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Hybrids: a new paradigm to treat Alzheimer’s disease

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Abstract

Alzheimer‘s disease (AD) is a complex neurodegenerative condition with several target proteins contributing to its etiology. With 35.6 million cases worldwide documented in 2011, AD constitutes a devastating health, political, economic, and social problem for all nations. The cases are expected to increase beyond 107 million in 2050; unless an advanced therapy having a capability to delay the disease progression is developed. The curative paradigm of one-compound one-target that has been followed so far has not reached the desired mark. The research focus moved towards single molecule targeting two or more pathogenic mechanisms involved in neuronal death. Over the last few years, medicinal chemists have been paying attention to the design and synthesis of the hybrid molecules that are comprised of two pharmacophores from well-established chemical scaffolds endowed with requisite biological activities in a single entity. The hybrid-based approach has grown to be a central point in the medicinal chemistry field. Various important pharmacophores used for AD have been combined with selected biologically active molecules to get homo- and heterodimers with improved efficacy with additional supplementary actions. This review summarizes the pathogenesis of AD and various progress in the design of hybrid molecules based on the one-compound-various targets paradigm for AD therapy.

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Abbreviations

A\(\beta \) :

\(\beta \)-Amyloid

ACh:

Acetylcholine

AChE:

Acetylchoinesterase

AChEIs:

Acetylchoinesterase inhibitors

AD:

Alzheimer‘s disease

AGEs:

Advanced glycation end products

APP:

Amyloid Precursor Protein

BACE:

\(\beta \)-Secretase

BBB:

Blood–brain barrier

BuChE:

Acetylcholinesterase

\(\hbox {CB}_{1}\) :

Cannabinoid 1

CBR:

Cannabinoid receptors

ChEs:

Cholinesterases

CNS:

Central nervous system

DNA:

Deoxyribonucleic acid

FDA:

Food & Drug Administration

MAO:

Monoamine oxygenase

MTDL:

Multi-target-directed ligand

NFTs:

Neurofibrillary tangles

NMDAR:

N-methyl-d-aspartate receptor

PAS:

Peripheral anionic site

PKC:

Protein kinase C

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SAR:

Structure–activity relationships

SERT:

Serotonin transporter

TcAChE:

Torpedo californica acetylcholinesterase

THA:

Tetrahydroacridine

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Acknowledgments

I am grateful to my many colleagues and assistants for critical review and editorial assistance with the manuscript. We wish to thank the ‘Indian Council of Medical Research (ICMR)’, New Delhi, for providing us a Senior Research Fellowship (ICMR-SRF); Award No. BIC/11(11)/2014 and BIC/11(02)/2013.

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  1. Molecular Modeling Lab, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India

    Manjinder Singh, Maninder Kaur, Navriti Chadha & Om Silakari

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  1. Manjinder Singh
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  2. Maninder Kaur
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Correspondence to Om Silakari.

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Singh, M., Kaur, M., Chadha, N. et al. Hybrids: a new paradigm to treat Alzheimer’s disease. Mol Divers 20, 271–297 (2016). https://doi.org/10.1007/s11030-015-9628-9

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