3-Hydroxy-3-alkylindolin-2-ones: regioselective synthesis, molecular docking and nematicidal studies against Meloidogyne incognita.

Regioselective nucleophilic addition of unsubstituted isatin (1) was carried out for the synthesis of pharmaceutically and to be agrochemically important 3-hydroxy-3-akylindolin-2-ones (3a-f) using discrete nucleophiles via generation of Grignard reagent. The synthesized derivatives were characterized by spectral techniques and were evaluated for nematicidal activity against Meloidogyne incognita. The nematicidal assay revealed that 1-ethyl-3-hydroxyindolin-2-one (3a) exhibited potent nematicidal activity against M. incognita. The most active member (3a) exhibited reasonably good ovicidal (LC50 = 0.077 mg/mL) and larvicidal activity (LC50 = 0.058 mg/mL), respectively. In support of the nematicidal activity, molecular docking of isatin (1) and its derivatives (3a-f) was performed using three parasitic proteins viz., carboxylic ester hydrolase, cytochrome c oxidase and aspartyl protease which revealed maximum interaction with amino acid residues Tyr 356, Tyr 170, Glu 238, Glu 327, Arg 271, Arg 112, Ser 29, Ser 31, Ser 368, Asn 115, Leu 326 and His 51 which act as supporting factors for compounds to curb the parasite.

N-alkyl isatin derivatives: Synthesis, nematicidal evaluation and protein target identifications for their mode of action.

Meloidogyne incognita is an economically dominant pathogen infesting a wide range of crops curbing their growth and productivity. Deregistration of frontline nematicides has necessitated exploration of innovative and novel class of structurally diverse nematicides with streamlined activity. In this context, N-alkylated derivatives of isatin known for their remarkable biological profile were synthesized, characterized and evaluated in vitro for their antinemic character followed by in silico studies for their mode of action and toxicological studies for their fitness as agrochemical. The antinemic evaluation was carried by egg hatch inhibition and juvenile mortality and its effect on egg hatching. Compounds 1 and 2a exhibited nematicidal potential and significantly decreased egg hatching and increased juvenile mortality. For egg hatch inhibition LC50 and LC95 values for 1 were found to be 0.125 and 1.380 mg/ml and for compound 2a, 0.457 and 8.511 mg/ml respectively. For juvenile mortality LC50 and LC95 values for 1 were found to be 0.109 and 0.776 mg/ml and for 2a, 0.190 and 1.380 mg/ml respectively. For insights into the mode of action of the synthesized molecules, in silico studies for the targeted effects were conducted which revealed novel interaction with pathogenic protein - Aspartyl protease. Computational studies on the drug-ability and potential toxicity of the selected compounds revealed they belonged to class IV and are safe. With good reasons, our compounds hold value for their exploration in agrochemical industry and thus, this study identifies a new scaffold with useful level of nematicidal activity for its use in agriculture industry.