3245-63-4Relevant articles and documents
Dual target ligands with 4-tert-butylphenoxy scaffold as histamine H3 receptor antagonists and monoamine oxidase B inhibitors
?a?ewska, Dorota,Doroz-P?onka, Agata,Frank, Annika,Kaleta, Maria,Karcz, Tadeusz,Kie?-Kononowicz, Katarzyna,Latacz, Gniewomir,Olejarz-Maciej, Agnieszka,Reiner, David,Stark, Holger,Zygmunt, Ma?gorzata
, (2020)
Dual target ligands are a promising concept for the treatment of Parkinson’s disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H3 receptor (H3R) antagonism could have positive effects on dopamine re
Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine H3R ligands
Szczepańska, Katarzyna,Karcz, Tadeusz,Mogilski, Szczepan,Siwek, Agata,Kuder, Kamil J.,Latacz, Gniewomir,Kubacka, Monika,Hagenow, Stefanie,Lubelska, Annamaria,Olejarz, Agnieszka,Kotańska, Magdalena,Sadek, Bassem,Stark, Holger,Kie?-Kononowicz, Katarzyna
supporting information, p. 223 - 234 (2018/05/09)
As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2?25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Ki = 16.0–120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H3R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands.
Design, synthesis, docking studies and biological evaluation of novel dihydro-1,3,5-triazines as human DHFR inhibitors
Zhou, Xiaotian,Lin, Kuaile,Ma, Xiang,Chui, Wai-Keung,Zhou, Weicheng
, p. 1279 - 1288 (2016/11/29)
A novel series of dihydro-1,3,5-triazine derivatives bearing a heteroatom spiro-ring were designed and synthesized on the basis of molecular flexible docking work, and their biological activities were evaluated. Compounds A2, A5, B1 and B3 showed potent human dihydrofolate reductase (hDHFR) inhibitory activity with IC50values of 7.46 nM, 3.72 nM, 6.46 nM, 4.08 nM, versus reference drug methotrexate (MTX). From the molecular docking result we concluded that the conformation space generated by deformation of the flexible residue Phe31 is favorable for the binding of the spiro-ring, and inserting heteroatom into spiro ring might increase the binding affinity. There were 24 compounds with broadspectrum antiproliferative activity against several tumor cell lines (HCT116, A549, HL-60, HepG2 and MDA-MB-231) with IC50values ranging from 0.79 to 0.001 μM. The antitumor activity in?vivo of compound A2 was determined in a human alveolar basal epithelial cell line A549 xenograft model. This study offered novel anticancer agents with high inhibitory activity that target hDHFR and have a binding mode of the novel molecular scaffold with hDHFR. This provides potent support for further development of novel hDHFR inhibitors.
