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At least 19 recordsLinked to original sources
PubMed1982

[Antimalarial 6-aminoquinolines XV. 6- and 4-aminoquinolines with a tertiary basic alkylated amino group].

Antimalarial 6-aminoquinolines (1a-c) were acylated (3a-c, 5a) and alkylated (4a-c, 6a) at the secondary aromatic 6-amino group with the aim of studying the influence of a tertiary aromatic 6-amino group on antimalarial activity and toxicity. 4 derivatives (9e-g) of 4-amino-7-chloroquinoline with a tertiary aromatic 4-amino group were synthesized to study the influence of such a variation on the biological activity of the 4-aminoquinolines. The N-alkylated derivatives 4a-c, 6a, 9f-g were active against malaria (P. vinckei/mice).

Aminoquinolines↗
PubMed2001

Comparative clinical characteristics and responses to oral 4-aminoquinoline therapy of malarious children who did and did not develop 4-aminoquinoline-induced pruritus.

The clinical characteristics and the responses to oral 4-aminoquinoline therapy of 150 malarious children presenting consecutively were investigated in an endemic area. At presentation, the 75 children who subsequently developed pruritus were significantly older and had significantly higher body temperatures than the 75 children who did not develop pruritus. There were no other significant differences in clinical presentation between the two groups. In children with pruritus, there was no correlation between age, weight, presenting body temperature, duration of illness or presenting peripheral parasite density and duration of pruritus. Responses to oral antimalarial drugs were similar in both groups. There was no correlation between indices of therapeutic response and the duration of pruritus. Analysis of the disposition kinetics of parasitaemia and of the hepatomegaly associated with malaria, using a non-compartmental model similar to that used in characterizing drug disposition, showed that the two groups had similar half-lives of parasitaemia (t(1/2 pd)), volumes of blood completely cleared of parasites per unit time (CL(Bpd)) and ratios of parasite-clearance time to t(1/2 pd), and similar values for the corresponding parameters derived from hepatomegaly resolution. There was no apparent relationship between the indices of parasite- or hepatomegaly-disposition kinetics and the duration of pruritus.

Acute Disease↗
PubMed1962

Mass administration of an antimalarial drug combining 4-aminoquinoline and 8-aminoquinoline in Tanganyika.

For the eradication of malaria from hyperendemic regions of tropical Africa it is apparent that use may have to be made of antimalarial drugs, administered individually on a census basis, in addition to measures directed against the mosquito. The suppressive activity of existing compounds among individuals having different degrees of immunity is well established, and trials among large groups of people have been conducted with single drugs and with combination of drugs. In the large-scale trials carried out in Tanganyika and described in this paper, such a combination, containing amodiaquine for schizontocidal effect and primaquine as a gametocytocide, was administered to three distinct population groups of more than 5000 at differing intervals of time, in order to determine the ability of this combination to interfere with transmission in the absence of other malaria control measures. It was found that treatment of 93% of the population at intervals of one or two weeks resulted in a reduction of the malaria indices to a very low level but such success was not obtained when the combination of drugs was administered every four weeks, although in the area concerned population coverage was less satisfactory owing to migration.

Africa↗
PubMed2005

Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands.

The Src homology 3 (SH3) domains are small protein-protein interaction domains that mediate a range of important biological processes and are considered valuable targets for the development of therapeutic agents. We have been developing 2-aminoquinolines as ligands for SH3 domains--so far the only reported examples of entirely small-molecule ligands for the SH3 domains. The highest affinity 2-aminoquinolines so far identified are 6-substituted compounds. In this article, the synthesis of several new 2-aminoquinolines, including 5-, 6- and 7-substituted compounds, for Tec SH3 domain ligand binding studies is presented. As a part of the synthetic investigation, the utility of different methods for the synthesis of 2-aminoquinolines was explored and potentially powerful methods were identified for the synthesis of 2-aminoquinolines with diverse functionality. Of the compounds prepared, the 5-substituted-2-aminoquinolines generally bound with similar affinities to unsubstituted 2-aminoquinoline, whilst the 7-substituted compounds generally bound with similar or lower affinity than unsubstituted 2-aminoquinoline. However, the 6-substituted-2-aminoquinolines generally bound with significantly higher affinity than unsubstituted 2-aminoquinoline. In addition, one 6-substituted-N-benzylated-2-aminoquinoline was also tested for SH3 binding and some evidence for the formation of additional contacts at other regions of the SH3 domain was found. These results provide new and useful SAR information that should greatly assist with the challenge of developing high affinity small-molecule ligands for the SH3 domains.

