Insight into the reactivity and antitumoral potential of allyl rhodanine derivatives: Azomethine ylide cycloadditions, molecular docking, and SAR studies.

In this work, a series of N-allyl-5-arylidene-rhodanine derivatives was prepared and their reactivity evaluated as dipolarophiles in 1,3-dipolar cycloaddition reactions. Cycloadducts of series 5 were obtained using sarcosine and 5-nitroisatin as precursors, while reactions with sarcosine and 2-pyridinecarboxaldehyde afforded new 2-pyridyl-substituted spiro derivatives (series 7). All compounds from both series were fully characterized and screened for their in vitro anticancer activity against the following five human cancer cell lines: A2780 (ovarian carcinoma), A549 (lung adenocarcinoma), MDA-MB-231 (breast carcinoma), NCI-N592 (small-cell lung cancer), and A431 (epidermoid carcinoma). Several derivatives exhibited pharmacologically relevant IC50 values, with compounds 5b and 7b demonstrating noteworthy antiproliferative activity in A549 cells, a standard model for non-small cell lung carcinoma. The apoptotic potential of the most active compounds was further confirmed by Annexin V/PI assays in A549 cells. Using baicalein as a reference inhibitor, both compound series were also subjected to molecular docking studies targeting the human enzyme 15-lipoxygenase-2 (h15-LOX-2), implicated in cancer-related pathways. In general, a consistent trend was observed between the antiproliferative activity of the compounds and their predicted inhibition of h15-LOX-2, as inferred from docking analysis of 28 structures, including the 10 final allyl rhodanine-based compounds and their required precursors. To further evaluate target engagement, molecular dynamics (MD) simulations were performed for the most active derivatives, providing mechanistic insight into binding-pocket rigidification and conformational stability. In addition, in silico ADMET predictions were carried out to assess the developability profile of the lead candidates. The integrated chemical synthesis, biological evaluation, and computational modeling provided key insights into the reactivity, bioactivity, and structure-activity relationships of the synthesized compounds.