New quinoline di-Mannich base compounds with greater antimalarial activity than chloroquine, amodiaquine, or pyronaridine.

We have compared the ex vivo antimalarial activity of 12 new quinoline di-Mannich base compounds containing the 7-dichloroquinoline or 7-trifluoromethylquinoline nucleus with amodiaquine, chloroquine, and pyronaridine using the Saimiri-bioassay model. Each compound was administered orally (30 mg/kg of body weight) to three or more noninfected Saimiri sciureus monkeys, and serum samples were collected at various times after drug administration and serially diluted with drug-free (control) serum. In vitro activity against the multidrug-resistant K1 isolate of Plasmodium falciparum was determined in serum samples by measuring the maximum inhibitory dilution at which the treated monkey serum inhibited schizont maturation in vitro. Of the 12 Mannich bases tested, 8 were associated with levels of ex vivo antimalarial activity in serum greater than those of amodiaquine, chloroquine, or pyronaridine 1 to 7 days after drug administration. Further studies were carried out with four of these compounds, and the results showed that the areas under the serum drug concentration-time curves for the four compounds were between 7- and 26-fold greater than that obtained for pyronaridine. Activity against four multidrug-resistant strains of P. falciparum was also much greater in serum samples collected from monkeys after administration of these four compounds than in serum samples collected after administration of pyronaridine or chloroquine. These findings suggest that these four quinoline Mannich base compounds possess a very marked and prolonged antimalarial activity and that further studies should be performed to determine their value as antimalarial drugs.

New imidazo[1,2-b]pyridazine ligands for peripheral-type benzodiazepine receptors on mitochondria and monocytes.

Several 6-chloro-2,3-disubstituted imidazo[1,2-b]pyridazines, selected from a number of synthetic imidazo[1,2-b]pyridazines which lacked significant binding activity at central benzodiazepine receptors, potently inhibit [3H]diazepam, [3H]Ro5-4864 and [3H]PK11195 binding to rat kidney mitochondrial membranes. In membrane preparations from cultures of THP-1 cells, a human monocytic leukaemia cell line, the isoquinoline carboxamide PK11195 is strongly bound but the benzodiazepine ligands, diazepam and Ro5-4864, are much more weakly bound. The imidazopyridazine compounds which bind strongly to mitochondrial benzodiazepine receptors are very potent displacers of [3H]PK11195 bound to the THP-1 membranes. It appears that the binding properties of these new imidazopyridazine ligands at 'peripheral-type' benzodiazepine receptors resemble those of the isoquinoline carboxamides more than those of the benzodiazepines.

Substituted imidazo[1,2-b]pyridazines. New compounds with activity at central and peripheral benzodiazepine receptors.

A large range of substituted imidazo[1,2-b]pyridazines have been synthesized, and a number of potent ligands at central benzodiazepine (Bz) receptors on rat brain membranes have been identified in initial binding screens using [3H]diazepam. For those tested more extensively, binding studies conducted in the presence and absence of gamma-aminobutyric acid suggest that they were full receptor agonists. Some preliminary evidence was found suggesting some species selectivity, i.e. several of the compounds were more active in in vivo tests in rats than in mice. The agonist activity of these 2-phenyl (and substituted phenyl) imidazo[1,2-b]pyridazines is consistent with the model of Bz receptor ligands as proposed by Fryer [Raven Press, 1983, pp. 7-20]. Several compounds were identified which had more selective activity at peripheral-type (mitochondrial) Bz binding sites. Thus, substituted imidazo[1,2-b]pyridazines represent yet another class of low molecular mass compounds which have activity at Bz receptor sites.

The in vitro and in vivo antimalarial activity of some Mannich bases derived from 4-(7'-trifluoromethyl-1',5'-naphthyridin-4'-ylamino)phenol, 2-(7'-trifluoromethyl-quinolin-4'-ylamino)phenol, and 4'-chloro-5-(7''-trifluoromethylquinolin-4''-ylamino)biphenyl -2-ols.

