1,2-substituted 4-(1H)-quinolones: synthesis, antimalarial and antitrypanosomal activities in vitro

• Published in: Molecules (Basel, Switzerland) Vol. 19; no. 9; pp. 14204 - 14220
• Main Authors: Wube, Abraham, Hüfner, Antje, Seebacher, Werner, Kaiser, Marcel, Brun, Reto, Bauer, Rudolf, Bucar, Franz
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.09.2014; MDPI
• Subjects: 4-(1H)-quinolone; Acetylation; Animals; antimalarial; Antimalarials - chemical synthesis; Antimalarials - pharmacology; Antiparasitic agents; antitrypanosomal; Cell Line; Cytotoxicity; Drug Evaluation, Preclinical; Infections; Inhibitory Concentration 50; Malaria; Parasitic Sensitivity Tests; Pharmaceutical sciences; Plasmodium falciparum - drug effects; Protozoa; Public health; Quinolones - chemical synthesis; Quinolones - pharmacology; Rats; SAR; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - pharmacology; Trypanosoma brucei rhodesiense - drug effects; Austria; Basel Switzerland; Switzerland; Africa
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules190914204

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.