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Seven analogues of monoterpenic fragment of aplasmomycin were synthesized as targeted antimalarial agents. The potency of the compound 6 was comparable with the sesquiterpene lactone artemisinin and the antibiotic aplasmomycin in vivo against Plasmodium berghei yoelli.
Six model amine peroxides (4-9) were synthesized as targeted antimalarial oxidants. They were approximately 1 order of magnitude more potent than tert-butyl hydroperoxide (3) in vitro against Plasmodium falciparum, but like 3, they were inactive in vivo against Plasmodium berghei.
N6-(Arylmethyl)-N6-methyl-2,4,6-pteridinetriamines (1-15) and related N6-substituted 2,4,6-pteridinetriamines (16-20) were obtained by the condensation of 6-chloro-2,4-pteridinediamine with N-methylarylmethanamine and other selected secondary amines. The requisite N-methylarylmethanamines (21-32) were prepared by the hydrogenation over Pt/C of the corresponding arylcarboxaldehyde in the presence of methanamine. Several of the N6-(arylmethyl)-N6-methyl-2,4,6-pteridinetriamines exhibited exceptional suppressive antimalarial activity against a drug-sensitive line of Plasmodium berghei in mice. N6-Methyl-N6-(1-naphthalenylmethyl)-2,4,6-pteridinetriamine (9), the most active of these compounds, was also shown to be curative at 3.16 mg/kg in a single oral dose against P. cynomolgi in the rhesus monkey. This compound was also shown to be effective against a chloroquine-resistant line of P. berghei in the mouse but showed cross-resistance to a pyrimethamine-resistant strain. Most of the 2,4,6-pteridinetriamines showed strong antibacterial action against Streptococcus faecalis and Staphylococcus aureus.
A series of 6-(arylthio)-2,4-pteridinediamines (IIIa) was prepared by allowing 6-chloro-2,4-pteridinediamine to react with the requisite benzenethiols in dimethyl sulfone at 190-200 degrees C. Attempts at oxidation to the corresponding sulfoxide (IIIb) or sulfone (IIIc) were unsuccessful. The compounds exhibited a spectrum of antibacterial activity similar to, but below the potency of, the related quinazolinediamines and pteridinediamines. Unlike these related types, however, they were devoid of antimalarial activity when tested against a normal drug-sensitive strain of Plasmodium berghei in mice by the parenteral route.
alpha-(1-Piperidinylmethyl)-9-acridinemethanol (3), alpha-[(dibutylamino)ethyl]-9-acridanmethanol (4a), and alpha-[(dibutylamino)methyl]-2-phenanthridinemethanol (5) have been made and all are ineffective as antimalarials against Plasmodium berghei in mice. 9-Acridinyloxirane showed no significant mutagenicity for strains TA 98 or TA 100 of Salmonella typhimurium.
A series of 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl] [1,1'-biphenyl]-2-ols and N omega-oxides was prepared from the substituted 1-phenyl-2-propanones proceeding through the 5-nitro[1,1'-biphenyl]-2-ols, the corresponding amino, and acetamido derivatives to the N-[5-[(alkylamino)methyl]-6-hydroxy[1,1'-biphenyl]-3-yl]acetamides and final condensation with 4,7-dichloroquinoline or the N-oxide. In a quantitative structure-activity relationship study first run on 28 and later expanded to 40 substituted phenyl analogues and their N omega-oxides, increasing antimalarial potency vs. Plasmodium berghei in mice was found to be correlated with decreasing size (sigma MR) and electron donation (sigma sigma) of the phenyl ring substituents. A significant correlation with N omega-oxidation could not be demonstrated. Initial high activity against P. berghei infections in mice led to expanded studies that demonstrated in addition excellent activity against resistant strains of parasite, activity in primate models, and pharmacokinetic properties apparently allowing protection against infection for extended periods of time even after oral administration. Such properties encourage the clinical trial of a member of this class in man.
L-Leucyl-O-methyl-L-threonine, O-methyl-L-threonyl-L-leucine, and O-methyl-L-threonyl-O-methyl-L-threonine were prepared and compared with O-methyl-L-threonine and L-leucine for antimalarial activity against Plasmodium berghei in mice. O-Methyl-L-threonine significantly prolonged survival time at doses of 160, 320, and 640 mg/kg. O-Methyl-L-threonyl-O-methyl-L-threonine was less active, significantly prolonging survival time only at 640 mg/kg. L-Leucine, as well as the other two dipeptides, exhibited no activity in this test.
The most effective antimalarial agents among the N4-monosubstituted 2-acetylpyridine thiosemicarbazones recently described by us have a cyclohexyl or a phenyl substituent and produce cures in Plasmodium berghei infected mice at a dose of 160 and 320 mg/kg, respectively. We report here on a related series of N4,N4-disubstituted 2-acetylpyridine thiosemicarbazones. Several members of this group bearing alkyl or cycloalkyl substituents at N4 show activity superior to the most active monosubstituted 2-acetylpyridine thiosemicarbazones. However, the greatest improvement in potency was seen when the N4-nitrogen atom was incorporated into a six- or seven-membered ring, such as the piperidine, piperazine, or azabicyclo[3.2.2]nonane systems, to give compounds with curative properties at a dose level as low as 20 mg/kg.
A number of 5-phenylthio and 5-anilino derivatives of primaquine have been prepared which are less toxic but less active than primaquine itself in murine and monkey antimalarial screens. It is apparent that the toxicity of primaquine can be diminished by introduction at position 5 of phenylthio, anilino, or phenoxy groups. However, the best hope for concomitant retention of high activity would seem to reside with the phenoxy moieties.
