6943-00-6Relevant articles and documents
Identification of two arylimides as cholinesterase inhibitors and testing of propranolol addition on impaired rat memory
Ciprés-Flores, Fabiola J.,Farfán-García, Eunice D.,Andrade-Jorge, Erik,Cuevas-Hernández, Roberto I.,Tamay-Cach, Feliciano,Martínez-Archundia, Marlet,Trujillo-Ferrara, José G.,Soriano-Ursúa, Marvin A.
, p. 256 - 266 (2019/12/30)
Alzheimer's disease (AD) is clearly linked to the decline of acetylcholine (ACh) effects in the brain. These effects are regulated by the hydrolytic action of acetylcholinesterase (AChE). Therefore, a central palliative treatment of AD is the administration of AChE inhibitors although additional mechanisms are currently described and tested for generating advantageous therapeutic strategies. In this work, we tested new arylamides and arylimides as potential inhibitors of AChE using in silico tools. Then, these compounds were tested in vitro, and two selected compounds, C7 and C8, as well as propranolol showed inhibition of AChE. In addition, they demonstrated an advantageous acute toxicity profile compared to that of galantamine as a reference AChE inhibitor. in vivo evaluation of memory performance enhancement was performed in an animal model of cognitive disturbance with each of these compounds and propranolol individually as well as each compound combined with propranolol. Memory improvement was observed in each case, but without a significant additive effect with the combinations.
Late-stage oxidative C(sp 3)–H methylation
Feng, Kaibo,Kohrt, Jeffrey T.,Oderinde, Martins S.,Quevedo, Raundi E.,Reilly, Usa,White, M. Christina
, p. 621 - 627 (2020/05/04)
Frequently referred to as the ‘magic methyl effect’, the installation of methyl groups—especially adjacent (α) to heteroatoms—has been shown to dramatically increase the potency of biologically active molecules1–3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)–H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C–H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C–H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)–H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites—including drugs (for example, tedizolid) and natural products—are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates—an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1—via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.
Synthesis of 3-(5-amino-1: H -1,2,4-triazol-3-yl)propanamides and their tautomerism
Lim, Felicia Phei Lin,Tan, Lin Yuing,Tiekink, Edward R. T.,Dolzhenko, Anton V.
, p. 22351 - 22360 (2018/07/03)
Two complementary pathways for the preparation of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (5) were proposed and successfully realized in the synthesis of 20 representative examples. These methods use the same types of starting material
