Synthesis of 2-substituted primaquine analogues as potential antimalarials.

A series of 2-substituted primaquine analogues has been synthesized and evaluated against Plasmodium berghei in the mouse and Leishmania donovani in the hamster. Three members (3a,d,e) of the series were evaluated against Plasmodium cynomolgi in the rhesus monkey. One analogue (3d) was evaluated against Trypanosoma rhodesiense in the mouse, and two (3b,e) were evaluated against Schistosoma mansoni in the mouse. Several analogues possessed significant activity against P. berghei (3e,f) and L. donovani (3a,e).     

Synthesis of 2-benzyloxy and 2-benzylthio analogues of primaquine as potential antimalarials.

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.     

Synthesis of 4-alkyl and 4-(beta-alkylvinyl) derivatives of primaquine as potential antimalarials.

4(beta-Alkylvinyl)-6-methoxy-8-nitroquinolines (6) were prepared from 6-methoxy-8-nitroquinoline-4-carboxaldehyde (5) via a Wittig reaction. Stannous chloride reduction of 6 gave 4-(beta-alkylvinyl)-8-amino-6-methoxyquinolines (8), whereas catalytic reduction of 6 using Raney nickel catalyst gave 4-alkyl-8-amino-6-methoxyquinolines (7). Alkylation of 7 and 8 with 4-iodo-1-phthalimidopentane, followed by removal of the phthaloyl-protecting group with hydrazine, gave 4-alkyl and 4-(beta-alkylvinyl) derivatives of primiquine, respectively. These compounds were evaluated for antimalarial activity against P. berghei and P. berghei yoelii in mice and against P. cynomolgi in rhesus monkeys. Several of the compounds were active in the P. bergheii yoelii screen. None of the compounds showed significant activity in the other two screens.     

Modifications of primaquine as antimalarials. 4. 5-Alkoxy derivatives of primaquine

Thirty-two 5-alkoxyprimaquines have been synthesized and evaluated as blood schizonticides (Plasmodium berghei, mouse) and tissue schizonticides (Plasmodium cynomolgi, monkey). Several of these compounds were extremely active in both screens. Such a broad spectrum of antimalarial efficacy offers the possibility of a single drug that could cure the various relapsing and nonrelapsing malarias.     

Antimalarials. 10. Synthesis of 4-substituted primaquine analogues as candidate antimalarials.

Primaquine (I) has been extensively used in combination with other drugs in the radical cure of relapsing malaria as well as for prophylaxis or the interruption of transmission. This, coupled with the activity data reported for 4-methylprimaquine (II), has led to the synthesis of a series of 14 4-substituted analogues of I. In addition, three side-chain analogues of II were prepared. The compounds were tested for suppressive antimalarial activity against Plasmodium berghei in the Rane mouse screen and for radical curative activity against Plasmodium cynomolgi in the rhesus monkey. Four of the 17 compounds prepared (1a, 9c, 15, and 17) exhibited activity in at least one of the test systems.     

Modifications of primaquine as antimalarials. 1. 5-Phenoxy derivatives of primaquine.

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.     

Imidazolidin-4-one derivatives of primaquine as novel transmission-blocking antimalarials

Imidazolidin-4-one derivatives of primaquine were synthesized as potential double prodrugs of the parent drug. The title compounds inhibit the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The imidazolidin-4-ones are very stable, both in human plasma and in pH 7.4 buffer, indicating that they are active per se. Thus, imidazolidin-4-ones derived from 8-aminoquinolines represent a new entry in antimalarial structure-activity relationships.     

Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials

A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.     

Amine peroxides as potential antimalarials

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.     

Interactions among primaquine, malaria infection and other antimalarials in Thai subjects.

1. The pharmacokinetics of rac-primaquine (45 mg base) and its principal plasma metabolite, carboxyprimaquine have been investigated in healthy Thai adults prior to and following a single oral dose of mefloquine (10 mg kg-1). 2. Primaquine was rapidly absorbed, attaining peak plasma concentrations (median and range) of 167 (113-532) micrograms l-1 in 2 (1-4) h. Thereafter, concentrations declined rapidly with an apparent terminal half-life of 6.1 (1.7-16.1) h and an oral clearance (CLpo) of 33.1 (17.6-49.3) l h-1. Administration of mefloquine had no effect on the values of any of these parameters at the 5% level of significance [Cmax 229 (114-503) micrograms l-1; tmax 3 (2-4) h; t1/2,z 3.9 (1.7-13.5) h; CLpo 34.0 (21.7-49.0) l h-1]. 3. The carboxylic acid metabolite of primaquine achieved maximum concentrations (median and range) of 890 (553-3634) micrograms l-1 at 6 (3-16) h. Thereafter, plasma concentrations of carboxyprimaquine declined to 346 (99-918) micrograms l-1 at 24 h. AUC (0,24 h) was 12737 (6837-27388) micrograms l-1 h. Administration of mefloquine had no effect on the plasma concentrations of this metabolite [Cmax 1035 (174-3015) micrograms l-1; tmax 8 (2-24) h; AUC(0,24) 13471 (2132-17863) micrograms l-1 h]. 4. The effect of falciparum malaria and treatment with quinine (10 mg salt kg-1 p.o.) on the pharmacokinetics of primaquine (45 mg base p.o.) has been investigated in adult Thai patients during and after infection with falciparum malaria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis of primaquine glyco‐conjugates as potential tissue schizontocidal antimalarial agents

