Préparation et évaluation biologique de composés polycycliques hybrides quinoléine-hétérocycles à visée thérapeutique

Abstract

A number of original hybrids as (2-chloroquinolin-3-yl)-heterocyclic compounds were prepared from differently substituted 2-chloroquinolin-3-carbaldehydes. A series of4H-pyrans derivatives carriers an ester or ketone (aliphatic and cyclic), a nitrile and an amine functions linked in position 4 with variously substituted(2-chloroquinolin-3-yl) patterns (4a-4i) were prepared in very good yields (82-92%). Two series of (2-chloroquinolin-3-yl)-pyridine hybrids such as 2-amino-4-(2-chloroquinolin-3-yl)-6-substituted-nicotinonitriles (compounds 13-20), and 2-amino-4-(2-chloroquinolin-3-yl)-5,6,7,8-tetrahydroquinolin-3-carbonitrile derivatives (21-24) were prepared in variable yields (24-46%) from 3-(2-chloro-quinolin-3- yl)-2-cyanoacrylonitriles (3a-3d) as key intermediates in moderate yields (43-47%). The same approach was used to access to new highly functionalized (quinolin-6-yl)- heterocycles with various structures such as (quinolin-6-yl)-4H-pyran (32a-b, 33a et 34a-b), - 2-aminobenzochromene (35 et 36), and -1,4-dihydropyridine (compound 37), and that from a single intermediate the ethyl 2-chloro-6-formylquinolin-3-carboxylate (30). Yields are relatively low (10-20%) to acceptable (41-58%). A ""recovery"" hybrid derivatives (quinoline-3-yl)-4H-pyran was undertaken and resulted in the preparation of some series of highly original and diversely functionalized structural analogues of Tacrine (a bioactive compound used in the treatment of Alzheimer's disease). These pyranotacrines (quinolin-3-yl)-4H-pyran-tacrine) carriers in position 5 of 4H-pyran ring an electron-withdrawing group (series 5, 6, 7, 8; and compounds 9-12) were prepared under the standard conditions of the Friedländer’s reaction in satisfactory yields for most (39- 70%). The same conditions apply to (2-chloroquinolin-3-yl)-pyridine derivatives (13-20) do not appear altered these substrates (no evolution of the reaction). The in vitro biological evaluation (anti-Alzheimer's tests) of products of series 5,6,7, and compounds 9-12 as the determination of hepatotoxicity, measurement of inhibitory power toward acetylcholinesterase, butyrylcholinesterase, and induced aggregation of -amyloïd A1-40, neuroprotection and neurotoxicity, have shown that these new pyranotacrines are multipotent, non-hepatotoxic, non competitive acetylcholinesterase inhibitors, A1-40 antiaggregants, neuroprotective, and non-neurotoxic agents for Alzheimer’s disease. All prepared compounds were identified by usual spectroscopic methods (IR, 1H NMR and13C), and for some of them additional analyzes were carried out (X-ray diffraction, elemental analysis, MS and/or HRMS).