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In Silico-Guided Rational Drug Design and Semi-synthesis of C(2)-Functionalized Huperzine A Derivatives as Acetylcholinesterase Inhibitors.

ABSTRACT: Huperzine A (1, Hup A), a lycodine-type Lycopodium alkaloid isolated from Thai clubmosses Huperzia squarrosa (G. Forst.) Trevis., H. carinata (Desv. ex. Poir.) Trevis., H. phlegmaria (L.), and Phlegmariurus nummulariifolius (Blume) Chambers (Lycopodiaceae), exerts inhibitory activity on acetylcholinesterase, a known target for Alzheimer's disease therapy. This study investigated the structure-activity relationship of C(2)-functionalized and O- or N-methyl-substituted huperzine A derivatives. In silico-guided screening was performed to search for potential active compounds. Molecular docking analysis suggested that substitution at the C(2) position of Hup A with small functional groups could enhance binding affinity with AChE. Consequently, 12 C(2)-functionalized and four O- or N-methyl-substituted compounds were semi-synthesized and evaluated for their eeAChE and eqBChE inhibitory activities. The result showed that 2-methoxyhuperzine A (10) displayed moderate to high eeAChE inhibitory potency (IC₅₀ = 0.16 μM) with the best selectivity over eqBChE (selectivity index = 3633). Notably, this work showed a case of which computational analysis could be utilized as a tool to rationally screen and design promising drug molecules, getting rid of impotent molecules before going more deeply on labor-intensive and time-consuming drug discovery and development processes.

SUBMITTER: Anukanon S

PROVIDER: S-EPMC8340427 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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In Silico-Guided Rational Drug Design and Semi-synthesis of C(2)-Functionalized Huperzine A Derivatives as Acetylcholinesterase Inhibitors.

Anukanon Shisanupong S Pongpamorn Pornkanok P Tiyabhorn Wareepat W Chatwichien Jaruwan J Niwetmarin Worawat W Sessions Richard B RB Ruchirawat Somsak S Thasana Nopporn N

ACS omega 20210726 30

Huperzine A (1, Hup A), a lycodine-type Lycopodium alkaloid isolated from Thai clubmosses Huperzia squarrosa (G. Forst.) Trevis., H. carinata (Desv. ex. Poir.) Trevis., H. phlegmaria (L.), and Phlegmariurus nummulariifolius (Blume) Chambers (Lycopodiaceae), exerts inhibitory activity on acetylcholinesterase, a known target for Alzheimer's disease therapy. This study investigated the structure-activity relationship of C(2)-functionalized and O- or ...[more]

PMID: 34368579

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Project description:Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 μM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 μM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.

Dataset Information

In Silico-Guided Rational Drug Design and Semi-synthesis of C(2)-Functionalized Huperzine A Derivatives as Acetylcholinesterase Inhibitors.

Publications

<i>In Silico</i>-Guided Rational Drug Design and Semi-synthesis of C(2)-Functionalized Huperzine A Derivatives as Acetylcholinesterase Inhibitors.

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