New phenylpiperazine-thiazolidine-2,4-dione hybrids targeting MAO inhibition: Synthesis, biological evaluation, kinetic study and in silico insights

Monoamine oxidase inhibitors are promising drug targets for many neurological diseases such as depression, Alzheimer’s disease, and Parkinson’s disease. The current study developed new hybrid compounds by merging phenyl piperazines, and 2,4-thiazolidinedione moieties based on their reported MAO inhibitory activities. The newly synthesized derivatives were screened for their MAOs inhibitory activity using in-vitro fluorometric assay. Most newly synthesized compounds elicited strong inhibitory activity against both hMAO isozymes. Hybrids 4a and 4c were the most potent hMAO-A inhibitors with IC₅₀ values of 0.194 and 0.188 µM, respectively, compared to toloxatone as reference (IC₅₀ = 1.080 µM), meanwhile, compound 4g exhibited the most potent inhibitory activity against MAO-B with an IC₅₀ value of 0.330 µM. The kinetic study of compound 4c revealed that it exhibited a mixed inhibition mode with a K_i value of 3.4 nM. Compound 4c was evaluated against the normal SH-SY5Y cell line and found to be non-cytotoxic at its active inhibition concentration. ADME profiles of the most active hybrids 4a, 4c, 4j, and 4k revealed that they could serve as successful drug candidates showing good CNS penetration. Molecular docking simulations were executed for the most active motifs 4a and 4c to demonstrate the binding pattern with the target proteins explaining their potential inhibitory activity. Lastly, this study will significantly contribute to developing novel safe, effective medications for treating various neurological disorders in the foreseeable future.