170147-88-3Relevant academic research and scientific papers
Novel carbamates as orally active acetylcholinesterase inhibitors found to improve scopolamine-induced cognition impairment: Pharmacophore-based virtual screening, synthesis, and pharmacology
Chaudhaery, Shailendra S.,Roy, Kuldeep K.,Shakya, Neeraj,Saxena, Gunjan,Sammi, Shreesh Raj,Nazir, Aamir,Nath, Chandishwar,Saxena, Anil K.
, p. 6490 - 6505 (2010)
A systematic virtual screening (VS) experiment, consisting of the development of 3D-pharmacophore, screening of virtual library, synthesis, and pharmacology, is reported. The predictive pharmacophore model (correlation = 0.955) with one H-bond donor and three hydrophobic features was developed using HypoGen on a training set of 24 carbamates as AChE inhibitors. The model was validated on a test set of 40 carbamates (correlation = 0.844). The pharmacophore-based VS of virtual library led to the identification of novel carbamates as potent AChE inhibitors. The synthesis and pharmacological evaluation of nine carbamates against three diverse assay systems, namely (i) in vitro Ellman method, (ii) in vivo passive avoidance test, and (iii) aldicarb-sensitivity assay, led to the discovery of orally active novel AChE inhibitors which improved scopolamine-induce cognition impairment in Swiss male mice. Finally, two novel lead compounds 85 and 86 are selected as candidate molecules for further optimization.
Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer's disease
Roy, Kuldeep K.,Tota, Santoshkumar,Tripathi, Tusha,Chander, Subhash,Nath, Chandishwar,Saxena, Anil K.
, p. 6313 - 6320 (2012/11/13)
The optimization of our previous lead compound 1 (AChE IC50 = 3.31 μM) through synthesis and pharmacology of a series of novel carbamates is reported. The synthesized compounds were evaluated against mouse brain AChE enzyme using the colorimetric method described by Ellman et al. The three compounds 6a (IC50 = 2.57 μM), 6b (IC50 = 0.70 μM) and 6i (IC50 = 2.56 μM) exhibited potent in vitro AChE inhibitory activities comparable to the drug rivastigmine (IC50 = 1.11 μM). Among them, the compound 6b has been selected as possible optimized lead for further neuropharmacological studies. In addition, the AChE-carbamate Michaelis complexes of these potent compounds including rivastigmine and ganstigmine have been modeled using covalent docking protocol of GOLD and important direct/indirect interactions contributing to stabilization of the AChE-carbamate Michaelis complexes have been investigated.
Substituted 1,2,3,4-tetrahydroquinolin-6-yloxypropanes as β3-adrenergic receptor agonists: Design, synthesis, biological evaluation and pharmacophore modeling
Shakya, Neeraj,Roy, Kuldeep K.,Saxena, Anil K.
experimental part, p. 830 - 847 (2009/07/25)
In search of potent β3-adrenergic receptor agonists, a series of novel substituted 1,2,3,4-tetrahydroquinolin-6-yloxypropanes has been synthesized and evaluated for their β3-adrenergic receptor agonistic activity (ranging from -17.73% to 90.64% inhibition at 10 μM) using well established Human SK-N-MC neuroblastoma cells model. Four molecules viz. 11, 15, 22 and 23 showed β3-AR agonistic IC50 value of 0.55, 0.59, 1.18 and 1.76 μM, respectively. These four candidates have been identified as possible leads for further development of β3-adrenergic receptor agonists for obesity and Type-II diabetes pharmacotherapy. The free OH and NH functions are found to be essential for β3-adrenergic receptor agonistic activity. Among the synthesized β3-adrenergic receptor agonists having 1,2,3,4-tetrahydroquinoline scaffold, the N-benzyl group is found to be superior over N-arylsulfonyl group. A putative pharmacophore model has been modeled considering the above four active molecules which distinguishes well between the active and inactive molecules.
