,10-bis(trifluoromethyl)-5H-dibenz-[c,e]azepines were synthesized via a condensation reaction between 5,5'-bis(trifluoromethyl)-2,2'-diformylbiphenyl and the appropriate amine. These compounds were screened for antimalarial activity and were found to be inactive.
5-(p-Anisyloxy)-6-methoxy-8-(5-isopropylaminopentylamino)quinoline was resynthesized for evaluation in the Plasmodium berghei and monkey prophylactic (Plasmodium cynomolgi) tests. A new primary amine, three secondary amines, and one structurally modified side-chain analog of the 5-aryloxy series were also prepared. None of these compounds showed significant antimalarial or prophylactic activity.
Isopropyl [(4-chlorophenyl)amino]iminomethylcarbamimidate was synthesized as a potential antimalarial agent. Biological activity was evaluated against Plasmodium lophurae in turkeys. The activity of this compound was compared to its nitrogen isostere, chloroguanide.
Variations of the absorption and fluorescence spectra of the experimental antimalarial drug, alpha-dibutylaminomethyl-2,6-bis(p-trifluoromethylphenyl)-4-pyridinemethanol, were investigated throughout the pH region in concentrated sulfuric acid media and in n-hexane. The predominant prototropic species at physiological pH is the singly charged cation. In the pH 6--12 region, the structured fluorescence of the monocation is quenched with the concomitant appearance of a diffuse, long wavelength emission while the corresponding absorption spectra shift only slightly to longer wavelengths. Furthermore, the dibutylamino group exhibits an unusually low basicity. This behavior is explained as due to the formation of an intramolecular hydrogen bond in the neutral molecule in the ground and lowest excited singlet states. A similar intramolecular hydrogen bond in the monocation is not spectroscopically visible.
The relative availability of the orally administered hydrophobic antimalarial alpha-(dibutylaminomethyl)-6,8-dichloro-2-(3',4'-dichlorophenyl)-4-quinolinemethanol (I) from two dosage forms was determined in beagle dogs. Compound I was soluble in oleic acid to the extent of 23.5% (w/w), and oleic acid was suitable for encapsulation in soft gelatin capsules. The availability of I formulated as its hydrochloride salt in a standard hard gelatin capsule formulation was significantly lower than that of I formulated in a soft gelatin capsule with oleic acid as the solvent. A 20% solution of I in oleic acid (soft gelatin capsules) maintained at 23 degrees provided 4% of the oleic acid ester of I iwithin 1 month. Further reaction, however, was not seen over 2 years.
Binding of the antimalarial alpha-dibutylaminomethyl-2,6-bis(trifluoromethylphenyl)-4-pyridinemethanol with human serum albumin was studied using difference spectroscopy, fluorescence quenching, and equilibrium dialysis. Results indicated that the number of high affinity binding sites of the drug on protein is 0.45, with the total number of binding sites being 3.3--4.0. The binding constants were in the range of 0.57--4.00 x 10(6) M-1. The drug was bound more strongly to a nonionic detergent than to either a cationic or anionic detergent. Interpretation of these data and fluorescence quenching results indicated that the drug is possibly bound to a hydrophobic site on human serum albumin.
1,9-Phenazine-bis(dialkylaminocarboxamides) were prepared for screening as potential antimalarials. No significant activity against Plasmodium berghei was observed. The phenazine targets were prepared from 1,9-phenazinedicarboxylic acid by standard methods. The reaction between 1,9-phenazinedicarboxylic acid and thionyl chloride in the presence of dimethylformamide unexpectedly gave 4-chloro-1,9-phenazinedicarbonyl chloride.
An assay was developed for determining mefloquine (quinolinemethanol) and pyridinemethanol derivative concentrations in whole blood. The method involved ion-pair extraction or usual solvent extraction for drug recovery from whole blood followed by trimethylsilylation. The silylated compounds were then submitted to GLC with electron-capture or flame-ionization detection. Mass spectrometry combined with GLC of the trimethylsilyl derivatives indicated that substitution of one trimethylsilyl group had occurred on the hydroxyl group. A phenyl methyl silicone column with temperature programming separated the drugs from normal blood extracts. The determination limit was 10 ng/ml of whole blood when an electron-capture detector was used with ion-pair extraction. Quantitation was achieved by using one antimalarial as an internal standard for the assay of the other. The utility of the present method was demonstrated by following the whole blood level time course after a single oral 250-mg tablet in beagle dogs.
