2095-17-2Relevant articles and documents
Phenothiazine-Tacrine Heterodimers: Pursuing Multitarget Directed Approach in Alzheimer's Disease
Gorecki, Lukas,Uliassi, Elisa,Bartolini, Manuela,Janockova, Jana,Hrabinova, Martina,Hepnarova, Vendula,Prchal, Lukas,Muckova, Lubica,Pejchal, Jaroslav,Karasova, Jana Z.,Mezeiova, Eva,Benkova, Marketa,Kobrlova, Tereza,Soukup, Ondrej,Petralla, Sabrina,Monti, Barbara,Korabecny, Jan,Bolognesi, Maria Laura
, p. 1698 - 1715 (2021)
Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand"approach and designed 36 novel tacrine-phenothiazine heterodimers which were in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC50 = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC50 = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward τ(306-336) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Aβ1-42 aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC50 value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.
Bacterial Biosynthetic P450 Enzyme PikCD50N: A Potential Biocatalyst for the Preparation of Human Drug Metabolites
Cheng, Fangyuan,Du, Lei,Durairaj, Pradeepraj,Guo, Jiawei,Li, Fengwei,Li, Shengying,Liu, Xiaohui,Long, Xiangtian,Ma, Li,Tang, Dandan,Zhang, Gang,Zhang, Wei,Zhang, Xingwang
, p. 14563 - 14571 (2021/11/12)
Human drug metabolites (HDMs) are important chemicals widely used in drug-related studies. However, acquiring these enzyme-derived and regio-/stereo-selectively modified compounds through chemical approaches is complicated. PikC is a biosynthetic P450 enz
POLYCYCLIC COMPOUNDS AND METHODS OF MAKING AND USING THE SAME
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Page/Page column 179; 180, (2014/07/07)
The present disclosure provides compounds, or pharmaceutically acceptable salts thereof, for inhibiting the growth of a microbe; treating a mammal having a microbial infection, malaria, mucositis, an ophthalmic infection, an otic infection, a cancer, or a Mycobacterium infection; killing or inhibiting the growth of a Plasmodium species; inhibiting the growth of a Mycobacterium species; modulating an immune response in a mammal; or antagonizing unfractionated heparin, low molecular weight heparin, or a heparin/low molecular weight heparin derivative.