Abstract
A diverse array of 4-(1H)-quinolone derivatives bearing substituents at positions 1 and 2 were synthesized and evaluated for antiprotozoal activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense, and cytotoxicity against L-6 cells in vitro. Furthermore, selectivity indices were also determined for both parasites. All compounds tested showed antimalarial activity at low micromolar concentrations, with varied degrees of selectivity against L-6 cells. Compound 5a was found to be the most active against P. falciparum, with an IC50 value of 90 nM and good selectivity for the malarial parasite compared to the L-6 cells. Compound 10a, on the other hand, showed a strong antitrypanosomal effect with an IC50 value of 1.25 µM. In this study side chain diversity was explored by varying the side chain length and substitution pattern on the aliphatic group at position-2 and a structure-antiprotozoal activity study revealed that the aromatic ring introduced at C-2 contributed significantly to the antiprotozoal activities.
Highlights
According to the latest World Health Organization report there were an estimated 207 million cases of malaria in 2012 and an estimated 627,000 deaths [1]
Our new series of compounds contains unique substituents including alkyls, alkenyl, alkynyl, and 1-bromoethyl at position-1; aliphatic groups having various degrees and position of unsaturation with and without aryl groups, and no substituents at C-3. 4-(1H)-Quinolone derivatives including the well-known antibiotic fluoroquinolones such as ciprofloxacin, gatifloxacin and moxifloxacin display potential antitrypanosomal effects [12]. This is further supported by a recent report by Hiltonsperger et al that 4-(1H)-quinolones with a benzyl amide group in position 3 and cyclic or acyclic amines in position 7 exhibited high antitrypanosomal activity [13]
The methyl-α,β-(E)-alkenyl ketones 15 and 16, which served as important intermediates for the synthesis of our diverse array of
Summary
According to the latest World Health Organization report there were an estimated 207 million cases of malaria in 2012 and an estimated 627,000 deaths [1]. Trypanosoma brucei rhodesiense causes sleeping sickness in East and South Africa, while T. b. Gambiense causes sleeping sickness in Central and West Africa. Both forms of the disease affect mainly poor rural people who have poor access to basic health facilities in their vicinity. 4-(1H)-Quinolone derivatives including the well-known antibiotic fluoroquinolones such as ciprofloxacin, gatifloxacin and moxifloxacin display potential antitrypanosomal effects [12]. This is further supported by a recent report by Hiltonsperger et al that 4-(1H)-quinolones with a benzyl amide group in position 3 and cyclic or acyclic amines in position 7 exhibited high antitrypanosomal activity [13]. We report the synthesis of a series of 1,2-substituted-4(1H)-quinolones, and examine their antiprotozoal and cytotoxic properties in vitro
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