Aminoquinolines↗
PubMed2006

8-Aminoquinolines: future role as antiprotozoal drugs.

PURPOSE OF REVIEW: This review focuses on recent developments on evaluation of 8-aminoquinoline analogs with broader efficacy and reduced toxicity, which would provide better drugs for treatment of protozoal infections. RECENT FINDINGS: The earlier efforts towards development of 8-aminoquinoline analogs have been directed to extensive derivatization programs. This has led to discovery of tafenoquine for prophylaxis against malaria infections and sitamaquine with utility for treatment of visceral leishmaniasis. Bulaquine, a primaquine pro-drug, has shown reduced methemoglobin toxicity and better malaria-transmission-blocking activity than primaquine. Stereoselective pharmacologic and toxicologic characteristics of chiral 8-aminoquinolines provided the lead for enantiomeric separation of an 8-aminoquinoline analog NPC1161B, with greatly reduced toxicity and potent antimalarial action against blood as well as tissue stages of the parasite. NPC1161B has also shown promising use as an antileishmanial agent. Better understanding of the mechanisms of toxicity and efficacy may help in development of 8-aminoquinoline analogs with superior therapeutic actions, reduced toxicity and broader utility. SUMMARY: Extensive derivatization approaches followed by better understanding of structure-activity relationships and biotransformation mechanisms of toxicity have provided 8-aminoquinoline analogs with better pharmacologic and reduced toxicologic profiles. The novel 8-aminoquinoline analogs may have broader utility in public health as future antiprotozoals.

Aminoquinolines↗
PubMed1999

8-Aminoquinolines active against blood stage Plasmodium falciparum in vitro inhibit hematin polymerization.

From the Walter Reed Army Institute of Research (WRAIR) inventory, thirteen 8-aminoquinoline analogs of primaquine were selected for screening against a panel of seven Plasmodium falciparum clones and isolates. Six of the 13 8-aminoquinolines had average 50% inhibitory concentrations between 50 and 100 nM against these P. falciparum clones and were thus an order of magnitude more potent than primaquine. However, excluding chloroquine-resistant clones and isolates, these 8-aminoquinolines were all an order of magnitude less potent than chloroquine. None of the 8-aminoquinolines was cross resistant with either chloroquine or mefloquine. In contrast to the inactive primaquine prototype, 8 of the 13 8-aminoquinolines inhibited hematin polymerization more efficiently than did chloroquine. Although alkoxy or aryloxy substituents at position 5 uniquely endowed these 13 8-aminoquinolines with impressive schizontocidal activity, the structural specificity of inhibition of both parasite growth and hematin polymerization was low.

Animals↗
PubMed1993

Effects of 8-aminoquinolines on the ultrastructural morphology of Pneumocystis carinii.

Primaquine and other 8-aminoquinolines are effective against Pneumocystis carinii in culture and animal models but the way(s) in which they affect P. carinii are not known. This study used transmission electron microscopy to observe early effects of 8-aminoquinolines on P. carinii grown with human embryonic lung fibroblasts in microcarrier suspension culture. The 8-aminoquinolines evaluated were primaquine and Walter Reed Army Institute for Research (WR) compounds WR6026, WR238605 and WR242511. Samples of P. carinii were taken at 0, 3, 6, 12, 24 and 48 hours from culture flasks containing selected concentrations of the drugs. Time matched samples from a parallel culture without drug served as controls. All the 8-aminoquinolines produced similar morphologic alterations of the internal structure of P. carinii. Initially, dilatation of the nuclear envelopes and membranous arrays arising from the reticular system were observed. Later, more organisms displayed large arrays of smooth membranous material often presenting a concentric membranous pattern. Subsequently, cellular organization was lost resulting in necrosis. At concentrations tested WR242511 appeared to be the most effective, producing alterations in many trophozoites after 6 hours of exposure; WR6026 appeared to be the least effective with some organisms unaffected after 48 hours. The changes observed are consistent with damage to the reticular system of P. carinii, which might be caused by oxidation by the 8-aminoquinolines or their metabolites.

