mannich-bases and Malaria

Topics: Animals; Antimalarials; Disease Models, Animal; Malaria; Mannich Bases; Mice; Plasmodium berghei; Plasmodium falciparum

A novel series of pyrido[1,2- a]benzimidazoles bearing Mannich base side chains and their metabolites were synthesized and evaluated for in vitro antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation, and in vivo antimalarial efficacy in a mouse model. Oral administration of one of the derivatives at 4 × 50 mg/kg reduced parasitemia by 95% in Plasmodium berghei-infected mice, with a mean survival period of 16 days post-treatment. The in vivo efficacy of these derivatives is likely a consequence of their active metabolites, two of which showed potent in vitro antiplasmodium activity against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum ( P. falciparum) strains. Rapid metabolism was observed for all the analogues with <40% of parent compound remaining after 30 min of incubation in liver microsomes. RM trapping studies detected glutathione adducts only in derivatives bearing 4-aminophenol moiety, with fragmentation signatures showing that this conjugation occurred on the phenyl ring of the Mannich base side chain. As with amodiaquine (AQ), interchanging the positions of the 4-hydroxyl and Mannich base side group or substituting the 4-hydroxyl with fluorine appeared to block bioactivation of the AQ-like derivatives though at the expense of antiplasmodium activity, which was significantly lowered.

Topics: Animals; Antimalarials; Benzimidazoles; Drug Evaluation, Preclinical; Humans; Malaria; Male; Mannich Bases; Mice; Mice, Inbred BALB C; Plasmodium berghei; Plasmodium falciparum; Structure-Activity Relationship

Topics: Administration, Oral; Amodiaquine; Animals; Antimalarials; Hemeproteins; Hemin; Humans; Malaria; Mannich Bases; Mice; Molecular Dynamics Simulation; Peroxides; Phenols; Plasmodium falciparum; Spiro Compounds; Structure-Activity Relationship; Tetraoxanes

Pyrido[3,2-b]indol-4-yl-amines--synthesis and investigation of activity against malaria Starting with 3-aminoindole-2-carboxylic acid ester 1 the annulated pyrido[3,2-b]indoles 6 and 8 were synthesized as key substances. The 4-chloropyridine derivative 8 reacted with the phenol Mannich bases 11 and the novaldiamine base 13, respectively, to yield the amodiaquine and cycloquine analogues 12 as well as the chloroquine analogue 14. The stability of the compounds 12 and 14 were proven by the half wave potentials measured by differential pulse voltammetry. Compounds 12 and 14 were tested for in vitro antimalarial activity using a chloroquine sensitive and a chloroquine resistant Plasmodium falciparum strain. The highest activity was shown by 12g with IC50 values of 50 nM and 38 nM, respectively. The in vivo activity of 12g was tested in Plasmodium vinckei infected mice resulting in ED50 values of 22 mg/kg and 26 mg/kg after intraperitoneal and oral administration, respectively.

Topics: Administration, Oral; Amines; Animals; Antimalarials; Electrochemistry; Indicators and Reagents; Indoles; Injections, Intraperitoneal; Malaria; Mannich Bases; Mice; Mice, Inbred BALB C; Plasmodium falciparum; Pyridines

2-Arylaminoquinoxalines were prepared by the condensation of 2-chloroquinoxaline with the appropriate Mannich bases in the presence of HCl. To synthesize the Mannich bases, 4-acetamidophenol was reacted with formaldehyde and dialkylamine to yield 3-[(dialkylamino) methyl]-4-hydroxyacetanilide, followed by hydrolysis. Antimalarial activities of the new arylaminoquinoxalines were evaluated against the rodent malaria parasite Plasmodium yoelii at a dose of 75 mg kg(-1). Three compounds synthesized (2-[3-[(diethylamino) methyl]-4-hydroxyanilino]-quinoxaline dihydrochloride (2b), 2-[3-[(pyrrolidinyl) methyl]-4-hydroxyanilino]-quinoxaline dihydrochloride (2f), and 2-[3-[(piperidinyl) methyl]-4-hydroxyanilino]-quinoxaline dihydrochloride (2g)) showed moderate antimalarial activity.

Topics: Animals; Antimalarials; Chloroquine; Indicators and Reagents; Malaria; Mannich Bases; Mice; Plasmodium yoelii; Quinoxalines

A new series of 4-aminoquinoline Mannich base derivatives have been synthesized, in which the 3'-diethylamino function of amodiaquine (AQ) is replaced by a 3'-tert-butylamino group and an aliphatic hydrocarbon entity is incorporated into the 5'-position of the 4'-hydroxyanilino side chain. Seven alkyl Mannich base derivatives were screened and found to be active against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. The propyl and isopropyl alkyl derivatives were found to be the most active; consequently these derivatives were tested against a nonsensitive strain of Plasmodium berghi in vivo and found to be 3-fold more active than AQ, irrespective of the route of administration (oral or intraperitoneal).

Topics: Aniline Compounds; Animals; Antimalarials; Inhibitory Concentration 50; Malaria; Male; Mannich Bases; Mice; Plasmodium berghei; Plasmodium falciparum; Quinolines; Structure-Activity Relationship

The activities of Mannich base antimalarials, including pyronaridine, have been explored against drug-sensitive (Plasmodium berghei N) and chloroquine-resistant (Plasmodium yoelii NS) rodent malaria parasites in vivo. Lines of these parasites have been developed with resistance to pyronaridine, amodiaquine, or WR 228,258. The responses and patterns of cross-resistance of these lines to Mannich bases and other blood schizontocides are inconsistent. It is concluded that some Mannich bases may prove still to be of value inthe treatment of chloroquine-resistant Plasmodium falciparum infection.

Topics: Aminoquinolines; Amodiaquine; Animals; Antimalarials; Drug Resistance; Malaria; Mannich Bases; Mice; Naphthyridines; Plasmodium berghei; Plasmodium yoelii