Neuroprotective Potential of Heterocyclic Scaffolds vs Herbal Treatments: An Overview

Divya Dhawal Bhandari¹, Prabhjot Kaur², Monika Maan³, Ruchika Garg⁴, Hitesh Chopra⁵, Mohammad Amjad Kamal^6-9*

¹University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.

²School of Pharmaceutical Sciences, RIMT University, Mandi Gobindgarh, Punjab, India.

³Faculty of Pharmaceutical Sciences, Lal Bahadur Shastri College of Pharmacy, Tilak Nagar, Jaipur, Rajasthan.

⁴University Institute of Pharmaceutical Sciences, Chandigarh University, Mohali, Punjab.

⁵Department of Biosciences, Saveetha School of Engineering,

Saveetha Institute of Medical and Technical Sciences, Chennai - 602105, Tamil Nadu, India.

⁶Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network,

West China Hospital, Sichuan University, China.

⁷King Fahd Medical Research Center, King Abdulaziz University, Saudi Arabia.

⁸Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Bangladesh.

⁹Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770;

Novel Global Community Educational Foundation, Australia.

*Corresponding Author E-mail: rrs.usa.au@gmail.com

ABSTRACT:

Degenerative diseases of nerves are associated with the progressive loss of a specific function of neurons resulting in cell death or some abnormal functions of organs. Neurodegeneration is associated with dysfunctioning of well-being and involves muscular symptoms like tremor, loss of memory, diminished intellect and speech problems, weak or paralyzed muscles, numbness, and partial loss of senses. Heterocyclic compounds have a wide range of structural diversity and have proven to be widely and economically useful as therapeutic agents. Extensive research on the therapeutic potentials of heterocyclic compounds has confirmed their enormous importance in the pathophysiology of neurodegenerative diseases. Various researchers have evaluated the neuroprotective activity of various heterocyclic nuclei. Despite the availability of many heterocyclic drugs against these disorders, a satisfactory treatment is still not available to rely upon. Herbal treatments are gaining the interest of researchers due to their wide availability with the least side effects. The purpose of this review article is to go over the research that has been done on the neuroprotective potentials of heterocyclic scaffolds in comparison with the upcoming herbal treatments to treat degeneration of nerves.

KEYWORDS: Alzheimer’s disease, Parkinson’s disease, Heterocycles compounds, Neuroprotective activity, Herbals.

Table 2: List of medicinal herbs for management of Alzheimer’s disease (AD)^5-19

S/N	Name of Plant/ Family	Common Name	Chemical Constituent	Actions Performed
1	Panax ginseng/ Araliaceae	Asian ginseng, Chinese ginseng, Ninjin	Ginsenoside Rg1	Secretase activity neprilysin, Improvement of learning and remembrance
2	Huperzia serrata/ Lycopodiaceae	Toothed clubmoss	Huperzine A	Inhibit the activity of AChE, Iinhibits the formation of Aβ peptides , Improve cognitive functions
3	Polygala tenuifolia/ Polygalaceae	Yuan Zhi	Tenuifolin (extract)	Morphological plasticity, Secretase activity Improvement of memory
4	Magnolia officinalis/ Magnoliaceae	Houpu magnolia	Honokiol and magnolol	Inhibition of AChE, COX and 5-LOX activity Releives disturbances of brain Anxiolytic effect
5	Uncaria rhynchophylla/ Rubiaceae	Fish hook vine	Triterpene esters and uncarinic acids	Aβ accumulation and fibril maintenance Improve cardiovascular and nervous system
6	Bacopa monnieri/ Scrophulariaceae	Brahmi, Indian pennywort	Bacopasides III–V, Bacosides, and Bacosaponins	Ameliorates ACh shortages in vivo Neuron protection: support intellect and remembrance
7	Celastrus paniculatus/ Celastraceae	Black oil plant, Mal- kangani, Intellect tree	Celastrine and paniculatin	Antioxidant activity Support intellect and remembrance
8	Convolvulus pluricaulis/ Convolvulaceae	Shankhpushpi, Morning glory	volatile oil, flavonoids, phytosterol (β-sitosterol)	Antioxidant activity Neuron protection: support intellect and remembrance
9	Withania somnifera/ Solanaceae	Ashwagandha, Winter cherry	Ashwagandhine, with anolides, asomniferin, and asomniferols,	Protect the neurons from apoptosis caused by amyloidplaques Fight against stress Enhance remembrance and locomotor activity Promote neural growth
10	Curcuma longa/ Zingiberaceae	Turmeric	Curcumin	Antioxidant activity Overcome nuclear transcription factors and molecular targets Inhibit inflammation and protect neurons
11	Galanthus alpines/ Amaryllidaceae	Snowdrop	Galantamine	Controls locomotor activity Prevents vascular dementia
12	Panax ginseng/ Araliaceae	Ginseng	Ginsenosides	Prevent amyloid beta induced neurotoxicity Increase expression of actin cytoskeleton proteins Increase antioxidant capacity in hippocampal neurons Upregulate plasticity related proteins
13	Foeniculum vulgare/ Umbelliferae	Fennel	Fenchene, Anethal, Limonene, Phellandrene	Inhibit acetylcholinesterase
14	Lawsonia inermis/ Lythraceae	Henna	3-O-β-acetyloleanolic acid, oleanolic acid	Inhibit butyrylcholinesterase activity Chelation of metals Antioxidant

