Browsing by Author "Jitendra Satija"

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Extraction, isolation, synthesis, and biological evaluation of novel piperic acid derivatives for the treatment of Alzheimer’s disease
(Springer Nature, 2024) Jitendra Kumar; Gauri Shankar; Sunil Kumar; Jobin Thomas; Neha Singh; Saripella Srikrishna; Jitendra Satija; Sairam Krishnamurthy; Gyan Modi; Sunil Kumar Mishra
In this paper, we developed a series of piperic acid (PA) analogs with the aim of overcoming the limitations associated with the natural products for the management of Alzheimer’s disease (AD). A comprehensive SAR study was performed to enhance cholinesterase inhibition of PA. The acetylcholinesterase inhibition and its kinetic data suggested 6j as the lead molecule (AChE IC50 = 2.13 ± 0.015 µM, BChE = 28.19 ± 0.20%), in comparison to PA (AChE = 7.14 ± 0.98%) which was further selected for various biological studies in AD models. 6j, exhibited interaction with the peripheral anionic site of AChE, BBB permeability (Pe = 7.98), and antioxidant property (% radical scavenging activity = 35.41 ± 1.09, 2.43 ± 1.65, for 6j and PA at 20 Mμ, respectively). The result from the metal chelation study suggests that 6j did not effectively chelate iron. The molecular modeling studies suggested that 6j could effectively interact with Ser293, Phe295, Arg296, and Tyr34 of AChE. In the cell-based cytotoxicity studies, 6j exhibited cytocompatibility at the different tested concentrations. The acute toxicity data on mice suggested that compound 6j had no renal and hepatotoxicity at 500 mg/kg. Moreover, 6j could effectively reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice. The above results strongly suggest that compound 6j may act as a novel multi-targeted lead for AD therapy. Graphical abstract: (Figure presented.) © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023.
Repurposing the in-house generated Alzheimer’s disease targeting molecules through computational and preliminary in-vitro studies for the management of SARS-coronavirus-2
(Springer Nature, 2024) Gourav Singh; Jobin Thomas; Sahil Wadhawa; Anurag Kashyap; Syed Ajijur Rahaman; Subhomoi Borkotoky; Agnisha Datta; Gireesh Kumar Singh; Indubhusan Mishra; Geeta Rai; Jitendra Satija; Vikash Kumar Dubey; Gyan Modi
Covid-19 was declared a world pandemic. Recent studies demonstrated that Covid-19 impairs CNS activity by crossing the blood–brain barrier and ensuing cognitive impairment. In this study, we have utilized Covid-19 main protease (Mpro) as a biological target to repurpose our previously reported multifunctional compounds targeting Alzheimer’s disease. Molecular docking, spatial orientation, molecular dynamics simulation, MM-GBSA energy calculation, and DFT studies were carried out with these molecules. Among all the compounds, F27, F44, and F56 exhibited higher binding energy (− 8.03, − 8.65, and − 8.68 kcal/mol, respectively) over the co-crystal ligand O6K (− 7.00 kcal/mol). In MD simulation, compounds F27, F44, and F56 could make a stable complex with Mpro target throughout the simulation. The compounds were synthesized following reported methods and subjected for cytotoxicity, and assessment of their capability to cross the blood–brain barrier in PAMPA assay, and antioxidant property evaluation through DPPH assay. The compounds F27, F44, and F56 exhibited cytocompatibility with the SiHA cell line and also displayed significant antioxidant properties with IC50 = 45.80 ± 0.27 μM, 44.42 ± 0.30 μM, and 42.74 ± 0.23 μM respectively. In the PAMPA assays, the permeability coefficient (Pe) value of F27, F44, and F56 lies in the acceptable range (Pe > 4). The results of the computational and preliminary in-vitro studies strongly corroborate the potential of F27, F44, and F56 as a lead for further optimization in treating the CNS complications associated with Covid-19. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023.