351-38-2Relevant articles and documents
Design, synthesis and biological evaluation of novel thienylpyridyl-and thioether-containing acetamides and their derivatives as pesticidal agents
Li, Huan,Wang, Baolei,Xiong, Lixia,Yang, Na
, (2021/09/28)
Referring to the structural information of the “hit” compound A from the reported pharmacophore-based virtual screening, a series of novel thienylpyridyl-and thioether/sulfoxide/ sulfone-containing acetamide derivatives have been designed and synthesized.
Thiazolidinedione "magic Bullets" Simultaneously Targeting PPARγand HDACs: Design, Synthesis, and Investigations of their in Vitro and in Vivo Antitumor Effects
Tilekar, Kalpana,Hess, Jessica D.,Upadhyay, Neha,Bianco, Alessandra Lo,Schweipert, Markus,Laghezza, Antonio,Loiodice, Fulvio,Meyer-Almes, Franz-Josef,Aguilera, Renato J.,Lavecchia, Antonio,Ramaa
, p. 6949 - 6971 (2021/06/25)
Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγagonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγand HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound 7i was the most potent, with activity toward PPARγEC50 = 0.245 μM and HDAC4 IC50 = 1.1 μM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC50 = 2.8 and 9.6 μM, respectively), induced apoptosis, and caused DNA fragmentation. Furthermore, compound 7c modulated the expression of c-Myc, cleaved caspase-3, and caused in vivo tumor regression in CCRF-CEM tumor xenografts. Thus, this study provides a basis for the rational design of dual/multitargeting agents that could be developed further as anticancer therapeutics.
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.
