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World is familiar with the viral pathogen Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2). The principle working enzymes of SARS CoV-2 have been identified as main proteases 3Cl pro which act as main regulators for SARS infection. The need for therapy is required immediately pertaining to the vulnerable conditions. Protein-ligand studies are imperative for understanding the functioning of biological interactions as they are crucial in providing a hypothetical origin for the design and unearthing of novel drug targets. Phytoconstituents from Glycyrrhiza glabra , earlier reported to be anticancerous in nature were used as repurposed drugs against SARS CoV-2 main protease 3Clpro. We analyzed the molecular interactions of protein-phytocompounds, by AutoDock Vina 4.2 tools. The best interactions of each algorithm were subjected to molecular dynamic (MD) simulations to have an insight of the molecular dynamic mechanisms involved. Selected phytoconstituents gave a good score for binding affinity with the main protease 6LU7 of SARS CoV-2 as compared to the antiviral drugs already being used in the disease therapy. DehydroglyasperinC(-8.7,-8.1,-6.7,-7.1)kcal/mol, Licochalcone D(-8.4,-8.2,-7.1,-7.9) kcal/mol, Liquiritin(-8.6,-9.0,-7.2,-7.8) kcal/mol have showed energy interactions with 3Clpro better than many FDA approved repurposed drugs; Remdesvir, Favipiravir, and Hydroxychloroquine. MD Simulation also corelates our findings for molecular docking studies.

Piperazine scaffolds or 2-azetidinone pharmacophores have been reported to show anti-cancer activities and apoptosis induction in different types of cancer cells. However, the mechanistic studies involve in induction of apoptosis addressing these two moieties for human cervical cancer cells remain uncertain. The present study emphasizes on the anti-proliferating properties and mechanism involved in induction of apoptosis for these structurally related azoles derivatives in HeLa cancer cells. 1-Phenylpiperazine clubbed with 2-azetidione derivatives (5a-5h) were synthesized, characterized using various spectroscopic techniques and evaluated for their in-vitro anti-proliferative activities and induction of apoptosis. Further, we also evaluated oxidative stress generated by these synthetic derivatives (5a-5h). Cell viability studies revealed that among all, the compound N-(3-chloro-2-(3-nitrophenyl)-4-oxoazetidin-1-yl)-2-(4-phenylpiperazin-1-yl) acetamide 5e remarkably inhibited the growth of HeLa cells in a concentration dependent manner having IC value of 29.44 ± 1.46 µg/ml. Morphological changes, colonies suppression and inhibition of migration clearly showed the antineoplasicity in HeLa cells treated with 5e. Simultaneously, phosphatidylserine externalization, DNA fragmentation and cell-cycle arrest showed ongoing apoptosis in the HeLa cancer cells induced by compound 5e in concentration dependent manner. Additionally, generation of intracellular ROS along with the decrease in mitochondrial membrane potential supported that compound 5e caused oxidative stress resulting in apoptosis through mitochondria mediated pathway. Elevation in the level of cytochrome c and upregulation in expression of caspase-3 clearly indicated the involvement of the intrinsic pathway of programmed cell death. In brief; compound 5e could serve as a promising lead for the development of an effective antitumor agent.

Based on the results of in vitro studies, it could be concluded that compound 5e showed a significant inhibitory growth effect on MCF-7 cells and have the potential to be developed as lead molecule and further structural modifications may result in promising new anticancer agents.