Plastic ion-selective electrode analysis of the hydrophobic amine antimalarial mefloquine in blood samples was investigated. The direct electrode response in plasma samples provided poor drug sensitivity due to high mefloquine protein binding. The drug was analyzed in whole blood by initial extraction into ether as its trichloroacetate ion-pair. Mefloquine was monitored in whole blood extracts with the electrode to moderately low levels (to 0.4 microgram/ml). Rapid blood mefloquine level monitoring by this electrode was demonstrated in a bioavailability study. Mefloquine alkylation with various alkyl halides produced derivatives detectable by the electrode at much lower levels (up to two orders of magnitude) than the parent. A kinetic study of this alkylation reaction revealed that an alkyl amine base was necessary to scavenge the acid produced during reaction and to allow the reaction to go to completion. At room temperature, with benzyl bromide as the reagent, reaction was 99% complete in 30 min and mefloquine could be detected to approximately to 10(-8) M, a 100-fold improvement in sensitivity over electrode monitoring of underivatized mefloquine.
beta-Arteether (1) is a new antimalarial drug derived from artemisinin (2, quinghaosu). Compound 1 is quite water insoluble, but very soluble in a variety of organic solvents. Solubilization in a variety of surfactants was investigated to obtain higher concentrations of 1 in aqueous solutions. Anionic and cationic surfactants exhibited dramatic solubilizing ability for 1, while nonionic surfactants showed significantly lower solubilizing ability. The solubilization data are analyzed on the basis of a pseudo-phase model with 1 exhibiting a high partition coefficient into the micellar phase. An empirical model is presented to identify the possible sites of solubilization of 1 in the micelle.
The interactions between the antimalarial drugs chloroquine (CQ) and amodiaquine (AQ), chloroquine and quinine (QN), and amodiaquine and quinine are studied by (13)C NMR. Experimental changes in chemical shift are compared to nucleus-independent chemical shifts to determine the best structure of the complex formed by each drug pair in solution. Structures of the CQ-AQ and CQ-QN complexes are found to be similar to those found previously for the drug dimers. On the other hand, the best solution structure for the AQ-QN complex suggests that the quinoline rings of the two drugs are at an angle with respect to each other.
Oxygen consumption in mouse erythrocytes infected with Plasmodium berghei has been followed by electron spin resonance (ESR) spectroscopy of nitroxide radical spin probes. The parasitized red cell suspension is mixed with the spin probe CTPO (3-carbamoyl-2,2,5,5-tetramethyl-3-pyrrolin-1-yloxy) in a closed chamber. Oxygen consumption is monitored by the increasing resolution of the superhyperfine splittings of the spin label. The antimalarial drugs quinacrine, primaquine, and quinine are shown to decrease the rate of oxygen consumption of the parasitized erythrocyte suspensions. The spin-label method offers advantages over conventional polarographic and spectrophotometric assays for highly parasitized cell populations where cells are fragile and contain oxidized hemoglobin as well as hemoglobin-derived pigments.
Four groups of Amaryllidaceae alkaloids, namely lycorine-, crinine-, tazettine-, and galanthamine-type, as well as plant extracts of the Amaryllidaceae plants (Pancratium maritimum, Leucojum aestivum, and Narcissus tazetta ssp. tazetta) growing in Turkey were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth by a high-throughput screening method with a 96-well microtiter plate. All four groups of alkaloids exhibited antimalarial activity at different potencies. 6-Hydroxyhaemanthamine, haemanthamine and lycorine were found to be the most potent alkaloids against P. falciparum (T9.96) and galanthamine and tazettine had the least potent activity against P. falciparum (K1).
Compounds isolated from Solanum nudum have shown in vitro antimalarial activity against the FCB-2 strain of Plasmodium falciparum. Diosgenone (C27H40O3) the main component isolated from the hexane extract and an aqueous extract were evaluated to measure their clastogenic potential using the micronucleus test. Three concentrations (16, 32 and 64 g/kg of weight) of the aqueous extract were administered intraperitoneally into mice, (the highest concentration corresponded to 80% LD50) and diosgenone solubilized in olive oil was inoculated at the highest concentration possible (11.187 g/kg of weight). After administration of the compounds, no induction of micronucleus was observed either in polychromatic or normochromatic erythrocytes. Interestingly, a reduction of 51% in the young/mature erythrocytes ratio was seen in cells treated with aqueous extract. We conclude that neither diosgenone nor the aqueous extract have clastogenic activity, and that the aqueous extract showed some toxicity at the above mentioned concentrations. These results are significant since diosgenone could be a new therapeutic alternative for the treatment of malaria.
The ionophore properties of cationomycin and monensin were studied on human erythrocytes by measuring Na+ influx by 23Na NMR and concomitant K+ efflux by potentiometry in the presence of increasing amounts of serum. Both ion currents (Na+ or K+) decreased linearly with the reciprocal of serum amount. The serum effects on ion currents were stronger with cationomycin than with monensin. Assuming this decreased transport activity was due to drug binding to serum proteins, a partition coefficient between the protein and the membrane phase was determined for each ionophore by using a novel model. This partition coefficient is about 30 times higher for cationomycin than for monensin; the same result was obtained with purified human serum albumin, indicating that albumin may be the major ionophore binding protein of serum. In parallel, we also measured IC50 for 50% in vitro growth inhibition of Plasmodium falciparum, the agent of malaria. In the presence of increasing serum concentrations, the antimalarial activity was decreased for both ionophores. Serum effect was less severe for monensin than for cationomycin, in agreement with the weaker interaction of monensin with proteins as shown from the partition coefficient values. A correlation was established between the ion transport currents (sodium and potassium) and the IC50 measured on P. falciparum in the presence of the various concentrations of serum. The relative value of the ion transport currents (expressed as percentage of control in absence of serum) can be indicative of the ionophore unbound fraction in the medium.
