Synthesis, computational docking and molecular dynamics studies of a new class of spiroquinoxalinopyrrolidine embedded chromanone hybrids as potent anti-cholinesterase agents.

Novel structurally intriguing heterocycles embedded with spiropyrrolidine, quinoxaline and chromanone units were synthesized in good yields using a [Bmim]Br accelerated multicomponent reaction strategy. The key step of the reaction is 1,3-dipolar cycloaddition involving highly functionalized dipolarophile, viz. 3-benzylidenechroman-4-one, to afford spiroquinoxalinopyrrolidine embedded chromanone hybrid heterocycles. The formation of spiro products occurs via two C-C, two N-C and one C-N bonds possessing four adjoining stereogenic centers, two of which are spiro carbons. The newly synthesized spiro compounds showed potent acetylcholinesterase and butyrylcholinesterase inhibitory activities. Moreover, compounds with fluorine displayed the highest AChE (3.20 ± 0.16 µM) and BChE (18.14 ± 0.06 µM) inhibitory activities. Further, docking studies, followed by all-atom molecular dynamics, showed results that are consistent with in vitro experimental findings. Although docking scores for the synthesized derivatives were higher than those of the standard drug, MD MMPBSA results showed better binding of synthesized derivatives (-93.5 ± 11.9 kcal mol-1) compared to the standard drug galantamine (-66.2 ± 12.3 kcal mol-1) for AChE but exhibited similar values (-98.1 ± 11.2 and -97.9 ± 11.5 kcal mol-1) for BChE. These differences observed in drug binding with AChE/BChE are consistent with RMSD, RMSF, LIG plots, and FEL structural analysis. Taken together, these derivatives could be potential candidates as inhibitors of AChE and BChE.

Integrated network pharmacology approach shows a potential role of Ginseng catechins and ginsenosides in modulating protein aggregation in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral Sclerosis is an incurable, progressive neurodegenerative motor neuron disease. The disease is characterized by protein aggregates. The symptoms include weakness, denervation of muscles, atrophy and progressive paralysis of bulbar and respiratory muscles and dysphagia. Various secondary metabolites are evaluated for their ability to improve symptoms in ALS. Ginseng has been traditionally used for treating several neurodegenerative diseases. Several studies using model systems have shown a potential role of Ginseng catechins and Ginsenosides in clearing protein aggregation associated with ALS. We focus on Network pharmacology approach to understand the effect of Ginseng catechins or ginsenosides on protein aggregation associated with ALS. A catechin/ginsenoside-protein interaction network was generated and the pathways obtained were compared with those obtained from transcriptomic datasets of ALS from GEO database. Knock out of MAPK14, AKT and GSK from Catechin and BACE 1 from ginsenoside modulated pathways inhibited protein aggregation. Catechins and ginsenosides have potential as therapeutic agents in the management of ALS. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03401-1.

Nucleotides modulate synoviocyte proliferation and osteoclast differentiation in macrophages with potential implications for rheumatoid arthritis.

P2 receptors are nucleotide-activated receptors involved in inflammation, cell proliferation osteoblastogenesis, osteoclastogenesis and their function. They can be potential role players in the pathophysiology of rheumatoid arthritis (RA). Our analysis of gene expression datasets of synovial tissue biopsy from the GEO database shows changes in the expression levels of P2 receptors. HIG-82, a synovial fibroblast cell line and RAW 264.7, a macrophage cell line are good in vitro models to study RA. Nucleotide addition experiments showed UDP Glucose significantly increased the proliferation of synovial fibroblasts (HIG-82). Similarly, nucleotides such as Adenosine tri-phosphate (ATP), Adenosine di-phosphate (ADP), Uridine tri-phosphate (UTP), Uridine di-phosphate (UDP) and Uridine diphosphoglucose (UDPG) induced elevated reactive oxygen species (ROS) and tartrate Resistant Acid Phosphatase (TRAP) activity in RAW264.7 cells. The ADP-induced TRAP could be inhibited by clopidogrel a P2Y12 inhibitor. ATP, ADP, UTP, UDP and UDPG also induced osteoclastogenesis as evident from fused multinucleate cells and expression of osteoclast markers (TRAP, Cathepsin K [CTSK]) as determined by Q-PCR. Apyrase (APY) a nucleotidase and an enzyme that is used to modulate extracellular nucleotide concentration is sufficient to induce osteoclastogenesis. Taken together our results show that nucleotides modulate synoviocyte proliferation and macrophage differentiation into osteoclast and play an important role in RA. Nucleotide receptors might be potential therapeutic targets in RA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-03052-8.