2a-Alkylnorlitebamines and (7a,8)-didehydroisohomoaporphines: Synthesis and antiacetylcholinesterase activity verified via in silico molecular docking

Abstract

As N-alkyl-norlitebamines have been demonstrated to possess antiacetylcholinesterase activity, this study aimed to prepare related analogs to verify their structure–activity relationship. The compounds with the chemical skeletons of 2a-alkylnorlitebamines (6b–6e) and (7a,8)-didehydroisohomoaporphines (8b–8e, 9a, and 10b–10e) were designed and synthesized. In silico molecular docking of the 13 compounds on the acetylcholinesterase template indicated that 8a and 10b showed the highest docking scores (ΔG) (−20.56 Kcal/mol and −19.76 Kcal/mol, respectively). The reaction of peracylsecolaurolitsines under the modified Bischler–Napieralski procedure and subsequent NaBH4 reduction yielded 7a-alkyl- B homoaurolitsines 8a−8e, possessing a new skeleton, besides the expected 2a-alkyl-norlitebamines 10b−10e. Among these compounds, the two with the highest docking scores [Δ7a (8)- B homoaurolitsine (8a) and 2a-methyl-norlitebamine (10b)] showed better inhibitory activities against acetylcholinesterase (eel) with IC50 value of 24.71 μM and 26.13 μM, respectively. Therefore, compounds 8a and 10b could serve as leads for exploring potential acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease.