Total synthesis and anti-cholinesterase activity of marine-derived bis-indole alkaloid fascaplysin

Bharate, Sandip B.; Manda, Sudhakar; Joshi, Prashant; Singh, Baljinder; Vishwakarma, Ram A.

doi:10.1039/c2md20076g

Cited by 52 publications

(47 citation statements)

References 37 publications

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“…This inhibition profile suggests a 60‐fold selectivity for AChE inhibition. In addition, kinetic experiments demonstrated that fascaplysin acts as a non‐competitive Ee AChE ( K i = 2.28 μ m ) and eqBChE ( K i = 48.5 μ m ) inhibitor, indicating that this ligand binds with high affinity to a site different from the catalytic one . Further docking studies revealed details regarding the binding mode of this compound in AChE and BChE active sites.…”

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 91%

“…β‐Carboline alkaloids, mainly the N 3‐alkylated β‐carbolinium salts, are well‐known cholinesterase inhibitors. The marine compound fascaplysin was evaluated using Ee AChE and eqBChE and displayed IC 50 values of 1.49 and 90.5 μ m , respectively . This inhibition profile suggests a 60‐fold selectivity for AChE inhibition.…”

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 99%

“…However, no direct hydrogen bonds were observed to occur between ligand and amino acids residues of the enzyme. Furthermore, hydrophobic interactions can be observed between fascaplysin and the residues Phe‐330, Phe‐331, Tyr‐334 and Tyr‐121 …”

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 99%

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Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Konrath

Passos

Klein‐Júnior

et al. 2013

Journal of Pharmacy and Pharmacology

172

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Objectives The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is currently the main pharmacological strategy available for Alzheimer's disease (AD). In this sense, many alkaloids isolated from natural sources, such as physostigmine, have been long recognized as acetyl-and butyrylcholinesterase (BChE) inhibitors. Since the approval of galantamine for the treatment of AD patients, the search for new anticholinesterase alkaloids has escalated, leading to promising candidates such as huperzine A. This review aims to summarize recent advances in current knowledge on alkaloids as AChE and BChE inhibitors, highlighting structure-activity relationship (SAR) and docking studies. Key findings Natural alkaloids belonging to the steroidal/triterpenoidal, quinolizidine, isoquinoline and indole classes, mainly distributed within Buxaceae, Amaryllidaceae and Lycopodiaceae, are considered important sources of alkaloids with anti-enzymatic properties. Investigations into the possible SARs for some active compounds are based on molecular modelling studies, predicting the mode of interaction of the molecules with amino acid residues in the active site of the enzymes. Following this view, an increasing interest in achieving more potent and effective analogues makes alkaloids good chemical templates for the development of new cholinesterase inhibitors. Summary The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD.

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Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 91%

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 99%

See 1 more Smart Citation

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Konrath

Passos

Klein‐Júnior

et al. 2013

Journal of Pharmacy and Pharmacology

172

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“…Despite these reports, development of a hazard-free, waste-free, and energy-efficient synthetic protocol will be of great use for economical synthesis of this class of compounds. In continuation to our efforts towards development of efficient synthetic methodologies for preparation of biologically important scaffolds [29-31], and our efforts in the area of indole chemistry [32-35], herein we have developed an efficient protocol (Figure 2) for preparation of potent antileishmanial 3,3′-diindolylmethanes.…”

Section: Introductionmentioning

confidence: 99%

Discovery of 3,3′-diindolylmethanes as potent antileishmanial agents

Bharate¹,

Bharate²,

Khan³

et al. 2013

European Journal of Medicinal Chemistry

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An efficient protocol for synthesis of 3,3′-diindolyl methanes using recyclable Fe – pillared interlayered clay (Fe-PILC) catalyst under aqueous medium have been developed. All synthesized 3,3′-diindolylmethanes showed promising antileishmanial activity against Leishmania donovani promastigotes as well as axenic amastigotes. Structure-activity relationship analysis revealed that nitroaryl substituted diindolylmethanes showed potent antileishmanial activity. The 4-nitrophenyl linked 3,3′-diindolylmethane 8g was found to be the most potent antileishmanial analog showing IC50 values of 7.88 and 8.37 μM against both L. donovani promastigotes and amastigotes, respectively. Further, a pharmacophore based QSAR model was established to understand the crucial molecular features of 3,3′-diindolylmethanes essential for potent antileishmanial activity. These compounds also exhibited promising antifungal activity against Cryptococcus neoformans, wherein fluorophenyl substituted 3,3′-diindolylmethanes were found to be most potent antifungal agents. Developed synthetic protocol will be useful for economical and eco-friendly synthesis of potent antileishmanial and antifungal 3,3′-diindolylmethane class of compounds.

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“…Historically NPs have been incredible as a source of molecules with diverse therapeutic potential ranging from anti-microbial and anti-infective to anticancer (Cragg, Newman, & Snader, 1997;Harvey, 2008). Bharate, Manda, Joshi, Singh, & Vishwakarma, 2012;Hostettmann, Borloz, Urbain, & Marston, 2006;Houghton, Ren, & Howes, 2006;Ng, Or, & Ip, 2015). Nitrogen containing compounds, particularly alkaloids, are considered to be the one of the most promising classes of NPs for use in the treatment of AD (S. B.…”

mentioning

confidence: 99%

Identification of embelin, a 3‐undecyl‐1,4‐benzoquinone from Embelia ribes as a multitargeted anti‐Alzheimer agent

Nuthakki

Sharma

Kumar

et al. 2019

Drug Development Research

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Beta-secreatse (BACE-1) and cholinesterases are clinically validated targets of Alzheimer's disease (AD), for which natural products have provided immense contribution.The multifaceted nature of AD signifies the need of multitargeted agents to tackle this disease. In the search of new natural products as dual BACE-1/cholinesterase inhibitors, a library of pure natural products was screened for inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE-1. The screening efforts have identified 1,4-benzoquinone "embelin," a natural product derived from Embelia ribes displaying inhibition of all three enzymes, with IC 50 values of 2.5, 5.4, and 2.1 μM, respectively. This screen has also identified isoquinoline alkaloids papaverine and L-tetrahydropalmatine as AChE inhibitors. Kinetic study has shown that embelin inhibits EeAChE and EqBChE with ki values of 4.59 and 0.57 μM, in an uncompetitive and noncompetitive manner, respectively. The interactions of embelin with allosteric peripheral anionic site of cholinesterases, has further supported the results of kinetic study. Embelin has also enhanced the activity of P-gp in LS-180 cells, the efflux pump which is involved in the clearance of amyloid-β from AD brain. Further, the cell viability study in neuronal cell line has indicated the excellent therapeutic window of embelin. These results are indicative of the fact that embelin is a multitargeted agent playing role in stopping the formation of amyloid-β oligomers (via inhibition of BACE-1), improves cholinergic-transmission (via inhibition of AChE/BChE) and increases amyloid-β clearance (via P-gp induction). K E Y W O R D Sacetylcholinesterase, Alzheimer's disease, BACE-1, butyrylcholinesterase, embelin, papaverine, L-tetrahydropalmatine

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Total synthesis and anti-cholinesterase activity of marine-derived bis-indole alkaloid fascaplysin

Cited by 52 publications

References 37 publications

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Discovery of 3,3′-diindolylmethanes as potent antileishmanial agents

Identification of embelin, a 3‐undecyl‐1,4‐benzoquinone from Embelia ribes as a multitargeted anti‐Alzheimer agent

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