enpiroline and halofantrine

Specific calculated molecular electronic properties of structurally diverse synthetic aromatic carbinolamines containing phenanthrene, quinoline, and N-substituted biphenyl rings are associated with antimalarial potency allowing use of these electronic features in the prediction of antimalarial efficacy, thus aiding the design of new antimalarial agents. These electronic features include the magnitude and location of 3-dimensional molecular electrostatic potentials, lowest unoccupied molecular orbitals, and highest occupied molecular orbitals. Stereoelectronic properties were calculated using quantum chemical AM1 methods on the optimized geometry of the lowest energy or most populated conformer in both gaseous and aqueous environments. In the phenanthrene carbinolamines, the aliphatic nitrogen atom and the hydroxyl proton are intrinsically more nucleophilic and less electrophilic, respectively, than in the non-phenanthrene compounds. Hydrogen bonding ability and the electrophilic nature of the aromatic ring appear to be two important features responsible for interaction with receptor molecules.

Topics: Antimalarials; Mefloquine; Models, Molecular; Molecular Conformation; Phenanthrenes; Pyridines; Quinolines; Static Electricity; Structure-Activity Relationship

The (+)-isomers of mefloquine and its threo analog are 1.69 to 1.95 times more active than the (-)-isomers against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum in vitro. This large a differential between the activity of (+)- and (-)-isomers was not observed for other synthetic amino alcohol antimalarial agents containing a piperidine ring. The enantiomers of amino alcohol antimalarial agents in which the amine is part of an acyclic group, such as in halofantrine, displayed little, if any, differential antimalarial activity. Thus, the effect of absolute stereochemistry of the amino alcohol antimalarial agents on antimalarial activity appears to depend upon both the flexibility of the amine portion of the molecule and the structure of the aromatic portion of the molecule.

Topics: Animals; Antimalarials; Chloroquine; Drug Resistance; Mefloquine; Phenanthrenes; Plasmodium falciparum; Pyridines; Quinolines; Stereoisomerism; Structure-Activity Relationship

The in vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline was compared against chloroquine-resistant and -susceptible strains of Plasmodium falciparum using a semi-micro drug susceptibility test. For each strain, the corresponding enantiomers exhibited similar activities. The enantiomers of halofantrine were the most active against both susceptible and resistant strains, followed by the enantiomers of mefloquine and enpiroline.

Topics: Animals; Antimalarials; Dose-Response Relationship, Drug; Mefloquine; Phenanthrenes; Plasmodium falciparum; Pyridines; Stereoisomerism

A series of isolates of Plasmodium falciparum from eastern Thailand was collected prior to and after treatment failure with mefloquine. Patterns of drug sensitivity to standard and new antimalarials were characterized by using an in vitro assay based on the inhibition of schizont maturation. In vitro levels of mefloquine sensitivity of isolates were correlated with clinical treatment failures. In vitro parasite resistance to mefloquine is defined as an inhibitory dose-50 value greater than 20 nM. For isolates collected prior to treatment, there was no significant difference in mefloquine sensitivity patterns between subsequent successes and failures, suggesting that mefloquine treatment failures could not be predicted based on in vitro sensitivity of pretreatment isolates. A series of paired isolates were collected both prior to treatment with mefloquine and after recrudescence. Recrudescent isolates showed significant decreases in sensitivity to mefloquine, WR 194965, enpiroline, and halofantrine; no significant changes in sensitivity to amodiaquine, qinghaosu, and pyrimethamine; and an increase in sensitivity to chloroquine.

Topics: Amodiaquine; Animals; Antimalarials; Artemisinins; Butylated Hydroxytoluene; Chloroquine; Drug Resistance; Drugs, Chinese Herbal; Mefloquine; Molecular Structure; Phenanthrenes; Plasmodium falciparum; Pyridines; Pyrimethamine; Quinine; Sesquiterpenes; Thailand

A genetically homogeneous population of Plasmodium falciparum prepared by a single erythrocyte micromanipulation technique was used to produce lines of P. falciparum resistant to mefloquine hydrochloride in vitro. Parasites were maintained in a culture medium containing gradually increased concentrations of mefloquine hydrochloride (CMP-mef) starting with 2 ng/ml. One of the mefloquine-resistant culture lines (W2-mef) was obtained after 96 weeks of continuous culture in CMP-mef, the last 4 weeks in medium containing 40 ng/ml of mefloquine hydrochloride. The W2-mef was four to six times more resistant to mefloquine than was the parent clone W2. Means of multiple determinations of 50% inhibitory concentrations (IC-50) of mefloquine hydrochloride against W2-mef and clone W2 were 20.39 +/- 5.08 ng/ml and 4.50 +/- 1.94 ng/ml, respectively.

Topics: Animals; Antimalarials; Butylated Hydroxytoluene; Chemical Phenomena; Chemistry; Culture Media; Drug Resistance; Isoenzymes; Mefloquine; Phenanthrenes; Plasmodium falciparum; Pyridines; Quinolines

An in vitro assay system has been developed to evaluate the susceptibility of field isolates of Plasmodium falciparum to standard and new antimalarials. The assay used drugs which were serially diluted in the field and determined effective drug concentrations by quantitating schizont maturation after a variable incubation period. Based on the ID50 values, a series of isolates from Yala in southern Thailand were shown to be resistant to chloroquine (187 nM) but only moderately resistant to amodiaquine (23.7 nM), a structurally related 4-aminoquinoline. Five aminocarbinols were evaluated. The parasites were resistant to quinine (219 nM), but comparatively much more susceptible to mefloquine (9.04 nM), halofantrine (1.23 nM), and enpiroline (6.23 nM). The isolates were also relatively sensitive to WR 194,965 (9.04 nM). Two dihydrofolate reductase inhibitors (WR 99,210 and pyrimethamine) were tested. The isolates were comparatively sensitive to a dihydrotriazine, WR 99,210 (2.85 nM). The in vitro values for pyrimethamine (1,870 nM) were higher than the values for the other drugs tested, but were less than values from other regions of Thailand. As compared to a survey conducted in this region four years previously, values for chloroquine, pyrimethamine, amodiaquine, and mefloquine have remained relatively unchanged. However, there was a greater than 20-fold rise in the susceptibility values for quinine, suggesting the introduction of quinine-resistant isolates from eastern Thailand into southern Thailand during this period.

Topics: Amodiaquine; Animals; Antimalarials; Butylated Hydroxytoluene; Chloroquine; Humans; Mefloquine; Parasitology; Phenanthrenes; Plasmodium falciparum; Pyridines; Pyrimethamine; Quinine; Quinolines; Thailand; Triazines

In a volunteer with infection induced by injection of the mefloquine-sensitive, multidrug-resistant Vietnam Smith isolate of P. falciparum, parasitemia recurred following treatment with the candidate antimalarial drug enpiroline. Parasitemia also recurred after subsequent treatment with mefloquine and again after retreatment with the same drug. All recurrences were at the RI level. Parasite drug sensitivities determined by a semi-automated isotope microdilution method after the second and third recurrences revealed a progressive decrease in sensitivity to all arylaminoalcohols tested (halofantrine, enpiroline, and mefloquine). Decreased sensitivity persisted after 30 days of isolate culture. The parallel changes in parasite sensitivity to the synthetic arylaminoalcohols argue for development of drugs which are chemically dissimilar.

Topics: Adult; Antimalarials; Chloroquine; Drug Resistance, Microbial; Humans; Malaria; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Pyridines; Quinine; Quinolines