Discovery of 3-[(5-nitro-2-heteroaryl)methylene]-2-indolinone derivatives as highly potent antileishmanial agents and their bioactivation by NTR1 and 2.

Abstract

A novel series of 2-indolinone derivatives bearing a nitroheteroarylmethylene moiety, including nitroimidazole, nitrofuran, and nitrothiophene at their 3-position, were synthesized as potential antileishmanial agents. The in vitro antileishmanial activity and cytotoxicity of these analogues were assessed using L.donovani axenic amastigotes and L6 cell lines, respectively. All compounds except 16k and 18c exhibited promising activity, with IC₅₀ values in the submicromolar range; however, only the nitroimidazole analogues achieved notable selectivity indices (SI). 5-Chloro-3-[(1-methyl-5-nitro-1H-imidazol-2-yl)methylene]-2-indolinone (16c) was the most potent compound, demonstrating impressive antileishmanial activity with an IC₅₀ value of 2.5 nM and an SI of 1760, relative to the reference drug miltefosine (IC₅₀ = 1252.3 nM). Further studies on the nitroimidazole analogues against intracellular amastigotes of L.donovani revealed promising activity for most compounds, with IC₅₀ values ranging from 1.5 to 29.5 μM and high SIs (5.8-42.9), relative to miltefosine (IC₅₀ = 3.9 μM, SI = 34.2). Subsequently, the bioactivation of the compounds by nitroreductases (NTR1 and NTR2) was studied. They were predominantly bioactivated by NTR1, producing DNA-damaging active amine metabolites. Owing to their high antileishmanial activity and selectivity indices, these compounds merit further investigation as potent agents against leishmaniasis, a critical health issue among the tropical diseases.