Synthesis, Biological Evaluation, Structure–Activity Relationship, and Mechanism of Action Studies of Quinoline–Metronidazole Derivatives Against Experimental Visceral Leishmaniasis

Abstract

In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, a series of quinoline–metronidazole hybrid compounds was synthesized and tested against the murine model of visceral leishmaniasis. Among all synthesized derivatives, 15b and 15i showed significant antileishmanial efficacy against both extracellular promastigote (IC50 9.54 and 5.42 μM, respectively) and intracellular amastigote (IC50 9.81 and 3.75 μM, respectively) forms of Leishmania donovani with negligible cytotoxicity toward the host (J774 macrophages, Vero cells). However, compound 15i effectively inhibited the parasite burden in the liver and spleen (>80%) of infected BALB/c mice. Mechanistic studies revealed that 15i triggers oxidative stress which induces bioenergetic collapse and apoptosis of the parasite by decreasing ATP production and mitochondrial membrane potential. Structure–activity analyses and pharmacokinetic studies suggest 15i as a promising antileishmanial lead and emphasize the importance of quinoline–metronidazole series as a suitable platform for the future development of antileishmanial agents.

Nitroaromatic Antibiotics as Nitrogen Oxide Sources

“…Compounds 4-methyl-2-(3-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)phenyl)quinolone (1) and 4methyl-2-(4-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)phenyl)quinolone (2) ( Figure 4) were found to be the most active as determined by a luciferase and 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while 2 most effectively inhibited parasites in the liver and spleen of infected mice [49]. To examine NO release in relation to leishmanicidal action, the DAF-2DA dye assay was utilized, which implies local NO formation in living cells at the intracellular level, and revealed 2 leads to oxidative stress through the enhancement of both ROS and NO generation [49]. While these compounds do not contain traditional NO donor groups, these results further show nitrogen oxide species release from 5-nitroimidazoles similar to metronidazole.…”

“…Similarly, the mechanism of action of quinoline-metronidazole hybrids was recently investigated against visceral leishmaniasis (VL) [49]. The rationale for merging the two compounds stems from the use of metronidazole to combat experimental VL, especially in combination with other drugs [50][51][52][53], along with the activity of quinolines and their derivatives against in vitro and in vivo forms of experimental and cutaneous VL [54,55].…”

“…The rationale for merging the two compounds stems from the use of metronidazole to combat experimental VL, especially in combination with other drugs [50][51][52][53], along with the activity of quinolines and their derivatives against in vitro and in vivo forms of experimental and cutaneous VL [54,55]. To determine the anti-leishmanial potency of quinoline−metronidazole derivatives, inhibition of promastigotes and intracellular amastigotes of Leishmania donovani was tested at various concentrations with various regioisomeric compounds [49]. Compounds 4-methyl-2-(3-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)phenyl)quinolone (1) and 4methyl-2-(4-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)phenyl)quinolone (2) ( Figure 4) were found to be the most active as determined by a luciferase and 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while 2 most effectively inhibited parasites in the liver and spleen of infected mice [49].…”

“…To determine the anti-leishmanial potency of quinoline−metronidazole derivatives, inhibition of promastigotes and intracellular amastigotes of Leishmania donovani was tested at various concentrations with various regioisomeric compounds [49]. Compounds 4-methyl-2-(3-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)phenyl)quinolone (1) and 4methyl-2-(4-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)phenyl)quinolone (2) ( Figure 4) were found to be the most active as determined by a luciferase and 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while 2 most effectively inhibited parasites in the liver and spleen of infected mice [49]. To examine NO release in relation to leishmanicidal action, the DAF-2DA dye assay was utilized, which implies local NO formation in living cells at the intracellular level, and revealed 2 leads to oxidative stress through the enhancement of both ROS and NO generation [49].…”

Report on Recently (2017–20) Designed Quinoline‐Based Human Cancer Cell Growth Inhibitors

“…Particularly quinoline-containing pharmaceutical drugs have rendered the strongest biological properties such as antibacterial activity, [30,31] antifungal activity, [32,33] antimalarial activity, [34][35][36] and anti-leishmanial activity. [37][38][39] Alongside this, some review studies reported quinoline scaffolds as remarkable anticancer agents. [40,41] Various action mechanisms have been postulated for the anticancer agents.…”