1,2-Substituted 4-(1H)-Quinolones: Synthesis, Antimalarial and Antitrypanosomal Activities in Vitro

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 IC 50 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 IC 50 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.

Scoping Studies into the Structure‐Activity Relationship (SAR) of Phenylephrine‐Derived Analogues as Inhibitors of Trypanosoma brucei rhodesiense

“…Some of these include inhibitors of trypanothione reductase, rhodesain, tryparedoxin, GSK3, N‐myristoyl transferase, trypanothione synthetase, ornithine decarboxylase, and phosphofructokinase . Many compounds from a broad range of structural classes have also been identified through more traditional phenotypic screening approaches, including pyridine based compounds, adamantanes, quinones and quinolones, and pyrimidines . Natural products such as cyanopicrin, ascofuranone, and cordycepin have also been reported to show some antitrypanosomal activity.…”

Synthesis of 3-Substituted Chromones and Quinolones from Enaminones

“…Quinolone derivatives have been studied for various therapeutic uses, and a number of these compounds have been investigated with respect to their antimicrobial, 1,2 antitumor, 3 and antimalarial activities. [4][5][6][7] Recent reviews have also been published on the biological activities of chromones. 8,9 On the other hand, enaminones are attractive functional groups because of their versatile utilization as building blocks for the synthesis of various heterocycles.…”

Synthesis, in vitro Cytotoxicity and Trypanocidal Evaluation of Novel 1,3,6-Substituted Non-fluoroquinolones

“…1b) in this series suffers from poor solubility, 31 necessitating further work on this class of compounds. Unlike fluoroquinolones, the anti-trypanosomal potentials of non-fluorinated quinolones have not been extensively investigated, with just one study on non-fluorinated quinolones bearing substituents at position -1 and -2, respectively, being reported 32 (Fig. 1c).…”