Browsing by Author "Samir Ranjan Panda"

Now showing 1 - 2 of 2

Design, Synthesis, and Biological Evaluation of Ferulic Acid Template-Based Novel Multifunctional Ligands Targeting NLRP3 Inflammasome for the Management of Alzheimer’s Disease
(American Chemical Society, 2024) Gourav Singh; Gauri Shankar; Samir Ranjan Panda; Sunil Kumar; Sanskriti Rai; Himanshu Verma; Prabhat Kumar; Prasanta Kumar Nayak; V.G.M. Naidu; Saripella Srikrishna; Saroj Kumar; Gyan Modi
Alzheimer’s disease (AD) is the most common cause of dementia, which arises due to low levels of acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aβ and tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multifunctional molecules for AD, systematic SAR studies on EJMC-4e were caried out to improve its multifunctional properties. The rigorous medicinal efforts led to the development of 12o, which displayed a 15-fold enhancement in antioxidant properties and a 2-fold increase in the activity against AChE and BChE over EJMC-4e. Molecular docking and dynamics studies revealed the binding sites and stability of the complex of 12o with AChE and BChE. The PAMPA-BBB assay clearly demonstrated that 12o can easily cross the blood-brain barrier. Interestingly, 12o also expresses promising metal chelation activity, while EJMC-4e was found to be devoid of this property. Further, 12o inhibited metal-induced or self Aβ1-42 aggregation. Observing the neuroprotection ability of 12o against H2O2-induced oxidative stress in the PC-12 cell line is noteworthy. Furthermore, 12o also inhibited NLRP3 inflammasome activation and attenuated mitochondrial-induced ROS and MMP damage caused by LPS and ATP in HMC-3 cells. In addition, 12o is able to effectively reduce mitochondrial and cellular oxidative stress in the AD Drosophila model. Finally, 12o could reverse memory impairment in the scopolamine-induced AD mice model, as evident through in vivo and ex vivo studies. These findings suggest that this compound may act as a promising candidate for further improvement in the management of AD. © 2024 American Chemical Society.
Design, Synthesis, and Biological Evaluation of Ferulic Acid-Piperazine Derivatives Targeting Pathological Hallmarks of Alzheimer’s Disease
(American Chemical Society, 2024) Gourav Singh; Sunil Kumar; Samir Ranjan Panda; Prabhat Kumar; Sanskriti Rai; Himanshu Verma; Yash Pal Singh; Saroj Kumar; Saripella Srikrishna; V.G.M. Naidu; Gyan Modi
Alzheimer’s disease (AD) is the most prevalent cause of dementia and is characterized by low levels of acetyl and butyrylcholine, increased oxidative stress, inflammation, accumulation of metals, and aggregations of Aβ and tau proteins. Current treatments for AD provide only symptomatic relief without impacting the pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multitarget molecules for AD, through extensive medicinal chemistry efforts, we have developed 13a, harboring the key functional groups to provide not only symptomatic relief but also targeting oxidative stress, able to chelate iron, inhibiting NLRP3, and Aβ1-42 aggregation in various AD models. 13a exhibited promising anticholinesterase activity against AChE (IC50 = 0.59 ± 0.19 μM) and BChE (IC50 = 5.02 ± 0.14 μM) with excellent antioxidant properties in DPPH assay (IC50 = 5.88 ± 0.21 μM) over ferulic acid (56.49 ± 0.62 μM). The molecular docking and dynamic simulations further corroborated the enzyme inhibition studies and confirmed the stability of these complexes. Importantly, in the PAMPA-BBB assay, 13a turned out to be a promising molecule that can efficiently cross the blood-brain barrier. Notably, 13a also exhibited iron-chelating properties. Furthermore, 13a effectively inhibited self- and metal-induced Aβ1-42 aggregation. It is worth mentioning that 13a demonstrated no symptom of cytotoxicity up to 30 μM concentration in PC-12 cells. Additionally, 13a inhibited the NLRP3 inflammasome and mitigated mitochondrial-induced reactive oxygen species and mitochondrial membrane potential damage triggered by LPS and ATP in HMC-3 cells. 13a could effectively reduce mitochondrial and cellular reactive oxygen species (ROS) in the Drosophila model of AD. Finally, 13a was found to be efficacious in reversing memory impairment in a scopolamine-induced AD mouse model in the in vivo studies. In ex vivo assessments, 13a notably modulates the levels of superoxide, catalase, and malondialdehyde along with AChE and BChE. These findings revealed that 13a holds promise as a potential candidate for further development in AD management. © 2024 American Chemical Society.