Remya, Chandran; Dileep, K. V.; Koti Reddy, Eeda; Mantosh, Kumar; Lakshmi, Kesavan; Sarah Jacob, Reena; Sajith, Ayyiliyath M.; Jayadevi Variyar, E.; Anwar, Shaik; Zhang, Kam Y. J.; Sadasivan, C.; Omkumar, R. V. published the artcile< Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase - Design, synthesis and biological evaluation>, SDS of cas: 329214-79-1, the main research area is aminotetrahydroacridine preparation NMDA receptor antagonist cholinesterase inhibition SAR docking; AChE, acetylcholinesterase; AChEIs, acetylcholinesterase inhibitors; AChT, acetylthiocholine; AD, Alzheimer’s disease; ADME, absorption, distribution, metabolism and excretion; Acetylcholinesterase; Alzheimer’s disease; BBB, blood brain barrier; Ca2+, calcium; ChE, Cholinesterases; DMEM, Dulbecco’s modified Eagle’s medium; DTNB, 5,5-dithiobis-(2-nitrobenzoic acid); ENM, elastic network modeling; ER, endoplasmic reticulum; FRET, fluorescence resonance energy transfer; G6PD, glucose-6-phosphate dehydrogenase; HBSS, Hank’s balanced salt solution; IP, intraperitoneal; LBD, Ligand binding domain; LC-MS, Liquid chromatography-mass spectrometry; LiCABEDS, Ligand Classifier of Adaptively Boosting Ensemble Decision Stumps; MAP2, microtubule associated protein 2; MD, Molecular dynamics; MTDLs; MTDLs, multi-target directed ligands; MWM, Morris water maze; NBM, neurobasal medium; NMA, normal mode analysis; NMDA receptor; NMDAR, N-methyl-D-aspartate receptor; Neuroprotection; OPLS, Optimized potential for liquid simulations; PBS, phosphate-buffered saline; PFA, paraformaldehyde; Polypharmacology; RMSD, root mean square deviation; SAR, structure-activity relationships; SD, standard deviation; SVM, support vector machine; Structure-based drug design; TBI, traumatic brain injury; TMD, transmembrane domain; Tacrine; h-NMDAR, human NMDAR; hAChE, human AChE; ppm, parts per million.
An novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, performed in-silico structure-based modifications on tacrine, chem. synthesis of the derivatives and in-vitro validation of their activities. Nineteen such derivatives I [R = H, methylcarbamoyl, hydrazinecarbonyl, ethoxycarbonyl; R1 = 2-furanyl, 1-methylpyrazol-4-yl, 2-FC6H4, etc.] showed inhibition with IC50 values in the range of 18.53 ± 2.09 – 184.09 ± 19.23 nM against AChE and 0.27 ± 0.05 – 38.84 ± 9.64μM against NMDAR. Some of the selected compounds protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, I [R = H, R1 = 1-methylpyrazol-4-yl; R = H, R1 = 2-FC6H4] exhibited in-vivo efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Addnl., several of these synthesized compounds also exhibited promising inhibitory activitiy against butyrylcholinesterase. MTDL-201 I [R = H, R1 = 1-methylpyrazol-4-yl] was also devoid of hepatotoxicity in-vivo. Given the therapeutic potential of MTDLs in disease-modifying therapy, studies revealed several promising MTDLs among which I [R = H, R1 = 1-methylpyrazol-4-yl] appeared to be a potential candidate for immediate preclin. evaluations.
Computational and Structural Biotechnology Journal published new progress about Aminoacridines Role: PAC (Pharmacological Activity), RCT (Reactant), SPN (Synthetic Preparation), THU (Therapeutic Use), BIOL (Biological Study), RACT (Reactant or Reagent), PREP (Preparation), USES (Uses). 329214-79-1 belongs to class pyridine-derivatives, and the molecular formula is C11H16BNO2, SDS of cas: 329214-79-1.