Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria

Abstract

On the basis of observations that several bisquinolines such as piperaquine possess notable activity against chloroquine-resistant malaria, 13 N,N-bis-(7-chloroquinolin-4-yl)alkanediamines were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Twelve of the thirteen bisquinolines had a significantly lower resistance index than did chloroquine; the resistance index was apparently unrelated to either in vitro or in vivo activity. Except for two compounds, there was a reasonable correlation between in vitro and in vivo activities. Seven of the thirteen bisquinolines had IC50's of less than 6 nM against both chloroquine-sensitive (D-6) and -resistant (W-2) clones of P. falciparum and were curative against P. berghei at doses of 640 mg/kg. In contrast to chloroquine, these bisquinolines did not show any toxic deaths at curative dose levels. Four bisquinolines, however, caused skin lesions at the site of injection. Maximum activity was seen in bisquinolines with a connecting bridge of two carbon atoms where decreased conformational mobility seemed to increase activity. Bisquinoline 3 (+/-)-trans-N1,N2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamin e was not only the most potent bisquinoline in vitro, but was clearly unique in its in vivo activity--80% and 100% cure rates were achieved at doses of 160 and 320 mg/kg, respectively. In summary, these preliminary results support the premise that bisquinolines may be useful agents against chloroquine-resistant malaria.

Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity

“…The NCI Diversity set was obtained in 96-well plate format from the National Cancer Institute (http://dtp.nci.nih.gov/ branches/dscb/diversity_explanation.html). The syntheses of N, N-bis(7-chloroquinolin-4-yl)alkanediamines and N,N-bis(7-chloroquinolin-4-yl)heteroalkanediamines used in these studies have been described previously [23,24]. Amodiaquine, chloroquine, quinacrine, quinidine, and quinine were obtained from Sigma-Aldrich (USA).…”

“…Congeneric series of N,N-bis(7-chloroquinolin-4-yl)alkanediamines [23] and N,N-bis(7-chloroquinolin-4-yl)heteroalkanediamines [24] (collectively referred to as BQs for the remainder of the text) were examined for BoNT/A LC inhibition. The compounds were tested in the HPLC-based assay at 20 lM concentration in the presence of 0.1 mM substrate [1,26].…”

A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

“…Amino ether 11 (43% from 14) was obtained in a reductive amination reaction between 6 and aldehyde 15 (Scheme 1). Alternatively, ketone 19 (obtained from 13) 43 underwent amination with 6 to afford quinoline epimers 2 and 3 (Scheme 1) in a ratio of 1.3:1. Interestingly, although the reactive intermediate is an imine (iminium cation, sp 2 C3), the reductive amination of the cholic acid derivative (5 -series) afforded epimeric 2 and 3 in comparable amounts, unlike the reductions of 5 -3-ketones affording almost exclusively equatorial 3R-epimer.…”

Efficacy and safety of dihydroartemisinin-piperaquine

“…However, piperaquine was never used to treat malaria elsewhere. Although structurally similar to chloroquine, in vitro experiments have shown piperaquine to be active against highly chloroquine-resistant Plasmodium falciparum (Raynes, 1999;Vennerstrom et al, 1992), and the DHA-PIP combination certainly retains both high efficacy and a prolonged post-treatment prophylactic effect in areas where highly chloroquine-resistant P. falciparum is prevalent.…”