Synthesis, Biological Evaluation, in Silico ADMET Prediction, Molecular Docking and Dynamics Studies

What is it about?

A series of novel thiazole‐Schiff base analogs (2a‐2i) were synthesized through a multicomponent reaction involving thiosemicarbazide, 4‐phenoxybenzaldehyde, and α‐haloketone/phenacyl bromide derivatives. IR, 1H NMR, and HRMS spectroscopic techniques characterized the newly synthesized derivatives. These compounds were subsequently employed for their antimicrobial and antioxidant activities using agar disc diffusion and DPPH free radical scavenging methods. The multi‐faceted activity of compound 2c was revealed in both In Vitro experiments. It exhibited the highest potency against Bacillus subtilis (26.0±1.0mm) and Aspergillus niger (22.3 ±0.6mm) which exceeded the inhibitory value of standard ceftriaxone (20.7 ± 0.6 mm) and amphotericin B (8.7 ± 0.6 mm), respectively. Additionally, 2c demonstrated a remarkable sevenfold increase in antioxidant capability (IC50= 7.17 ± 2.61 μg/mL) compared to the standard ascorbic acid (IC50 = 49.69 ±19.18 μg/mL). The in silico ADMET prediction demonstrated that most synthesized compounds adhered to Lipinski's rule of five and Veber's rule, with 2i being the exception with one violation. Molecular docking studies and dynamics simulation were conducted to explore potential binding sites, interactions, and stability of the ligandprotein complexes, providing insights aligned with the In Vitro results.

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Why is it important?

This study presents an efficient two‐step synthesis of nine novel thiazole‐Schiff base derivatives incorporating phenoxyphenyl moieties (2a‐2i). The structures of the newly synthesized compounds were confirmed based on spectroscopic methods (IR, ¹H NMR, and HRMS). These new compounds demonstrated promising in vitro antimicrobial activity, especially 2c, showing diverse bacterial activity. Additionally, compound 2c displayed significant antioxidant activity, surpassing standard ascorbic acid (49.69 ± 19.18 μg/mL) by a factor of seven‐fold higher activity (IC₅₀ = 7.17 ± 2.61 μg/mL) in DPPH free radical scavenging assay. In silico analysis revealed favorable pharmacokinetic and physicochemical properties for most compounds, suggesting potential oral bioavailability. Molecular docking studies indicated a strong binding affinity of 2c against the three selected target proteins. MD simulations further confirmed the stability of this complex, with low RMSD, RMSF, and Rg values. The binding free energy remained favorable throughout the 25 ns simulation, underscoring the strength of the complex. Based on these promising results, compound 2c emerged as a potential lead compound for further development. The findings of this study provide valuable insights for the advancement of novel therapeutic agents.