Farghaly_2025_Bioorg.Chem_164_108812

This study unveils the rational design and stepwise synthesis of new thiazole-based thiazolidinone Schiff base derivatives (1-15), harnessing 2-amino-5-nitrothiazole as a crucial precursor. These newly synthesized derivatives were structurally characterized through spectroscopic techniques (1)HNMR, (13)CNMR and HREI-MS. Moreover, consider the crucial role of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition in Alzheimer's disease (AD) therapy, the synthesized compounds were evaluated for their cholinergic enzyme inhibitory potential against AChE and BuChE, with Donepezil (IC(50) = 5.10 +/- 0.10 microM) as the reference drug. Among all the derivatives, the compounds 2, 3, 5, and 7 has shown the best biological inhibition potency with the values of (IC(50) = 2.98 +/- 0.19 and 3.22 +/- 0.51 microM), (IC(50) = 2.80 +/- 1.23 and 3.11 +/- 0.78 microM), (IC(50) = 4.34 +/- 0.86 and 5.55 +/- 0.91 microM) and (IC(50) = 3.90 +/- 1.42 and 3.75 +/- 0.98 microM) respectively as compared to the standard drug. Additionally, molecular docking studies were conducted against AChE and BuChE enzymes, with docking validation confirming accuracy via RMSD values of 1.15 A and 0.19 A, respectively, indicating reliable binding predictions. Among the screened compounds, compound-5 showed the strongest binding affinity and was further investigated through in-silico techniques. Similarly, density Functional Theory (DFT) analysis revealed that compound-5 had the lowest HOMO-LUMO gap (2.36 eV), indicating high reactivity, while compound-2 exhibited the highest energy gap (3.39 eV), suggesting greater stability. Furthermore, molecular electrostatic potential (MESP) maps supported these findings by highlighting distinct charge distribution patterns. Similarly, ADMET predictions showed that compound-5 possessed favorable drug-like properties, including membrane permeability and optimal lipophilicity. Moreover, toxicity analysis confirmed that all selected compounds were non-carcinogenic, moderately toxic (LD(50) <= 1000 mg/kg) and non-cytotoxic, with compound-3 having the highest LD(50) (2604 mg/kg) and lowest toxicity class. None of the compounds were predicted to cross the blood-brain barrier or inhibit major cytochrome P450 enzymes. Hence, these findings highlight the potential of these newly synthesized thiazole-thiazolidinone Schiff base derivatives as promising therapeutic targets for Alzheimer's disease that were contributing to the development of next-generation cholinesterase inhibitors with promising efficacy and selectivity.