Novel isatinspirooxazine derivatives were designed and synthesized as potential anti-proliferative agents. The new compounds were obtained from aldol condensation reactions between isatin and 3-(hydroxyimino)butan-2-one in the presence of an organic base in order to generate an aldol adduct, followed by cyclization in trifluoroacetic acid, providing the desired isatinspirooxazines in 30 to 80% yield. All the synthesized compounds, including the starting material and the synthetic intermediates, were tested for in vitro anti-proliferative activity against cell lines MCF-7 and MDA-MB231 (breast cancer) and A549 (lung cancer), highlighting the compound 4-methyl,5'-methyl-spiro[(5-aza-4-eno-3-one-cyclohexane)-1,3'-(1H-indol-one)] with an IC 50 (half maximal inhibitory concentration) = 0.34 μM, more potent than the reference drug, doxorubicin (IC 50 = 1.88 μM), in breast cancer line MDA-MB231.

SELEST is a procedure for identifiability of parameters in which selection and estimation steps are simultaneous, ensuring a well-conditioned estimation problem for a subset of identifiable parameters. Nevertheless, since SELEST is based on local sensitivity analysis, the identifiability criteria are dependent on the parameters initial values, requiring intensive parameters evaluation. In order to improve the convergence of the algorithm, we propose to update the values of the selected parameters and their sensitivity submatrix when re-ranking the remaining parameters. Therefore, the parameters estimations are performed using more appropriate values than the initial estimates. Two cases studies illustrate the performance of the proposed procedure: a hypothetical model, and an enzymatic hydrolysis model. Results demonstrate that the proposed modifications improved the performance of the algorithm, reducing the computational time significantly.

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