Computational Study of Potential MAO-B Inhibitors Based on 4-(3-Nitrophenyl) Thiazol-2-ylhydrazone.

This study used a dataset comprising thirty-four derivatives of 4-(3-nitrophenyl) thiazol-2-ylhydrazone as selective monoamine oxidase B (h-MAO-B) inhibitors to design more effective h-MAO-B inhibitors. This was achieved by applying molecular modeling methods. Among the different field models examined, the CoMSIA/SEA model emerged as the most effective, compared to the other models (Q^2 = 0.60; R2 = 0.97; R^2test = 0.711; F = 151.84; SEE = 0.21; ONC = 4). Contour maps helped identify structural features important for inhibitory activity, leading to the design of four highly active inhibitors. The study explored the interaction between the new compounds (M1, M2, M3, and M4) and the most active molecule, No.3, using molecular docking simulations. This process revealed a positive interaction characterized by the formation of significant bonds with key protein residues such as Arg:42, Glu:58, Met:436, Tyr:398, Tyr:435, and Tyr:60. The ADMET properties of the predicted molecules (M1-M4) were generally favorable, except for molecule No.3, which retained its toxicity. Both M1 and the most active compound 3 underwent 100 ns molecular dynamics simulations, The results of these simulations indicate that the proposed molecule, M1, exhibits a slightly higher structural stability compared to the most active compound, 3. This positions M1 as a promising candidate for further studies. A retrosynthesis strategy was employed to efficiently plan the synthesis of molecule M1 as a potential MAO-B inhibitor, identifying the key steps and precursors required for its realization.