Primaquine ( PQ ) is the only drug used to prevent relapse of malaria due to P. vivax and P. ovale, by eradicating the dormant liver form of the parasite (hypnozoites). The side‐effects associated with PQ limits is uses in treatment of malaria. To overcome the premature oxidative deamination and to increase the life span of drug in the biological system, the novel glyco‐conjugates of PQ were synthesized by coupling of primaquine with hexoses in phosphate buffer. The saccharide part of the hybrid molecules thought to direct the drug to the liver, where hypnozoites resides. All the synthesized compounds were fully characterized and evaluated for their radical curative activities. The three compounds viz glucoside ( 15a ), galactoside ( 15b ) and mannoside ( 15c ) with high activity were tested for their activity in rhesus monkeys where the most active compound 15b showed twofold activity (100% radical curative activity at 1.92 mmol/kg) than the standard drug PQ diphosphate (3.861 mmol/kg). It is proposed that results from these studies may be advantageous to develop a new potent tissue schizonticide antimalarial compound.     

Synthesis of some 4-substituted 8-amino-6-methoxyquinolines as potential antimalarials.

The 4-vinyl, 4-ethyl, and three 4-[beta-(arylthio)ethyl] derivatives of primaquine and other 8-aminoquinoline antimalarial agents were prepared for antimalarial evaluation. 8-[(4'-Amino-1'-methylbutyl)amino]-4-ethyl-6-methoxyquinoline (4-ethylprimaquine), which showed activity approximately equal to that of primaquine against Plasmodia cynomolgi in Rhesus monkey, was the most active of the compounds tested. 4-Ethylprimaquine was also less toxic than primaquine, as measured in the Rane mouse screen.     

Synthesis of sparsomycin analogs as potential antitumor agents.

No information is available on the structural requirements for the antitumor activity of sparsomycin, an antibiotic obtained from the fermentation broth of Streptomyces sparsogenes. Its high in vivo and in vitro activity, novel structure, and uncommon mode of action have, therefore, suggested the synthesis of analogs. This report describes the preparation and screening of a series of N-substituted 3-aryl acrylamides which are closely related to sparsomycin. Three compounds exhibited some tumor inhibition but insufficient to warrant further testing.     

Dipeptides of O-methyl-L-threonine as potential antimalarials.

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.     

Synthesis and biological evaluation of potential hypoglycemic agents I: Carnitine analogs.

A series of 4-dialkylamino-3-hydroxybutyric acid hydrochlorides and methochlorides, analogs of carnitine, was synthesized by treatment of tert-butyl 3,4-epoxybutyrate with the appropriate amine or amine hydrochloride in methanol followed by mild acid hydrolysis. The compounds had no effect on blood glucose or serum fatty acid levels in rats.     

Synthesis of antineoplaston A10 analogs as potential antitumor agents

Several aniline mustard analogues were obtained by introducingN,N-bis(2-chloroethyl)amino moiety to phenyl ring of A10 analogues in order to increase reactivity of A10 analogs and selectivity into DNA. Thein vitro antitumor activity of synthesized compounds was evaluated using five different solid tumor cell lines by SRB method. Aniline mustard analogues exhibited more potent antitumor activity than A10 analogs. Especially,m-aniline mustard of benzoyl analogue displayed remarkable antitumor activity.     

Synthesis of pyrimido[5,4-c]quinolines and related quinolines as potential antimalarials.

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.     

Antimalarials. 11. Synthesis of 3- and 5-aminoquinolines as potential antimalarials.

A series of 3-quinolinediamines (1g, 2c, and 3e) structurally related to primaquine and 4-methylprimaquine have been prepared and tested for antimalarial activity against Plasmodium berghei in mice and antileishmanial activity against Leishmania donovani in the hamster. All were inactive. In addition, three 5-quinolinediamines (4b, 5, and 6) were prepared. All were inactive against Leishmania donovani in hamsters. One of the examples, 6, was curative against Plasmodium cynmolgi in the rhesus monkey.