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Ten 2- or 4-amino derivatives 10b-I of 6-(4-diethylamino-1-methylbutylamino)-5,8-dimethoxyquinoline were synthesised with the aim of studying the influence of these substituents on antimalarial activity and toxicity of the 6-aminoquinolines. The 4-dialkylamino derivatives 10c-h were less active against P. vinckei (mouse) than 4-alkoxy derivatives. The 4-amino derivative 10b was inactive.
Spirogermanium, a new investigational drug of novel structure currently under clinical studies in various neoplastic diseases, has revealed significant in vitro activity against chloroquine-resistant (FCB, FTA, FVO) and sensitive (FSL, FUI, FH) strains of Plasmodium falciparum. Inhibition of the growth and maturation of parasites after 36-h exposures to Spirogermanium started at concentrations ranging from 2.48 to 9.9 nM/ml. These concentrations appear to be within the range of Spirogermanium plasma levels reported in clinical studies with this drug. Since its clinical toxicities are unusually low in comparison with other anticancer drugs, our results on its in vitro activity against Plasmodium falciparum indicate Spirogermanium is an antimalarial drug of entirely novel structure, active in resistant strains.
Antimalarial activities of chloroquine, mefloquine, amodiaquine, and quinine in vitro against Plasmodium falciparum were diminished as a consequence of membrane filtration. Filtered drug solutions gave ID(50) values up to 25-fold greater than those of non-filtered (ethanol-sterilized) drug solutions. Loss of activity by filtration was overcome by increasing the drug concentration prior to filtration. Water solutions filtered through Millex-GS filter units consistently showed an absorbance maximum at 277 nm, accompanied by a lesser peak at 225 nm. Water filtrates from Nucleopore and Millex-GV filters showed no absorbance at 277 nm and only slight absorbance was evident for the Gelman filter unit. Activity losses were attributed to extractable contaminating moieties in the membrane filters and/or drug binding to the membrane filters.
In view of the antimalarial properties observed for many 2-acetylpyridine thiosemicarbazones, a series of N4,N4-disubstituted thiosemicarbazones derived from 2-propionyl-, 2-butyryl-, and 2-(2-methylpropionyl)pyridine was prepared for evaluation against the malaria parasite, Plasmodium berghei, in the mouse. The thiosemicarbazones were made by the reaction of methyl hydrazinecarbodithioate with a 2-acylpyridine to give the intermediate methyl 3-[1-2-pyridinyl)alkylidene]hydrazinecarbodithioates. Reaction of the latter with 3-azabicyclo[3.2.2]nonane, 1-(2-pyridinyl)piperazine, or 1H-hexahydroazepine gave the requisite thiosemicarbazones. The three thiosemicarbazones derived from 3-azabicyclo[3.2.2]nonane were most effective, the greatest potency being exhibited by 3-azabicyclo-[3.2.2]nonane-3-thiocarboxylic acid 2-[1-(2-pyridinyl)butylidene]hydrazide (4) which cured 4/5 mice at a dose of 160 mg/kg. In contrast to the related thiosemicarbazones derived from 2-acetylpyridine, virtually no toxic effects were observed in the series described here.
The spread of multiresistant strains of Plasmodium falciparum in south-east Asia and South America and the appearance of chloroquine resistance in Africa indicates the urgent need for alternative drugs against these parasites. Mefloquine, a 4-quinoline methanol, is the only new drug that is currently at an advanced stage of development.Studies in animal models and in the clinic have shown that it is highly active as a blood schizontocide against strains that are resistant to many established antimalarials, e.g., chloroquine and pyrimethamine. It is not, however, effective as a causal prophylactic agent. Preclinical toxicological, teratological, and carcinogenicity studies do not indicate any major contraindications to its use.Intensive clinical studies have been carried out in Africa, North and South America, south-east Asia, and Europe. These studies have indicated that the compound is generally well tolerated, safe, and effective in the treatment of malaria, particularly infections with chloroquine-resistant parasites.In order to protect this new and promising drug against the development of resistance to it in endemic areas, it is important that its introduction should be accomplished in a rational and deliberate manner. Appropriate precautionary measures include the development of mefloquine combinations (a combination of mefloquine with pyrimethamine-sulfadoxine is presently under investigation), its use with primaquine as a gametocytocidal drug to prevent transmission, and its deployment primarily for treatment, being used for prophylaxis only in special risk groups.
The effect of several antimalarial drugs, commonly used for prophylaxis and therapy of human malaria, on polymorphonuclear leukocyte chemotaxis was studied. A modified, reversible Boyden chamber method was used. Various concentrations of each drug was mixed with neutrophils and incubated in the chambers for 2 1/2 hours. After the incubation period percent inhibition of chemotaxis was determined. It was shown that chloroquine, quinine, proguanil, and tetracycline at concentrations frequently obtained in clinical situations significantly inhibited chemotaxis of neutrophils towards casein. There was a direct correlation between increasing drug concentration and percent inhibition of chemotaxis. Drugs such as pyrimethamine and fansidar at any concentration tested had no effect on chemotaxis.
