In silico design of novel 2H-chromen-2-one derivatives as potent and selective MAO-B inhibitors

•Highly predictive Gaussian-field based 3D-QSAR model for coumarin MAO-B inhibitors.•Computational studies highlighted the key role of the steric effect at position 4.•Successful design of novel MAO-B inhibitors guided by the 3D-QSAR model.•Most of the newly designed compounds inhibited MAO-B in the nanomolar range.•The 4-CH2CH2OH, 4-CH2CH2Cl, 4-CH2CH2CONH2 groups led to the best MAO-B inhibitors.

Inhibition data on rat monoamine oxidase B isoform of a large number of 7-metahalobenzyloxy-2H-chromen-2-one derivatives (67 compounds) carrying at position 4 a variety of substituents differing in steric, electrostatic, lipophilic and H-bonding properties, were modeled by Gaussian field-based 3D-QSAR and docking simulations carried out on rat MAO-B homology model. The computational study combining two different approaches provided easily interpretable binding modes, highlighting the dominant role of the steric effects at position 4, and guided the design of new, potent and selective MAO-B inhibitors. The 4-hydroxyethyl-, 4-chloroethyl-, 4-carboxamidoethyl-coumarin derivatives 70, 71, and 76, respectively, were endowed with high MAO-B inhibitory potency (pIC50 = 8.13, 7.89 and 7.82, respectively) and good selectivity over MAO-A (pIC50 = 5.33, 3% inhibition at 10 μM, and pIC50 = 5.37, respectively). New compounds with moderate to low MAO-B inhibitory activity were also designed and prepared to challenge the predictive power of our docking-based 3D-QSAR model. The good match between predicted and experimental pIC50 values for all the newly designed compounds confirmed the robustness of our model (r2 = 0.856, RMSE = 0.421) and its transparent rationale in unveiling the main molecular determinants for high potency towards MAO-B.

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