Piperidine Nucleus as a Promising Scaffold for Alzheimer’s Disease:
Current Landscape and Future Perspective

Grover, Parul; Rohilla, Suman; Bhardwaj, Monika; Mehta, Lovekesh; Malhotra, Anjleena

doi:10.2174/1568026623666230406084315

Cited by 6 publications

(2 citation statements)

References 96 publications

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“…Piperidine is a heterocyclic amine that consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–) [ 140 ]. Piperidine analogs include compound 82, RB-005, SK1-5c (CAY10621), and Compound 1/2/3, Table 1 .…”

Section: Piperidine-based Sphk Inhibitorsmentioning

confidence: 99%

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

Alkafaas,

Elsalahaty,

Ismail

et al. 2024

Cancer Cell Int

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Cancer chemoresistance is a problematic dilemma that significantly restrains numerous cancer management protocols. It can promote cancer recurrence, spreading of cancer, and finally, mortality. Accordingly, enhancing the responsiveness of cancer cells towards chemotherapies could be a vital approach to overcoming cancer chemoresistance. Tumour cells express a high level of sphingosine kinase-1 (SphK1), which acts as a protooncogenic factor and is responsible for the synthesis of sphingosine-1 phosphate (S1P). S1P is released through a Human ATP-binding cassette (ABC) transporter to interact with other phosphosphingolipids components in the interstitial fluid in the tumor microenvironment (TME), provoking communication, progression, invasion, and tumor metastasis. Also, S1P is associated with several impacts, including anti-apoptotic behavior, metastasis, mesenchymal transition (EMT), angiogenesis, and chemotherapy resistance. Recent reports addressed high levels of S1P in several carcinomas, including ovarian, prostate, colorectal, breast, and HCC. Therefore, targeting the S1P/SphK signaling pathway is an emerging therapeutic approach to efficiently attenuate chemoresistance. In this review, we comprehensively discussed S1P functions, metabolism, transport, and signaling. Also, through a bioinformatic framework, we pointed out the alterations of SphK1 gene expression within different cancers with their impact on patient survival, and we demonstrated the protein–protein network of SphK1, elaborating its sparse roles. Furthermore, we made emphasis on different machineries of cancer resistance and the tight link with S1P. We evaluated all publicly available SphK1 inhibitors and their inhibition activity using molecular docking and how SphK1 inhibitors reduce the production of S1P and might reduce chemoresistance, an approach that might be vital in the course of cancer treatment and prognosis. Graphical Abstract

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Section: Piperidine-based Sphk Inhibitorsmentioning

confidence: 99%

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

Alkafaas,

Elsalahaty,

Ismail

et al. 2024

Cancer Cell Int

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“…Since the BACE-1 enzyme is involved in the first step, the rate-determining step in producing Aβ, it is viewed as a viable target for anti-Alzheimer’s treatments. No BACE-1 inhibitor is commercially available for anti-AD treatment, but many of these have entered human clinical trials [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics

et al. 2023

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Alzheimer’s disease (AD) is the prime cause of 65–80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. β-secretase (BACE-1) is a key enzyme responsible for depositing extracellular plaques made of β-amyloid protein. Therefore, efforts are being applied to develop novel BACE-1 enzyme inhibitors to halt plaque build-up. In our study, we analyzed some Elenbecestat analogues (a BACE-1 inhibitor currently in clinical trials) using a structure-based drug design and scaffold morphing approach to achieve a superior therapeutic profile, followed by in silico studies, including molecular docking and pharmacokinetics methodologies. Among all the designed compounds, SB306 and SB12 showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of the BACE-1 enzyme with drug-likeliness properties and a high degree of thermodynamic stability confirmed by the molecular dynamic and stability of the simulated system indicating the inhibitory nature of the SB306 and SB12 on BACE 1.

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Bitter yet beneficial: The dual role of dietary alkaloids in managing diabetes and enhancing cognitive function

Alkanad,

Hani,

et al. 2024

BioFactors

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With the rising prevalence of diabetes and its association with cognitive impairment, interest in the use of dietary alkaloids and other natural products has grown significantly. Understanding how these compounds manage diabetic cognitive dysfunction (DCD) is crucial. This comprehensive review explores the etiology of DCD and the effects of alkaloids in foods and dietary supplements that have been investigated as DCD therapies. Data on how dietary alkaloids like berberine, trigonelline, caffeine, capsaicin, 1‐deoxynojirimycin, nuciferine, neferine, aegeline, tetramethylpyrazine, piperine, and others regulate cognition in diabetic disorders were collected from PubMed, Research Gate, Web of Science, Science Direct, and other relevant databases. Dietary alkaloids could improve memory in behavioral models and modulate the mechanisms underlying the cognitive benefits of these compounds, including their effects on glucose metabolism, gut microbiota, vasculopathy, neuroinflammation, and oxidative stress. Evidence suggests that dietary alkaloids hold promise for improving cognition in diabetic patients and could open exciting avenues for future research in diabetes management.

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Piperidine Nucleus as a Promising Scaffold for Alzheimer’s Disease: Current Landscape and Future Perspective

Cited by 6 publications

References 96 publications

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics

Bitter yet beneficial: The dual role of dietary alkaloids in managing diabetes and enhancing cognitive function

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