3-Ethylaminomethyl-2-methyl-4(1H)-quinolone (1a) and its 6-CH3, 6-OCH3, and 7-Cl derivatives were prepared by means of the Mannich reaction. Conversion to the 4-chloro derivatives and condensation with 3-chloroaniline gave the corresponding 4-(3-chloroanilino) derivatives. Cyclization of 4-(3-chloroanilino)-2,6-dimethyl-3-ethyl-aminomethylquinoline (3a) and its 6-OCH3 derivative with paraformaldehyde gave 1-(3-chlorophenyl)-3,9-dimethyl-3-ethyltetrahydropyrimido[5,4-c]quinoline (4a) and the 9-OCH3 derivative 4b. Treatment of 4b with benzaldehyde gave 1-(3-chlorophenyl)-3-ethyl-9-methoxy-5-styryltetrahydropyrimido[5,4-c]quinoline (5). 3-Benzylaminomethyl-6-methoxy-2-methyl-4(1H)-quinolone (1e) and 3,3'-(1,3-benzyliminodimethylene)di[2-methyl-4(1H)-quinolone] (6b) were also synthesized. The compounds were inactive as antimalarials.
Various 6-[[(aryl and aralkyl)amino]methyl]-2,4-pteridinediamines and their 8-oxides have been synthesized for antimalarial evaluation. Condensation of 3-amino-6-(bromomethyl)-2-pyrazinecarbonitrile 4-oxide (V) with the appropriately substituted amine afforded a series of 3-amino-6-[[(aryl and aralkyl)amino]methyl]-2-pyrazinecarbonitrile 4-oxides VI. Deoxygenation gave the corresponding pyrazines VII. Cyclization of VI and VII with guanidine then produced the desired 6-(aminomethyl)-2,4-pteridinediamine N-oxides VIII and teridinediamines IX, respectively. Formylation of 6-[[(3,4-dichlorophenyl)amino]methyl]-2,4-pteridinediamine gave N-[(2,4-diamino-6-pteridinyl)-methyl]-N-(3,4-dichlorophenyl)formamide. The N-oxides VIII did not exhibit significant activity against Plasmodium berghei infections in mice. Activity among the 2,4-pteridinediamines IX was generally poor with the exception of the 3,4,5-trimethoxyphenyl and 1-naphthalenyl analogues which showed strong suppressive activity at doses ranging from 80 to 640 mg/kg. Furthermore, several of the 2,4-pteridinediamines exhibited potent prophylactic activity against Plasmodium gallinaceum infections in the chick and also showed strong antibacterial action against Streptococcus faecalis and Staphylococcus aureus.
A series of substituted benzothiopyrans was synthesized and examined for antimalarial activity. Some were found to be active and curative at dose levels of 160--360 mg/kg against Plasmodium berghei in mice. Afew observations concerning structure-activity relationships were made. The benzothiopyrans were prepared by treatment of either the gem-dichloro- or the thionothioflavone intermediate with various primary amines. The thionothioflavone intermediates were made from thioflavones. Condensation of thiophenols with benzoyl acetates gave the thioflavones.
Various 5-phenoxy derivatives of primaquine have been prepared which are more active and less toxic than the parent compound in murine and monkey antimalarial screens. An improved method for the phthalimido alkylation of amines is described.
A series of 2-benzyloxy and 2-benzylthio analogues of primaquine has been synthesized and evaluated against Plasmodium berghei in the mouse and Plasmodium cynomolgi in the rhesus monkey. 8-Aminoquinoline toxicity, as measured in the Rane mouse screen, was reduced, and these compounds showed significant blood schizonticidal antimalarial activity in mice. In monkeys, significant tissue-schizonticidal activity was observed.
As an approach to the problem of the nature of the forces responsible for the stacking interactions between the aminoquinoline ring of the antimalarial chloroquine and the monomeric nucleotide bases, we have examined models in which the aromatic nucleus of the drug is linked to the nucleotide bases by a trimethylene chain. The degree of stacking of the models was determined in different conditions of solvent, pH, and temperature by hypochromism measurement in the UV. The results show that forces of the donor-acceptor type, due to the presence of a positive charge on the quinoline ring at neutral pH, do not bring an important contribution to the stacking interaction between the aminoquinoline and the nucleotide bases, while the influence of the solvent water is fundamental.
A striking difference in antimalarial activity between the diastereomers of 6-bromo-alpha-[2-(1-methylpiperidyl)]-9-phenanthrenemethanol, alpha-(3-peperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanol, and alpha-(3-piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol was observed. A possible explanation involving the N-O distance and active site binding requirements is suggested.
Nine alpha-dibutylaminomethylbenzo[h]quinoline-4-methanols were synthesized from the corresponding 1-amino-naphthalenes by the following sequence: 1-aminonaphthalene leads to 1H-benz[g]indole-2,3-dione leads to benzo[h]quinoline-4-carboxylic acid leads to acid chloride leads to bromomethyl ketone leads to epoxide leads to benzo[h]quinoline-4-methanol. Several acid chlorides substituted in the 3 position reacted incompletely with ethereal diazomethane but were efficiently converted, without isolation of the intermediates, to the bromomethyl ketones by reaction with ethoxymagnesium diethylmalonate, bromination, hydrolysis, and decarboxylation. Several compounds prepared, especially alpha-dibutylaminomethyl-2-(2',4'-dimethylphenyl)-3-methyl-6-chlorobenzo[h]quinoline-4-methanol, showed significant antimalarial activity against Plasmodium berghei in infected mice but were moderately phototoxic.
Nine di- and trisubstituted 9-phenanthrenemethanols bearing methylthio and methylfulfonyl substituents in the 2 and/or 6 positions of the phenanthrene nucleus were prepared and screened for antimalarial activity against Plasmodium berghei in mice. Six of the nine compounds were curative at or below 160 mg/kg. The most active structures contained a methylthio substituent in combination with two chlorine atoms.