Browsing by Author "Gauri Shankar"

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Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease
(Elsevier Masson SAS, 2020) Yash Pal Singh; Gullanki Naga Venkata Charan Tej; Amruta Pandey; Khushbu Priya; Pankaj Pandey; Gauri Shankar; Prasanta Kumar Nayak; Geeta Rai; Amar G. Chittiboyina; Robert J. Doerksen; Swati Vishwakarma; Gyan Modi
In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 μM; BChE IC50 = 14.05 ± 0.10 μM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 μM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 μM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid β1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders. © 2020 Elsevier Masson SAS
Design, synthesis and biological evaluation of novel piperic acid and benzylpiperazine hybrid molecules for improvement of memory impairment via cholinesterase inhibitory activity
(Springer Science and Business Media Deutschland GmbH, 2025) Jitendra Kumar; Gauri Shankar; S. Dasaratha Kumar; Gourav Singh; T. A. Gajendra; Sanskriti Rai; Upesh Mandloi; Saripella Srikrishna; Saroj Kumar; Amit Kumar Singh; Pradeep Harish Kumar; Kavindra Nath Tiwari; Sairam Krishnamurthy; Gyan Prakash Modi; Sunil Kumar Mishra
In this paper, we have developed a series of piperic acid (PA) derivatives to overcome the inherent constraints linked to PA for Alzheimer's disease (AD) management. We have carried out a comprehensive study to investigate the structure–activity relationship (SAR) of PAanalogs to enhance their inhibitory properties towards cholinesterase enzymes. Compound 3m exhibited notable inhibition against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) among all developed analogs (BChE (µM), 1.03 ± 0.011; AChE (µM), 4.26 ± 0.13 respectively) over PA (AChE% inhibition at 20 µM, 7.14 ± 0.98; BChE% inhibition at 20 µM, 5.87 ± 0.76). Compound 3m was chosen for further biological investigations based on these encouraging outcomes. 3 m demonstrated a binding affinity for AChE’s peripheral anionic site, indicating its interaction with this specific enzyme region. Additionally, it also possesses favorable permeability across the blood–brain barrier, with a Pe (permeability coefficient) value of 5.79 ± 1.12. The molecular docking investigations unveiled the ability of 3mto intricately engage with AChE and BChE.In cell-based cytotoxicity tests, compound 3m displayed cell-friendly characteristics across different tested concentrations. Notably, 3m exhibited the ability to counteract scopolamine-induced memory impairmentin mice, enhancing both spatial and cognitive memories. These results strongly suggest that 3m can behave as a potential compound for AD management. © The Author(s), under exclusive licence to the Institute of Chemistry, Slovak Academy of Sciences 2024.
Design, synthesis and biological evaluation of novel piperic acid and benzylpiperazine hybrid molecules for improvement of memory impairment via cholinesterase inhibitory activity
(Springer Science and Business Media Deutschland GmbH, 2024) Jitendra Kumar; Gauri Shankar; Sunil Kumar; Gourav Singh; T.A. Gajendra; Sanskriti Rai; Upesh Mandloi; Saripella Srikrishna; Saroj Kumar; Amit Kumar Singh; Pradeep Kumar; Kavindra Nath Tiwari; Sairam Krishnamurthy; Gyan Modi; Sunil Kumar Mishra
In this paper, we have developed a series of piperic acid (PA) derivatives to overcome the inherent constraints linked to PA for Alzheimer's disease (AD) management. We have carried out a comprehensive study to investigate the structure–activity relationship (SAR) of PAanalogs to enhance their inhibitory properties towards cholinesterase enzymes. Compound 3m exhibited notable inhibition against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) among all developed analogs (BChE (µM), 1.03 ± 0.011; AChE (µM), 4.26 ± 0.13 respectively) over PA (AChE% inhibition at 20 µM, 7.14 ± 0.98; BChE% inhibition at 20 µM, 5.87 ± 0.76). Compound 3m was chosen for further biological investigations based on these encouraging outcomes. 3 m demonstrated a binding affinity for AChE’s peripheral anionic site, indicating its interaction with this specific enzyme region. Additionally, it also possesses favorable permeability across the blood–brain barrier, with a Pe (permeability coefficient) value of 5.79 ± 1.12. The molecular docking investigations unveiled the ability of 3mto intricately engage with AChE and BChE.In cell-based cytotoxicity tests, compound 3m displayed cell-friendly characteristics across different tested concentrations. Notably, 3m exhibited the ability to counteract scopolamine-induced memory impairmentin mice, enhancing both spatial and cognitive memories. These results strongly suggest that 3m can behave as a potential compound for AD management. Graphical abstract: (Figure presented.) © The Author(s), under exclusive licence to the Institute of Chemistry, Slovak Academy of Sciences 2024.
