938338-35-3Relevant academic research and scientific papers
Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease
Chittiboyina, Amar G.,Doerksen, Robert J.,Modi, Gyan,Nayak, Prasanta Kumar,Pandey, Amruta,Pandey, Pankaj,Priya, Khushbu,Rai, Geeta,Shankar, Gauri,Singh, Yash Pal,Tej, Gullanki Naga Venkata Charan,Vishwakarma, Swati
, (2020/05/05)
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.
Discovery of Potent, Reversible, and Competitive Cruzain Inhibitors with Trypanocidal Activity: A Structure-Based Drug Design Approach
De Souza, Mariana L.,De Oliveira Rezende Junior, Celso,Ferreira, Rafaela S.,Espinoza Chávez, Rocio Marisol,Ferreira, Leonardo L. G.,Slafer, Brian W.,Magalh?es, Luma G.,Krogh, Renata,Oliva, Glaucius,Cruz, Fabio Cardoso,Dias, Luiz Carlos,Andricopulo, Adriano D.
, p. 1028 - 1041 (2019/12/27)
A virtual screening conducted with nearly 4?000?000 compounds from lead-like and fragment-like subsets enabled the identification of a small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug target for Chagas disease. Subsequent comprehensive structure-based drug design and structure-activity relationship studies led to the discovery of carbamoyl imidazoles as potent, reversible, and competitive cruzain inhibitors. The most potent carbamoyl imidazole inhibitor (45) exhibited high affinity with a Ki value of 20 nM, presenting both in vitro and in vivo activity against T. cruzi. Furthermore, the most promising compounds reduced parasite burden in vivo and showed no toxicity at a dose of 100 mg/kg. These carbamoyl imidazoles are structurally attractive, nonpeptidic, and easy to prepare and synthetically modify. Finally, these results further advance our understanding of the noncovalent mode of inhibition of this pharmaceutically relevant enzyme, building strong foundations for drug discovery efforts.
SERINE RACEMASE INHIBITOR
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Paragraph 0215 - 0218, (2014/12/12)
A novel serine racemase inhibitor exhibits sufficient activity and specificity. The serine racemase inhibitor includes one or more compounds selected from compounds respectively represented by the following general formulas [MM_1], [DR_1], [DR'_1], [LW_1], and [ED_1] as an active ingredient.
In silico and pharmacological screenings identify novel serine racemase inhibitors
Mori, Hisashi,Wada, Ryogo,Li, Jie,Ishimoto, Tetsuya,Mizuguchi, Mineyuki,Obita, Takayuki,Gouda, Hiroaki,Hirono, Shuichi,Toyooka, Naoki
supporting information, p. 3732 - 3735 (2014/09/03)
d-Serine is a coagonist of the N-methyl-d-aspartate (NMDA)-type glutamate receptor and its biosynthesis is catalyzed by serine racemase (SR). The overactivation of the NMDA receptor has been implicated in the development of neurodegenerative diseases, strokes, and epileptic seizures, thus, the inhibitors of SR have potential against these pathological states. Here, we have developed novel inhibitors of SR by in silico screening and in vitro enzyme assay. The newly developed inhibitors have lower IC50 value comparing with that of malonate, one of the standard SR inhibitor. The structural features of novel inhibitors suggest the importance of central amide structure having a phenoxy substituent in their structure for the SR inhibitory activity. The present findings suggest the importance and rational development of new drugs for diseases of NMDAR overactivation.
