Cholinesterase inhibitors as Alzheimer's therapeutics (Review)

Abstract

Alzheimer's disease (AD) is one of the most common forms of dementia. AD is a chronic syndrome of the central nervous system that causes a decline in cognitive function and language ability. Cholinergic deficiency is associated with AD, and various cholinesterase inhibitors have been developed for the treatment of AD, including naturally‑derived inhibitors, synthetic analogues and hybrids. Currently, the available drugs for AD are predominantly cholinesterase inhibitors. However, the efficacy of these drugs is limited as they may cause adverse side effects and are not able to completely arrest the progression of the disease. Since AD is multifactorial disease, dual and multi‑target inhibitors have been developed. The clinical applications and the limitations of the inhibitors used to treat AD are discussed in the present review. Additionally, this review presents the current status and future directions for the development of novel drugs with reduced toxicity and preserved pharmacological activity.

Figure 1.

Schematic representation of AChE catalysis. AChE, acetylcholinesterase.

Figure 2.

Traditional cholinesterase inhibitors. The molecular structures of (A) physostigmine, (B) tacrine, (C) donepezil, (D) rivastigmine, (E) galantamine and (F) metrifonate are presented.

Figure 3.

Novel cholinesterase inhibitors. The molecular structures of (A) phenserine, (B) tolserine and (C) eseroline are presented. The circle indicates the active moiety of eseroline.

Figure 4.

Naturally-derived cholinesterase inhibitors. The molecular structures of (A) huperzine A, (B) huperzine B, (C) galangin and (D) cardanol are presented.

Figure 5.

Hybrid cholinesterase inhibitors. The molecular structures of (A) donepezil-AP2238, (B) donepezil-tacrine, (C) T6FA and (D) tacrine-hydroxyquinoline are presented. The drugs forming the hybrids are indicated by circles.

Figure 6.

Synthetic analogues of cholinesterase inhibitors. (A) Tacrine analogue, (B) heteroarylacrylonitrile derivative, (C) indenyl derivative and (D) Ladostigil.