Selective in vitro and in silico butyrylcholinesterase inhibitory activity of diterpenes and polyphenols from traditional Asian medicinal plants

Cholinesterase inhibition is one of the treatment strategies against Alzheimer's disease (AD) where metal accumulation is also strongly associated with AD pathogenesis. In this study, we assessed inhibition of acetyl-(AChE) and butyrylcholinesterase (BChE) and metal-chelating capacity of 17 diterpenes from roots of Perovskia and Salvia species and 8 isoflavonoids isolated from Belamcandae chinesis rhizoma. Terpenoids included 13 known (arucadiol, miltirone, tanshinone IIa, 1-oxomiltirone, cryptotanshinone, 1,2-didehydromiltirone, 1,2-didehydrotanshinone IIa, 1b-hydroxycryptotanshinone, 15,16-dihydrotanshinone, tanshinone I, isotanshinone II, 1(S)-hydroxytanshinone IIa, isogradifoliol) and three new natural diterpenes (1-acetyloxy-cryptotanshinone, 1-acetyloxy-tanshinone IIa and 3,10,10-trimethyl-2,3,9,10-tetrahydroanthra[1,2-b]furan-4,5,7(8 H)-trione (Figure). All these compounds were isolated from Perovskia atriplicifolia Benth. and Salvia glutinosa L. The compounds were tested at 10 mg/mL using ELISA microtiter assays against AChE and BChE. QSAR and molecular docking studies have been also performed on the active compounds. Most of the compounds showed significant inhibition of BChE in vitro with IC₅₀ between 1.12 and ca. 6 mg/mL (e.g, IC₅₀= 1.12 mg/mL for 1,2-didehydromiltirone, 1.15 mg/mL for cryptotanshinone, 1.20 mg/mL for arucadiol) markedly stronger than galanthamine (IC₅₀= 12.56 mg/mL), whereas only 15,16-dihydrotanshinone moderately inhibited AChE (65.17 ± 1.39%). 1,2-Didehydrotanshinone IIa (48.94 ± 0.26%) and 1(S)-hydroxytanshinone IIa (47.18 ± 5.10%) had the highest metal-chelation capacity. The present study affords an evidence for the fact that selective BChE inhibitors should be further investigated as promising candidate molecules for AD therapy.

The study was supported by the Polish National Science Center postdoctoral grant” to S. Ślusarczyk (No. FUGA – DEC/2014/12/S/NZ9/00715)