Aminoquinolines↗
PubMed1978

Gas chromatography mass spectrometry studies on biologically important 8-aminoquinoline derivatives.

Several substituted 8-aminoquinolines related to known antimalarial drugs have been studied by gas chromatography mass spectrometry. 5,6-Dihydroxy-8-aminoquinoline, a possible metabolite of Primaquine, can be detected by single ion monitoring after conversion to a trimethylsilyl ether derivative. The mass spectra obtained in this study indicate that there are certain ions which are characteristic of the trimethylsilyl ethers of hydroxylated 8-aminoquinolines and 5,6-dimethoxy-8-aminoquinolines. These compounds should thus be amenable to analysis if they were produced during in vivo metabolism studies. Using selected ion monitoring the derivatized compounds can be detected at submicrogram levels.

Aminoquinolines↗
PubMed2005

Synthesis of N-benzylated-2-aminoquinolines as ligands for the Tec SH3 domain.

In recent work, we have been developing 2-aminoquinolines as ligands for Src Homology 3 (SH3) domains, so far the only reported examples of small-molecule ligands for these domains. In this paper, we report the synthesis of a series of N-benzylated-2-aminoquinolines by reductive amination of aryl aldehydes with 2-aminoquinoline. These ligands bound the SH3 domain with ca. one and a half to twofold reduced affinity relative to 2-aminoquinoline; however, some evidence was found to suggest that the benzylic substituents made new contacts with the SH3 domain surface. These results provide useful SAR information that may assist in future ligand design.

Aminoquinolines↗
PubMed1997

Structural features of aminoquinolines necessary for antagonist activity against botulinum neurotoxin.

Certain aminoquinoline antimalarial compounds, such as chloroquine, antagonize the paralytic actions of botulinum neurotoxins (BoNT). These studies have been extended to determine the critical structural groups necessary for synthetic aminoquinolines to have antagonist activity against BoNT. Isolated mouse hemidiaphragms were maintained at 36 degrees C and indirectly stimulated; the resulting isometric twitch tensions were recorded as a measure of synaptic function. The muscles were exposed to the test compounds before being treated with a challenge concentration of BoNT (typically 0.2 nM of serotype A). The time to onset of 50% muscle paralysis due to BoNT was used to assess quantitatively the efficacy of the test compounds, which were then ranked on the basis of the concentrations necessary to delay paralysis by a specified time increment. Of the compounds tested, those having a 7-chloro-4-aminoquinoline configuration, similar to chloroquine (or the structurally similar 6-chloro-9-amino acridine group in quinacrine), were most effective. Truncation of the alkyl-amino-alkyl group from chloroquine and conversion of the 4-amino nitrogen to a primary amine did not significantly alter its effectiveness as a BoNT antagonist. However, the 6-chloro- or 8-chloro- isomers of chloroquine were essentially ineffective. These results suggest that aminoquinolines antagonize the paralytic actions of BoNT through interaction with a selective, stereospecific site that is not well correlated with antimalarial activity.

Aminoquinolines↗
PubMed2000

Structure-function relationships in aminoquinolines: effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity.

Comparison of 19 aminoquinolines supports the hypothesis that chloroquine and related antimalarials act by complexing ferriprotoporphyrin IX (Fe(III)PPIX), inhibiting its conversion to beta-hematin (hemozoin) and hence its detoxification. The study suggests that a basic amino side chain is also essential for antiplasmodial activity. 2- And 4-aminoquinolines are unique in their strong affinity for Fe(III)PPIX, and attachment of side chains to the amino group has relatively little influence on the strength of complex formation. Association with Fe(III)PPIX is necessary, but not sufficient, for inhibiting beta-hematin formation. Presence of a 7-chloro group in the 4-aminoquinoline ring is a requirement for beta-hematin inhibitory activity, and this is also unaffected by side chains attached to the amino group. In turn, beta-hematin inhibitory activity is necessary, but not sufficient, for antiplasmodial activity as the presence of an aminoalkyl group attached to the 4-amino-7-chloroquinoline template is essential for strong activity. We thus propose that the 4-aminoquinoline nucleus of chloroquine and related antimalarials is responsible for complexing Fe(III)PPIX, the 7-chloro group is required for inhibition of beta-hematin formation, and the basic amino side chain is required for drug accumulation in the food vacuole of the parasite.

