Molecular docking and synthesis of N-alkyl-isatin-3-imino aromatic amine derivatives and their antileishmanial and cytotoxic activities.

Abstract

Background and purpose: Isatin derivatives have excited attention due to their biological attractions, especially, anticancer properties. Isatin analogs such as semaxanib and sunitinib were exposed to tyrosine kinase inhibitory properties. N-substituted isatins were reported to show cytotoxic activity. On the other, the extension of impressive and cost-effective agents against leishmaniasis is necessary in third-world countries. The capability of isatin derivatives to create novel anticancer and anti-leishmanial compounds has been identified in medicinal chemistry research. The current study aimed to synthesize N-alkyl-isatin-3-imino aromatic amine compounds and evaluate their biological effects.

Experimental approach: Synthesis started with the formation of 2-chloro-N-phenylacetamide derivatives by the reaction of aniline derivatives with chloroacetyl chloride. N-alkylation of isatin was performed in the presence of K2CO3 in N, N-dimethylformamide. Final products were prepared via the condensation of N-alkyl isatin derivatives with aromatic amines. Cell viability was checked out by using the MTT assay against cancer cells. Final compounds were screened for anti-leishmanial activity. The molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to define the possible interactions.

Findings/results: Compounds 5c and 4d with IC₅₀ value of 50 μΜ showed cytotoxic activity on the MCF-7 cell line. Compound 5b presented anti-leishmanial activity against promastigote form after 48 h (IC₅₀:59 μΜ) and 72 h (IC₅₀: 41 μΜ) incubations. The highest docking score was -7.33 kcal/mol for compound 4d.

Conclusions and implications: The nature of substitution in the N1 region of isatin seems to be able to influence the cytotoxic activity. Based on the obtained results of docking and cytotoxic tests, compound 4d seems to be a good compound for further investigations.