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.
Discovery of novel hybrid tryptamine-rivastigmine molecules as potent AChE and BChE inhibitors exhibiting multifunctional properties for the management of Alzheimer's disease
(Elsevier Masson s.r.l., 2025) Gauri Shankar; Prabhat Kumar; Sanskriti Rai; Aparajita Ghosh; Tanmaykumar Varma; Mushtaq Ahmad Wani; Sunil N. Kumar; Upesh Mandloi; Gireesh Kumar Singh; Prabha Garg; Onkar Prakash Kulkarni; Saripella Srikrishna; Saroj Kumar; Gyan Prakash Modi
Contemporary research evidence has corroborated a gradual loss of central cholinergic neurons in Alzheimer's Disease (AD). This progressive deterioration leads to cognitive dysfunction and impaired motor activity, culminating in the brain cell's death in the disease. The approved drugs for AD treatment can only offer relief from symptoms without addressing the underlying pathological hallmarks of the disease. To address the limitations associated with rivastigmine (RIV), a marketed drug for AD, a series of tryptamine derivatives was designed, synthesized, and evaluated in various in-vitro and in-vivo AD models. Enzyme inhibition studies identified compounds 6d and 6e as the lead molecules with potent inhibitors against AChE (6d, IC50: 0.99 ± 0.009 nM and 6e IC50: 7.97 ± 0.016 nM and BChE (6d, IC50: 27.79 ± 0.21 nM and 6e, IC50: 0.79 ± 0.005 nM), compared to the marketed drug Riv (AChE, IC50: 6630 ± 0.76 nM, BChE IC50 = 91 ± 0.40 nM). The molecular docking and dynamics studies corroborated the enzyme inhibition studies. The PAMPA assay strongly suggested the BBB crossing ability of the lead molecules. Further, 6d and 6e demonstrated the capability to counteract oxidative stress and Aβ1-42 in various in-vitro studies. Compound 6e exhibited remarkable radical scavenging activity in the DPPH assay (IC50: 22.91 ± 1.73 μM) compared to rivastigmine (% radical scavenging activity: 3.71 ± 0.09 at 200 μM). Interestingly, 6d and 6e exhibited promising activity in the AD Drosophila model by protecting eye phenotypes from degeneration induced by Aβ1-42 toxicity and reduced mitochondrial and cellular oxidative stress in this model. Furthermore, upon oral administration, 6d and 6e could reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice at 0.3 and 0.5 mg/kg compared to rivastigmine at 3 mg/kg and were found to have potent ex-vivo anti-ChEs properties, which are correlated with the observed pro-cognitive effects in the Morris Water Maze, likely mediated through the inhibition of both cholinesterases. The expression of various neuroprotection markers, such as BDNF and TRKB, was significantly overexpressed compared to the disease control group. © 2024 Elsevier Masson SAS
Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid β Induced Neurotoxicity in Alzheimer’s Disease Models
(American Chemical Society, 2022) Yash Pal Singh; Navneet Kumar; Khushbu Priya; Brijesh Singh Chauhan; Gauri Shankar; Saroj Kumar; Gireesh Kumar Singh; Saripella Srikrishna; Prabha Garg; Gourav Singh; Geeta Rai; Gyan Modi
The pathological hallmarks of Alzheimer’s disease (AD) are manifested as an increase in the level of oxidative stress and aggregation of the amyloid-β protein. In vitro, in vivo, and in silico experiments were designed and carried out with multifunctional cholinergic inhibitor, F24 (EJMC-7a) to explore its neuroprotective effects in AD models. The neuroprotection ability of F24 was tested in SH-SY5Y cells, a widely used neuronal cell line. The pretreatment and subsequent co-treatment of SH-SY5Y cells with different doses of F24 was effective in rescuing the cells from H2O2 induced neurotoxicity. F24 treated