Structural and functional insight into thiazolidinone derivatives as novel candidates for anticancer drug design: in vitro biological and in-silico strategies.

The compounds 2a-2h containing a thiazolidinone pharmacophore were synthesized via hetrerocylization of thiosemicarbazones with dimethyl acetylenedicarboxylate. The hybrid molecules were evaluated for anticancer activity against the human cell lines MCF-7, T47D (human breast adenocarcinoma) and HeLa (cervical cancer). Compounds 2c showed effective cytotoxicity on MCF-7 and HeLa (GI50 6.40 ± 0.10 µM/mL and GI5010.30 ± 1.09 µM/mL), and compound 2d also showed effective cytotoxicity against MCF-7 and HeLa cell lines i.e., (GI50 16.60 ± 0.21 µM/mL and GI50 15.02 ± 0.14 µM/mL). These findings were comparable to cisplatin (azane;dichloroplatinum) the standard drug (GI50 13.20 ± µM/mL and 15.10 µM/mL respectively) and consequently nominated for determination of the mode of cell death. The results revealed the cytotoxic effects of 2c and 2d by induction of apoptosis in MCF-7 and HeLa cell lines. Moreover the results were further supported by the Molecular Docking which predicts the binding interactions of the best anticancer ligands with Ribonucleotide reductase (RNR), which is essential enzyme required for de-novo synthesis of DNA precursors. Molecular dynamic simulations were also performed to determine the stability of protein-ligand complex under different simulated conditions. In addition, the computational studies including DFTs, ADMET properties suggested these compounds can act as lead molecules, for the synthesis of novel drug candidates for the treatment of specific cancer and its associated malignancies.

4-Phthalimidobenzenesulfonamide Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: DFTs, 3D-QSAR, ADMET, and Molecular Dynamics Simulation.

INTRODUCTION: Alzheimer's disease is a form of dementia which affects majority of the people. It is characterized by memory loss and other cognitive function disabilities and is one of the most challenging neurodegenerative disorders to treat because of its progressive nature. The disease affects millions of people all around the world, and the number of those affected is expanding every day. In the previous study, the 4-phthalimidobenzenesulfonamide derivatives were synthesized as AChE and BChE inhibitors, and here, we were aiming to further reporting in silico studies of these compounds for efficient drug discovery process and to find out the potential lead compounds. METHODS: In silico characterization included density functional theory (DFT) studies, 3D-QSAR, ADMET properties, molecular docking, and molecular dynamic simulations. The geometries of all derivatives were optimized using B3LYP method and 6-311G basis set. RESULTS: The findings of the current study revealed that 4-phthalimidobenzenesulfonamide derivatives exhibited a reactive electronic property which is essential for anticholinesterase activity. Moreover, optimized structures were subjected to molecular docking studies with targeted protein. The compounds 2c and 2g showed excellent binding score of -37.44 and -33.67 kJ/mol with BChE and AChE, respectively, and exhibited strong binding affinity. The potent derivatives produced stable complex with amino acid residues of active pocket of both BChE and AChE. The stability of protein-ligand complexes was determined by molecular dynamic simulation studies, and results were found in correlation with molecular docking findings. CONCLUSION: Findings of the current study suggested that these derivatives are potent inhibitors of cholinesterase enzyme.