3 derivatives 2g--i of 6-(4-diethylamino-1-methylbutylamino)-4-methoxy-2-methylquinoline and 6 derivatives 2k--p of 6-(4-diethylamino-1-methylbutylamino)-2,4-dimethylquinoline were synthesized with variations of substituents in positions 5 and 8 (--H, --OH, --OCH3, --CH3, --Cl) with the aim of studying the influence of these substituents, which facilitate, complicate or prevent oxidation to o- and (or) p-quinones, on antimalarial activity and toxicity. One methoxy group is necessary for activity against Plasmodium vinckei in position 5 or 8, no substituent that prevents oxidation is allowed in para position to this methoxy group.
Some of the most effective antimalarial agents are derivatives of 8-aminoquinoline. The metabolic products of many of these compounds appear to be toxic to the erythrocytes of certain human subjects, especially those deficient in glucose-6-phosphate dehydrogenase. Although a number of studies have been conducted over many years, the metabolism of most of these compounds has not been determined. These studies are reviewed.Adult dogs dosed with tritium-labelled primaquine were observed to excrete approximately 16% of the injected radioactivity in the urine within 8 hours. Organic extracts of the urine were fractionated by thin-layer chromatography and the metabolic pattern obtained. Some primaquine was excreted along with at least five metabolites including 5-hydroxy-6-methoxy-8-(4-amino-1-methylbutylamino)quinoline (5HPQ) and a small amount of 6-hydroxy-8-(4-amino-1-methylbutylamino)quinoline (6HPQ). The 5HPQ could form a quinoneimine-type compound which may be a methaemoglobin-forming compound. This and other metabolites isolated from urine were found to be active methaemoglobin formers in in vitro studies. In vitro metabolism of primaquine by mouse liver enzymes also produced compounds capable of methaemoglobin formation. One of these had a blue colour when exposed to alkaline conditions, air, and light, and mass spectral data and nuclear magnetic resonance analysis indicated a structure similar to a 5,6-dihydroxy derivative of primaquine. However, the chemical structure of the metabolite was not identified in these studies.
A discussion of the structure-activity relationships (SAR) of 8-aminoquinoline antimalarial drugs is presented. Consideration is given to the potential role of metabolic transformations in the in vivo activation of 8-aminoquinolines. It is emphasized that the mechanism of action of 8-aminoquinoline agents has not yet been established and thus any analysis of SAR must be speculative.
Over 700 causal prophylactic and radical curative antimalarial drugs have been discovered during the screening of approximately 4000 chemical compounds in rodent and simian malaria models. Causal prophylactic activity in the Plasmodium berghei-rodent model was demonstrated by 10 distinct groups of chemicals: 1) tetrahydrofolate dehydrogenase inhibitors, 2) naphthoquinones, 3) dihydroacridinediones, 4) tetrahydrofurans, 5) guanylhydrazones, 6) analogues of clopidol, 7) quinoline esters, 8) dibenzyltetrahydro-pyrimidines, 9) 6-aminoquinolines, 10) 8-aminoquinolines.Of the causal prophylactic compounds, only the 6- and 8-aminoquinolines were capable of curing persistent exoerythrocytic infections of P. cynomolgi in rhesus monkeys. The 6-aminoquinolines were substantially less active than primaquine.This report describes a series of 4-methyl-5-phenoxy-6-methoxy-8-aminoquinolines, which are potent blood schizontocides and radical curative drugs. The most active member of this series, 4-methyl-5-(3-trifluoromethylphenoxy)-6-methoxy-8-[(4-amino-1-methylbutyl)| amino]quinoline succinate (WR 225448), was 5 times more active than primaquine in curing persistent exoerythrocytic infections of P. cynomolgi in rhesus monkeys.As a blood schizontocide, WR 225448 was effective in animal models against P. berghei, P. cynomolgi, P. vivax, and both drug-sensitive and drug-resistant strains of P. falciparum. WR 225448 was also more toxic than primaquine in rats on subacute (28-day) administration.
13 analogues 3c-p of 6-(4-diethylamino-1-methylbutylamino)-5,8-dimethoxy-2-methylquinoline (2a) and 6-(4-diethylamino-1-methylbutylamino)-5,8-dimethoxy-2,4-dimethylquinoline (2b) were synthesized with variations of alkoxysubstituents (-O-n-C4H9, -O-n-C8H17, -O CH(CH3)2, -O(CH2)2OCH3, -O(CH2-CH2O)2CH3, -O(CH2)2N(C2H5)2) in positions 5 and(or) 8 with the aim of studying the influence on antimalarial activity and toxicity. All derivatives were active against P, vinckei (mouse).
Antimalarial therapy is directed more and more towards the use of associated substances: Pyrimethamine, sulfadoxime, quinine et chloroquine. The authors propose a method of direct determination of these four molecules mixed in biological fluids. The recommended extraction process followed by a spectrophotometric UV determination is fast, reproductible and sufficiently sensitive to study the evolution of a therapy.