A series of di-Mannich base derivatives (4 and 5) from 4-(7'-trifluoromethyl-1',5'-naphthyridin-4'-ylamino)phenol and 2-(7'-trifluoromethylquinolin-4'-ylamino)phenol, respectively, and mono-Mannich base derivatives (6) from 4'-chloro-5-(7''-trifluoromethylquinolin-4''- ylamino)biphenyl-2-ol were assayed for activity against the chloroquine-sensitive (FCQ-27) isolate of cultured Plasmodium falciparum using the inhibition of uptake of radiolabelled hypoxanthine. All seven di-Mannich base derivatives (5) revealed a higher activity than chloroquine, whereas the di-Mannich base derivatives (4) were slightly less active (with some derivatives more active and some less active than chloroquine). The mono-Mannich base derivatives (6) were less active than chloroquine. Comparative tests of selected compounds of (4 and 5) using a morphological assay revealed no significant differences in activity between the chloroquine-sensitive (FCQ-27) and chloroquine-resistant (K-1) isolates. Selected di-Mannich bases (4 and 5) and the mono-Mannich bases 5-7''-bromo (and 7-trifluoromethyl)-1'',5''-naphthyridin-4''-ylamino)-3-(t- butylaminomethyl)-4'-chlorobiphenyl-2-ols (7, X = Br, CF3) markedly suppressed parasitaemia in Plasmodium vinckei vinckei infected mice when administered (i.p.) in a single dose of 200 mg kg-1.

The in vitro and in vivo antimalarial activity of some Mannich bases derived from 4-[7'-bromo (and chloro)-1',5'-naphthyridin-4'-ylamino]phenol and 4-(7'-trifluoromethylquinolin-4'-ylamino)phenol.

A series of di-Mannich bases derived from 4-[7'-bromo (and chloro)-1',5'-naphthyridin-4'-ylamino]phenol and 4-(7'-trifluoromethylquinolin-4'-ylamino)phenol were assayed for activity against chloroquine-sensitive and chloroquine-resistant isolates of cultured Plasmodium falciparum using the inhibition of uptake of radiolabelled hypoxanthine. A number of the 4-(7'-trifluoromethylquinolinyl-amino)phenols showed statistically superior activity to chloroquine and amodiaquine against both isolates. Analysis of the antimalarial activity of some of these compounds against Plasmodium berghei in mice following oral administration again demonstrated activity equal or superior to that of the established antimalarials against a chloroquine-sensitive strain, and in some cases appreciably superior activity against a chloroquine-resistant strain.

Antimalarial activity of Mannich bases derived from 4-(7'-bromo-1',5'-naphthyridin-4'-ylamino)phenol and 4-(7'-trifluoromethylquinolin-4'-ylamino)phenol against Plasmodium falciparum in vitro.

Mono- and di-Mannich bases derived from 4-(7'-bromo-1',5'-naphthyridin-4'-ylamino)phenol and 4-(7'-trifluoromethylquinolin-4'-ylamino)phenol were assayed for antimalarial activity (using an in vitro radioisotopic technique) against two isolates of Plasmodium falciparum. Many from these two series of compounds had an IC50 value (concentration of compound causing 50% inhibition of 3H-hypoxanthine incorporation) comparable to or better than those of mefloquine and amodiaquine, for both a chloroquine-sensitive isolate (FCQ-27) and the chloroquine-resistant isolate (K1). At least one compound, 2,6-bis (piperidin-1''-ylmethyl)-4-(7'-trifluoromethylquinolin -4'-ylamino)phenol (TN112), showed significant superior activity to the three antimalarials chloroquine, mefloquine and amodiaquine against both isolates. (Statistically superior activity compared to these three antimalarials was found for TN112, except that against the K1 isolate its activity was just outside the range of significance relative to mefloquine.) Some of the 7-bromo-1,5-naphthyridine Mannich bases were appreciably less toxic in mice than amodiaquine.