Experimental and Theoretical Approaches in the Study of Phenanthroline‐Tetrahydroquinolines for Alzheimer's Disease

Abstract

The imino‐Diels‐Alder reaction is one of the most common strategies in organic chemistry and is an important tool for providing a broad spectrum of biologically active heterocyclic systems. A combined theoretical and experimental study of the imino‐Diels‐Alder reaction is described. The new phenanthroline‐tetrahydroquinolines were evaluated as cholinesterase inhibitors. Their cytotoxicity in human neuroblastoma SH‐SY5Y cells was also evaluated. The theoretical results suggest that compounds formation in stages can be explained by endo cycloadducts under the established reaction conditions, thereby confirming experimental results obtained for percentage yield. These results allowed us to establish that pyridine substituent remarkably influences activation energy and reaction yield, as well as in acetylcholinesterase (AChE) activity. Among these derivatives, compounds with 4‐pyridyl and 4‐nitrophenyl showed favorable AChE activity and proved to be non‐cytotoxic.

Validation of Acetylcholinesterase Inhibition Machine Learning Models for Multiple Species

“…The majority of the original 309 compounds compiled by the EPA in the ToxCast Phase 1 chemical library were pesticides or the active ingredients thereof, and a recent screen of the ten-thousand-compound Tox21 library used three different in vitro HTS assays to identify AChE inhibitors . Despite divergence in primary sequences, and several duplication events in invertebrates, the 3D structure of the enzyme is mostly shared across species. − Although the electric eel AChE is regularly used in the search for human drugs, − some studies have documented interspecies differences in inhibition for certain classes of compounds. − …”

“… 38 Despite divergence in primary sequences, and several duplication events in invertebrates, the 3D structure of the enzyme is mostly shared across species. 39 − 43 Although the electric eel AChE is regularly used in the search for human drugs, 44 − 53 some studies have documented interspecies differences in inhibition for certain classes of compounds. 54 − 56 …”

Main Group Metal‐Mediated Transformations of Imines

“…Thirdly,i ts reactive C=Nb ond, a key intermediate for accessing many valuable nitrogen-containingo rganic molecules. For example nucleophilic addition, imine Diels-Alder [22][23][24][25] and cascade reactions to construct sophisticated N-heterocyclic rings, such as those found in alkaloids. [26] The Scope of this Review This review will encompass the development of synthetic protocols employing classic imines and main group metals.…”

“…Thirdly, its reactive C=N bond, a key intermediate for accessing many valuable nitrogen‐containing organic molecules. For example nucleophilic addition, imine Diels–Alder [22–25] and cascade reactions to construct sophisticated N‐heterocyclic rings, such as those found in alkaloids [26] …”