The clinico-pathological findings in a 17-year-old girl with an "oeil de boeuf" maculopathy are reported together with the aetiological elements involved (hereditary or toxic maculopathy). The case was a second stage typical maculopathy due to antimalarial drugs. These patients were particularly susceptible, probably because of impaired renal function, since the total dose absorbed (140 g. chloroquine) was low. Ophthalmologic monitoring is required to prevent intoxication. Clinical examination, angiography and automatic perimetry and contrast sensitivity test are needed to detect the first effect of toxicity.
The widely used 8-aminoquinoline antimalarial group of compounds and the derivatives such as WR242511 that are being developed for possible prophylactic anticyanide applications have complex interactions with erythrocytes. Methemoglobin (MetHb) levels following the use of this drug predicted by earlier authors grossly deviated from the observed steady state levels under multiple-dose conditions. We propose a pharmacokinetic-pharmacodynamic model to characterize literature data for blood levels of MetHb generated after administration of WR242511. The model is based on an indirect mechanism involving WR242511 putative metabolite concentration, Cm on the formation of MetHb (rate constant, kr) and on depletion of reducing equivalents leading to accumulation of MetHb. Eventual depletion of MetHb is modeled as related to the disposition of both the drug metabolite and MetHb. The rate of change of MetHb concentration in the blood under the influence of a dose of WR242511 in dogs was governed by this relationship: d[MetHb]/d(t) = kr.Cm.[Hb]-kh.[MetHb], where kr is 2.9 x 10(-5) ml.ng-1.hr-1 and kh is 0.0418 hr-1. This model was validated with multiple-dose data. The model is simple and compatible with the physiological behavior of MetHb in vivo under single-dose and multiple-dose conditions of WR242511 administration.
The practices of health care workers and the population with regard to diagnosis of malaria and use of antimalarial drugs were studied in the city of Dakar from September 1991 to March 1992. Study included 847 heads of family, 191 treatment prescribers including 77 physicians, 53 nurses and 61 midwives, and 60 pharmacists. Three separate questionnaires were used: one for the population, one for physicians and paramedical staff, and one for pharmacists. The data collected showed that the 4 main symptoms used by both health care workers and the general population for diagnosis of malaria were fever, chills, vomiting, and headache. Treatment was administered upon suspicion of infection by 72% of treatment prescribers. Chloroquine was the drug most widely used by prescribers and for self-treatment of malaria. Prophylactic drug treatment was practised by all groups studied except treatment prescribers but was unappropriate for the target groups. Chloroquine is the drug most widely used to protect against the disease. Pharmacists have adequate supplies but distribution is poor. Despite promising results in the fight against malaria, further effort is needed to train health care workers and provide information to the population.
With the purpose of obtaining salts of sulfonamides with low toxicity but prolonged action, embonates of seven known sulfonamides, with antimalarila activity, were prepared by double exchange reaction between embonic acid and the antimalarial agents. Six of the seven embonates prepared showed activity against Plasmodium berghei in experimentally infected mice, one of them being significantly more active than the original sulfonamide (sulfadimethoxine).
The drugs commonly used in the treatment of malaria are photochemically unstable. Several of these compounds cause dermal and ocular toxic reactions that may be light induced. The in vitro photopolymerization of calf lens proteins in the presence of antimalarial drugs was studied as part of a screening of the photochemical properties and phototoxic capabilities of these compounds. The pseudo-first-order rate constant for the reaction was calculated, and related to the amount of light absorbed by the compounds in order to determine the relative photosensitizing effect of each drug. The reaction mechanisms were evaluated by adding a variety of quenchers to the reaction medium during irradiation. Based on the results obtained in this study and previous knowledge about the pharmacokinetic behavior of these compounds, several of the drugs investigated have to be considered as potential photosensitizers in the human lens, the retina and the skin.
The discovery of the natural peroxides qinghaosu (arteannuin A, artemisinin) (1) and yingzhaosu A (3) from traditional Chinese herbal medicines was a major advance in the search for new antimalarials (Fig. 1). Whereas qinghaosu can be produced from natural sources and has been well studied, yingzhaosu A has never been available for full evaluation as anti-malarial. We have designed a synthesis of the novel ring system present in yingzhaosu A, the 2,3-dioxabicyclo[3.3.1]nonane and prepared a series of yingzhaosu A analogues which were tested against Plasmodium berghei in mice. Structure-activity rules could be established and used for lead optimization. The best anti-malarial activity was observed for analogues having a keto group within the ring system and an aliphatic or aromatic lipophilic tail as ring substituent. The optimized analogues possessed activity comparable to qinghaosu. In spite of the presence of a peroxide ring, the new compounds were chemically stable against common reagents. In contrast to qinghaosu and its derivatives, they were also stable against hydrolytic decomposition and could therefore be expected to show improved pharmacokinetic properties. As one of the best compounds, Ro 42-1611 (arteflene) (26n, Fig. 2) was selected for detailed preclinical evaluation. Ro 42-1611 (arteflene) was found negative in a battery of mutagenicity tests. It had low acute toxicity after oral or subcutaneous administration. In a 4-week oral tolerance study in rats, doses of up to 400 mg/kg/day were well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)