Dihydroorotate dehydrogenase (DHOD) is a key enzyme in de novo pyrimidine biosynthesis and the major source of electrons for the mitochondrial electron transport chain of intraerythrocytic malaria parasites. DHOD and the electron transport chain may also be the site of inhibition by certain antimalarial drugs. In order to test this, Plasmodium falciparum-infected erythrocytes were exposed in vitro to artemisinin or various 8-aminoquinolines, such as primaquine, WR 238605, WR 225448, and WR 255956, and then assayed for both enzyme activity and [3H]hypoxanthine incorporation, which is an indicator of viability. Atovaquone inhibits DHOD activity to a much greater extent than hypoxanthine incorporation, which is consistent with previous reports that it targets the parasite respiratory chain. However, artemisinin and the 8-aminoquinolines inhibit DHOD to the same or lesser extent than hypoxanthine incorporation, suggesting that these compounds have different modes of action.
The spectrum of antimalarial activity of the new macrolide antibiotic azithromycin was evaluated against blood- and sporozoite-induced infections with a chloroquine-resistant strain of Plasmodium yoelii nigeriensis (N-67) in Swiss mice and with simian parasite Plasmodium cynomolgi B in rhesus monkeys. Against experimental rodent malaria, a 70 mg/kg/day dose showed curative blood-schizontocidal activity in a four-dose regimen administered orally from day 0 to day 3 or from day 2 to day 5 to mice harboring established infection. The curative response was also obtained with a 40 mg/kg/day dose administered in an extended seven-dose (days 0-6) regimen. Azithromycin was also effective in the causal prophylactic test, since a 50 mg/kg dose from day -1 to day +2 protected mice against P. y. nigeriensis (N-67) sporozoite challenge. In comparison, erythromycin did not show either of the above activities up to a 405 mg/kg/day dose in identical regimens. Comparison of the ED(90) values showed that azithromycin was 31-fold more effective than erythromycin as a blood schizontocide. In the simian model, trophozoite-induced infections of P. cynomolgi B were cured with 25 mg/kg/day azithromycin administered for 7 days. In the causal prophylactic test, the prepatent period was significantly extended in monkeys challenged with P. cynomolgi B sporozoites, presumably because of the growth inhibition of preerythrocytic schizonts in hepatocytes. Azithromycin did not exhibit any hypnozoitocidal (dormant exoerythrocytic stages) activity at 25 mg/kg/day in a seven-dose regimen.
Intraerythrocytic plasmodia form hemozoin as a detoxification product of hemoglobin-derived heme. An identical substance, beta-hematin (BH), can be obtained in vitro from hematin at acidic pH. Quinoline-antimalarials inhibit BH formation. Standardization of test conditions is essential for studying the interaction of compounds with this process and screening potential inhibitors. A spectrophotometric microassay of heme polymerization inhibitory activity (HPIA) (Basilico et al., Journal of Antimicrobial Chemotherapy 42, 55-60, 1998) previously reported was used to investigate the effect of pH and salt concentration on BH formation. The yield of BH formation decreased with pH. Moreover, under conditions used in the above HPIA assay (18 h, 37 degrees C, pH = 2.7), several salts including chloride and phosphate inhibited the process. Aminoquinoline drugs formulated as salts (chloroquine-phosphate, primaquine-diphosphate), but not chloroquine-base, also inhibited the reaction. Interference by salts was highest at low pH and decreased at higher pH (pH 4). Here, we describe different assay conditions that eliminate these problems (BHIA, beta-hematin inhibitory activity). By replacing hematin with hemin as the porphyrin and NaOH solution with DMSO as solvent, the formation of BH was independent of pH up to pH 5.1. No interference by salts was observed over the pH range 2.7-5.1. Dose-dependent inhibition of BH formation was obtained with chloroquine-base, chloroquine-phosphate, and chloroquine-sulfate at pH 5.1. Primaquine was not inhibitory. The final product, characterized by solubility in DMSO, consists of pure BH by FT-IR spectroscopy. The BHIA assay (hemin in DMSO, acetate buffer pH 5 +/- 0.1, 18 h at 37 degrees C) is designed to screen for those molecules forming pi-pi interactions with hematin and thus inhibiting beta-hematin formation.