Isolation and characterization of N98-1272 A, B and C, selective acetylcholinesterase inhibitors from metabolites of an actinomycete strain

Abstract

A high throughput screening was carried out in order to search for inhibitors of acetylcholinesterase (AChE) from microorganism metabolites. An actinomycete strain was found to produce active compounds named N98-1272 A, B and C with IC 50 of 15.0, 11.5, 12.5 mM, respectively. Structural studies revealed that the three compounds are identical to the known antibiotics, Manumycin C, B and A. Kinetic analyses showed that N98-1272 C (Manumycin A) acted as a reversible noncompetitive inhibitor of acetylcholinesterase, with a Ki value of 7.2 mM. The cyclohexenone epoxide part of the structure plays a crucial role in the inhibitory activity against AChE. Compared with Tacrine, N98-1272 A, B, and C exhibit much better selectivity toward AChE over BuChE.

Anticancer activities of cyclohexenone derivatives

“…As compounds containing a cyclohexenone moiety can inhibit AChE [44], we tested whether cyclohexenone derivatives inhibit AChE enzyme activity. In vitro AChE enzyme activity assay shows that the half-maximal enzyme inhibitory concentration (IC 50 ) values ranged from 0.93 to 133.12 μM ( Fig.…”

“…To verify the biological activity of the cyclohexenone derivatives, we determined the activation of the apoptosis regulatory protein caspases [19], through immunoblotting and immunofluorescence microscopy in HCT116 colon cancer cells. Compounds containing a cyclohexenone moiety have been reported to inhibit acetylcholinesterase (AChE) [20]. In this study, we predicted that ethyl 3,5-diphenyl-2-cyclohexenone-6-carboxylate derivative binds to AChE using an in silico docking experiments.…”

Inhibition of Pro-Inflammatory Cytokines by Metabolites of Streptomycetes—A Potential Alternative to Current Anti-Inflammatory Drugs?

“…Manumycin-type metabolites show quite complex inhibitory effects on key human enzymes [20,21,[24][25][26]36]. Many of these can be directly linked either to the regulation of cell proliferation and apoptosis or to the control of inflammatory response.…”

Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer’s Disease

“…These compounds inhibit the enzyme differently: several ligands, e.g., galantamine, covalently bind to the serine residue and form a bond that is stable for about 15–20 min; during this time, the enzyme is inhibited. Tacrine blocks the passage of the neurotransmitter due to a strong π-stacking interaction with Trp84 (Figure 20) [100].…”

“…Overlay of the trigonal crystal structure of tacrine (black) and Tc AChE (gray) complex: showing the catalytic anionic site, aromatic gorge, and peripheral anionic site. Reproduced with permission from [100]. …”