Management of Alzheimer’s Diseaseby Heterocyclics:

In medicinal chemistry, heterocyclic compounds play a key role in the various therapeutic agents. Every year number of heterocyclic compounds is synthesized by various research groups, of which nitrogen containing compounds are considered to be the most important in the medicinal chemistry. Pyrimidine, a heterocyclic compound, have a wide range of biological activities as the scaffold mimics building blocks of nucleic acids which contain thymine, cytosine and uracil. Pyrimidine derivatives showed a wide variety of biological and pharmacological activities including anti-bacterial, anti-fungal, anti-cancer, anti-viral, anti-oxidant, anti-convulsant, analgesic, anti-tubercular, anti-HIV and anti-Alzheimer’s²⁰. The 2,4-disubstituted pyrimidine derivative is also one of the leading non-fused heterocyclic ring template which has been found to possess the remarkable in vitroChE (AChE and BuChE) inhibition activity^21-23. The 2nd -position (C-2 substituent) of the pyrimidine nucleus has been reported to modulate the ChE inhibitory profile. The pyrimidine nucleus has emerged as a new scaffold for the drug development against neurodegenerative diseases. The pyrimidine ring system prompted us to design its derivatives because it contains biodynamic property, by introducing various substituent’s in the ring which have responsible for the different pharmacological activities including the treatment of AD.Various research groups have published number of active molecules with a goal to find and develop new chemical entities for the treatment of AD. Extensive literature survey reports some pyrimidine derivatives as effective AD drugs.

One specific treatment cannot prevent or cure AD. Wide research and testing of a range of AD possible treatments is going on. The study about the pathogenesis of AD gave a view on various available targets whose activation or blockage will be beneficial in the treatment of AD²⁴. Possible treatments of AD includes to find out a method to prevent or delay the disease neurologists are currently doing research studies by marking the fundamental disease process. Realizable approach involves:

· Drugs which affect fundamental processes can be in Alzheimer's disease, Immunization therapy and other interventions summary are decrease AD pathologies levels in the brain.

· Treatments for heart disease and diabetes type 2 can related to health issue of AD

· Training for cognitive function

· Particular diets

· Work out

Anti-Alzheimer's drugs²⁰

· Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine, Eptastigmine, Metrifonate, Ensaculin, Synapton (physostigmine)

· Glutamate (NMDA) antagonist: Memantine

· Gamma secretase inhibitors: Semagacestat

· Antioxidants: Alpha-Tocopherol, O-acetyl-L-Carnitine, Ginkgo biloba

· Xanthine derivative: Propentofylline

· Monoamine oxidase inhibitor: Selegiline

· Benzoquinone derivative: Idebenone,

· Estrogen

· Anti-inflammatory drugs: Edrophonium

· Antidepressants: Sertraline, Citalopram

· Miscellaneous drugs: Piracetam, Pyritinol(Pyrithioxine), Dihydro-ergotoxine (Codergocine), Citicoline, Piribedil.

The chemical structure of some approved anti-Alzheimer’s drugs is given in Fig. 2 and 3.