cells were found to be effective in the reduction of cellular reactive oxygen species, DNA damage, and Aβ1–42 induced neurotoxicity, which validated its neuroprotective effectiveness. F24 exhibited efficacy in an in vivo Drosophila model by rescuing eye phenotypes from degeneration caused by Aβ toxicity. Further, computational studies were carried out to monitor the interaction between F24 and Aβ1–42 aggregates. The computational studies corroborated our in vitro and in vivo studies suggesting Aβ1–42 aggregation modulation ability of F24. The brain entry ability of F24 was studied in the parallel artificial membrane permeability assay. Finally, F24 was tested at doses of 1 and 2.5 mg/kg in the Morris water maze AD model. The neuroprotective properties shown by F24 strongly suggest that multifunctional features of this molecule provide symptomatic relief and act as a disease-modifying agent in the treatment of AD. The results from our experiments strongly indicated that natural template-based F24 could serve as a lead molecule for further investigation to explore multifunctional therapeutic agents for AD management. © 2021 American Chemical Society
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.
Multicomponent Synthesis of S-Benzyl Dithiocarbamates from para-Quinone Methides and Their Biological Evaluation for the Treatment of Alzheimer’s Disease
(American Chemical Society, 2022) Rapelly Venkatesh; Gauri Shankar; Aswathi C. Narayanan; Gyan Modi; Shahulhameed Sabiah; Jeyakumar Kandasamy
Multicomponent synthesis of biologically relevant S-benzyl dithiocarbamates from para-quinone methides, amines, and carbon disulfide are described under catalyst and additive-free conditions. The reactions proceeded at room temperature in a short span of time with excellent yields. One of the synthesized compounds, 3e showed considerable acetylcholinesterase (AChE) inhibitory (51.70 + 5.63% at 20 μm) and antioxidant (63.52 ± 1.15 at 20 μm) activities. © 2022 American Chemical Society.
Some parasitic fungi on piper betle L. In Varanasi, Uttar Pradesh
(Kluwer Academic Publishers, 1971) R.A. Singh; Gauri Shankar
[No abstract available]
Voltage Stabilization Control with Hybrid Renewable Power Sources in DC Microgrid
(Institute of Electrical and Electronics Engineers Inc., 2024) Khalid Raza Khan; Suryakant Kumar; Vedantham Lakshmi Srinivas; Ram Khelawan Saket; Kartick Chandra Jana; Gauri Shankar
The rapid rise in renewable power generation, Energy storage devices, DC electronic loads, and electric vehicles has forced the technical evolvement of the present Microgrid structure from AC to DC. The DC Microgrid (DCMG) can still work with the AC system but with reduced conversion stages, improved reliability, and efficiency. A single AC-DC converter connected to the utility can source the DC bus, supporting multiple DC generation to feed both AC and DC loads. This reduces the grid's burden and makes the generation system environment-friendly. The present work demonstrates the detailed control strategy of one such DCMG with a hardware setup working at 600V DC. The sources considered are Solar Photovoltaic System (SPVS), Permanent Magnet Synchronous Generator (PMSG)-based wind energy conversion system, Battery, and utility grid. The proposed DCMG can maintain stable DC bus voltage under various dynamic conditions by balancing the power on either side of the DC bus. The presence of a grid is considered to maintain stable AC voltage and frequency for AC loads. The control strategy is simulated in MATLAB/Simulink environment and validated through hardware experiments in the WAVECT WCU300 controller. © 1972-2012 IEEE.