Aminoquinolines↗
PubMed1994

Antimalarial 4-aminoquinolines: mode of action and pharmacokinetics.

In the last ten years, the widespread increase in Plasmodium falciparum resistance to chloroquine has prompted research into antimalarial 4-aminoquinolines, empirically used up to now. The mechanism of action of 4-aminoquinolines is characterized by the concentration of the drug in the digestive vacuole of the intraerythrocytic parasite. Various hypotheses have been advanced to explain the specificity of action on the parasite; the most recent one is the inhibition of the haem polymerase of the parasite, leading to the accumulation of soluble haem toxic for the parasite. Chloroquine-resistant parasites accumulate the drug to a lesser extent than do sensitive parasites. Recent findings have shown that chloroquine resistance can be reversed by various tricyclic drugs, which are able to restore the effective concentrations of chloroquine in the infected erythrocyte, but intrinsic mechanisms of action of these reversing agents are unknown. Four-aminoquinolines are extensively distributed in tissues and characterized by a long elimination half-life. Despite similarities in their chemical structures, these drugs show differences in their biotransformation and routes of elimination: chloroquine is partly metabolized into a monodesethylderivative and eliminated mainly by the kidney. In contrast, amodiaquine is a prodrug and amopyroquine is poorly metabolized; both drugs are excreted mainly in the bile. The understanding of the pharmacokinetics of 4-aminoquinolines has led to an improvement in empirically defined therapeutic regimens. Finally, the emergence of severe adverse-effects after prolonged prophylaxis with amodiaquine and the lack of cross resistance of Plasmodium falciparum between chloroquine and amopyroquine, have led to a proposal for the use of intramuscular amopyroquine as an alternative for the treatment of chloroquine-resistant malaria.

Aminoquinolines↗
PubMed1977

Activities of various 4-aminoquinolines against infections with chloroquine-resistant strains of Plasmodium falciparum.

The studies reported here stemmed from a personal report by Geiman on the capacity of the 4-aminoquinoline amodiaquin to inhibit in vitro maturation of ring stages of the chloroquine-resistant Monterey strain of Plasmodium falciparum. This observation, confirmed in owl monkeys infected with this strain, led to a comparison of the activities of chloroquine, amodiaquin, amopyroquin, and dichlorquinazine (12,278 RP) against infections with various chloroquine-susceptible and chloroquine-resistant strains. The results showed that: (i) these 4-aminoquinolines were essentially equally active against infections with chloroquine-susceptible strains and (ii) the activities of amodiaquin, amopyroquin, and dichlorquinazine were reduced significantly in the face of chloroquine resistance, but (iii) well-tolerated doses of these compounds would cure infections with strains that fully resisted treatment with maximally tolerated doses of chloroquine. Two other 4-aminoquinolines, SN-8137 and SN-9584, which also exhibited activity against chloroquine-resistant parasites in vitro, displayed curative activity in monkeys infected with a chloroquine-resistant strain. These observations show that there is cross-resistance among the 4-aminoquinolines, confirming earlier findings, but indicate that the dimensions of this phenomenon are sufficiently limited so that some derivatives are therapeutically effective against infections refractory to maximally tolerated doses of chloroquine.

Aminoquinolines↗
PubMed1983

Activity of 8-aminoquinolines against Leishmania tropica within human macrophages in vitro.

Antileishmanial activity of 8-aminoquinolines with substitutions on the quinoline ring or on the 8-amino side-chain was assessed in the Leishmania tropica-infected human macrophage in vitro model of leishmaniasis. The 4-methyl-5,6-dimethoxy compounds were more active than 6-methoxy compounds, which were approximately as active as 4-methyl-6-methoxy compounds. Certain 6-hydroxy compounds were the most active drugs tested. The precise composition of substituents on the 8-amino side-chain had little effect on activity. These investigations identify WR 226292 (a 4-methyl-5,6-dimethoxy compound) and WR 6881 and WR 49577 (6-hydroxy compounds) as the most active 8-aminoquinolines in this in vitro model. The 6-hydroxy compounds also can be considered to be the 6-demethyl derivatives of 6-methoxy-8-aminoquinolines. This study therefore indicates that 6-demethyl-8-aminoquinolines may be generally more active in vitro than the parent 6-methoxy structures against macrophage-contained Leishmania.

Aminoquinolines↗