Figure 2: Cholinesterase inhibitors drugs

Figure 3: Various Anti Alzheimer's drugs

Targets of action:

There are many different mechanisms of action for various targets, but here we are focusing on acetylcholinesterase inhibitors (often abbreviated AChEI). Acetylcholinesterase enzyme is responsible for breaking down acetylcholine. The drug or chemical anti-cholinesterase inhibit this enzyme; this results in enhance the acetylcholine neurotransmitter level and action of duration. The cholinesterase hydrolytic (ChE) enzymes.; acetylcholine esterase (AChE) and butrylcholine esterase (BuChE) act on acetylcholine (ACh) to terminate its action through cleavage the neurotransmitter to choline and acetate in synaptic cleft. Recent research studies have shown that pathogenesis of AD is characterized by acetylcholinesterase (AChE) activity is the rapid loss, in the disease early stages along with the increasing proportion of BuChE to AChE as the progresses of disease²¹. These outcome support that must have control the ChE enzymes activity at the different type of stages of AD progression as shown in figure 4²².

Based on the cholinergic hypothesis, AD can treated by enhance cholinergic function to sustain or prolong the action of remaining ACh neurons using cholinesterase inhibitors as shown in figure 5.^25-28

Figure 5: AChE inhibitors mechanism

From 2018, In worldwide, the safety and effectiveness of more than 400 pharmaceutical drugs are in study in clinical trials, and around one-fourth of these drugs are in trials of Phase III, this is the last step before reviewing by agencies regulator²⁹. Drugs related to AD which is under clinical trials phases I to phase III are summarized in table 4.

Table 4: Cholinesterase inhibitors under clinical trails

S. No	Cholinesterase inhibitors	Structure	Status (Phase II-III)
1	BACE Inhibitor		Ongoing
2	BACE inhibitor		Completed
3	β-Secretase		Completed

According to Gray J. et. al., after 2003 not even a single drug has successfully completed phase III trial. Most of the trials fails at final stage. For the treatment of AD, four drugs are mainly clinically approved and marketed such as, Donepezil, Galantamine, Rivastigmine and Tacrine. These four are AChE inhibitors-BuChE inhibitors in nature³⁰.

HETEROCYCLIC SCAFFOLDS VS HERBAL TREATMENTS:

Neurodegenerative diseases are recognized as a social problem and the number of cases are rising day by day. In past few decades, it has been observed that more research is going on towards development of bioactive moieties to get better therapeutics and less adverse effects. A number of synthetic as well as natural compounds have emerged as newer candidates against neuronal degradation. A number of studies mentioned the importance of 5- and 6-membered heterocyclics. FDA has approved only few drugs to be used as alone for such diseases or in most of the cases a combination therapy is preferable but the results were not good enough to be rely upon. The diagnosis, prevention and treatment of neurodegenerative diseases is creating a new challenge for public institutes, physicians, patients and pharmaceutical industries. There is an urgent need to search for a safer and effective way to cure neurodegenerative diseases and should not be delayed further. The pathophysiology of neurodegenerative diseases is associated with multiple origins so a multi-target strategy is currently strongly pursued by researchers^31-34. Future insights includes the search of a moiety which is having multi-targeted profile and can be found by screening of already effective old drugs or their interaction with new targets for neurodegenerative disorders. The combination of a natural-synthetic moiety may proven effective to achieve this multi-targeted goalnand restore hope for Earth’s population.^35-41

CONCLUSION:

Heterocyclic compounds have a wide range of structural diversity and have proven to be widely and economically useful as therapeutic agents. Extensive research on the therapeutic potentials of heterocyclic compounds has confirmed their enormous importance in the pathophysiology of neurodegenerative diseases. Various researchers have evaluated the neuroprotective activity of various heterocyclic nuclei. Despite the availability of many heterocyclic drugs against these disorders, a satisfactory treatment is still not available to rely upon. Plants are the infinite springs of primary and secondary bioactive metabolites helping in the improvement of human health. The compilation of medicinal herbs in this article have unlocked an innovative horizon for researchers to use effective methods, techniques and performing deep investigation in order to reveal beneficial medicinal products in the treatment of neurological diseases like Parkinson's disease, Alzheimer’s Disease and Multiple Sclerosis.

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest.

ACKNOWLEDGEMENTS:

Authors are thankful to Panjab University, RIMT University, Lal Bahadaur Shastri College of Pharmacy, Jaipur, Rayat-Bahra University, Chitkara University and Daffodil International University, Bangladesh.

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Received on 12.07.2023 Modified on 03.01.2024

Research J. Pharm. and Tech 2024; 17(6):2943-2948.

DOI: 10.52711/0974-360X.2024.00460