Browsing by Author "Piyoosh Sharma"

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Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory
(Academic Press Inc., 2019) Prabhash Nath Tripathi; Pavan Srivastava; Piyoosh Sharma; Manish Kumar Tripathi; Ankit Seth; Avanish Tripathi; Sachchida Nand Rai; Surya Pratap Singh; Sushant K. Shrivastava
A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC 50 ; 0.2 ± 0.01 μM) compared to standard donepezil (AChE, IC 50 : 0.1 ± 0.002 μM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ± 1.11%) and showed good CNS permeability in PAMPA-BBB assay (P e (exp) , 6.93 ± 0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE. © 2018 Elsevier Inc.
Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease
(Academic Press Inc., 2019) Sushant K. Shrivastava; Saurabh K. Sinha; Pavan Srivastava; Prabhash N. Tripathi; Piyoosh Sharma; Manish K. Tripathi; Avanish Tripathi; Priyanka K. Choubey; Digambar K. Waiker; Lalit M. Aggarwal; Manish Dixit; Subhash C. Kheruka; Sanjay Gambhir; Sharmila Shankar; Rakesh K. Srivastava
Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE. © 2018 Elsevier Inc.
Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory
(Elsevier Masson SAS, 2019) Pavan Srivastava; Prabhash Nath Tripathi; Piyoosh Sharma; Sachchida Nand Rai; Surya Pratap Singh; Rakesh K. Srivastava; Sharmila Shankar; Sushant K. Shrivastava
Based on the Gaussian-based quantitative structure-activity relationship (QSAR) and virtual screening (VS) processes, some promising acetylcholinesterase inhibitors (AChEIs) having antioxidant potential were designed synthesized, characterized, and evaluated for their ability to enhance learning and memory. The synthesized phenyl benzoxazole derivatives exhibited significant antioxidant potential and AChE inhibitory activity, whereas the antioxidant potential of compound 34 (49.6%) was observed significantly better than standard donepezil (<10%) and parallel to ascorbic acid (56.6%). Enzyme kinetics study of most potent compound 34 (AChE IC50 = 0.363 ± 0.017 μM; Ki = 0.19 ± 0.03 μM) revealed the true nature and competitive type of inhibition on AChE. The compound 34 was further assessed for in vivo and ex vivo studies and the results showed the significant reversal of cognitive deficits and antioxidant potential at the dose of 5 mg/kg comparable to standard drug donepezil. © 2018 Elsevier Masson SAS
Dissolution Profile Consideration in Pharmaceutical Product Development
(Elsevier, 2018) Disha Mehtani; Ankit Seth; Piyoosh Sharma; Rahul Maheshwari; Sara Nidal Abed; Pran Kishore Deb; Mahavir B. Chougule; Rakesh K. Tekade
Dissolution testing has been evolved as an approach based on risk and science, to control the quality of pharmaceutical dosage forms, as well as to assist pharmaceutical product development, approval, and postapproval dossier submissions. It reduces regulatory burden, resource requirements, and thus development times and cost in the long, arduous, and expensive process of formulation development. It is considered as an important tool used in formulation development and optimization; estimation of drug release under physiological conditions; assurance of batch-to-batch consistency; stability monitoring; bioequivalence determination between pharmaceutical formulations. This chapter highlights the significance of the dissolution and the related concepts throughout the pharmaceutical drug development continuum. The initial part of the chapter outlines the development of a relevant dissolution test; taking into consideration all the parameters that influence its performance and results. The later part highlights the concepts of dissolution profile comparison, IVIVC and BCS (integrating with QbD), and their roles from nonclinical to the postmarketing stage of drug development to ensure a high-quality biopharmaceutical product of desirable attributes. © 2018 Elsevier Inc. All rights reserved.
Drug Disposition Considerations in Pharmaceutical Product
(Elsevier, 2018) Rahul Maheshwari; Piyoosh Sharma; Ankit Seth; Neha Taneja; Muktika Tekade; Rakesh K. Tekade
An understanding of the fate of the biomolecules/drugs, pharmaceutical product development is mostly based on its drug disposition and pharmacokinetic characteristics. The understandings of drug disposition principles are beneficial in drug discovery of new products and helpful in drug toxicity analysis. Drug disposition is an essential phenomenon in humans which affects the fate of external chemical entering in the system. An ADME investigation is most critical in developing and designing the drug for human use by performing a thorough animal investigation. This chapter expounds the concept of drug disposition/pharmacokinetics, its role in pharmaceutical product development and various parameters affecting drug disposition. © 2018 Elsevier Inc. All rights reserved.
Novel Molecular Hybrids of N-Benzylpiperidine and 1,3,4-Oxadiazole as Multitargeted Therapeutics to Treat Alzheimer's Disease
(American Chemical Society, 2019) Piyoosh Sharma; Avanish Tripathi; Prabhash Nath Tripathi; Saumitra Sen Singh; Surya Pratap Singh; Sushant Kumar Shrivastava
Multitargeted hybrids of N-benzylpiperidine and substituted 5-phenyl-1,3,4-oxadiazoles were designed, synthesized, and evaluated against Alzheimer's disease (AD). Tested compounds exhibited moderate to excellent inhibition against human acetylcholinesterase (hAChE), butyrylcholinesterase (hBChE), and beta-secretase-1 (hBACE-1). The potential leads 6g and 10f exhibited balanced inhibitory profiles against all the targets, with a substantial displacement of propidium iodide from the peripheral anionic site of hAChE. Hybrids 6g and 10f also elicited favorable permeation across the blood-brain barrier and were devoid of neurotoxic liability toward SH-SY5Y neuroblastoma cells. Both leads remarkably disassembled Aβ aggregation in thioflavin T-based self- and AChE-induced experiments. Compounds 6g and 10f ameliorated scopolamine-induced cognitive dysfunctions in the Y-maze test. The ex vivo studies of rat brain homogenates established the reduced AChE levels and antioxidant activity of both compounds. Compound 6g also elicited noteworthy improvement in Aβ-induced cognitive dysfunctions in the Morris water maze test with downregulation in the expression of Aβ and BACE-1 proteins corroborated by Western blot and immunohistochemical analysis. The pharmacokinetic study showed excellent oral absorption characteristics of compound 6g. The in silico molecular docking and dynamics simulation studies of lead compounds affirmed their consensual binding interactions with PAS-AChE and aspartate dyad of BACE-1. © 2019 American Chemical Society.