Plant-based Isoquinoline Alkaloids: A Chemical and Pharmacological Profile of Some Important Leads

 

Arjun Singh*

Department of Medicine, Sidney Kimmel Medical College,

Thomas Jefferson University, Philadelphia, PA 19107, United States.

*Corresponding Author E-mail: arjunphar@gmail.com

 

ABSTRACT:

Plant-based products are a one-of-a-kind source of favoured molecules with a wide scaffold variety and broad multi-target potential for the treatment of complicated disorders. Among multi-target NPs, alkaloids have showed anti-inflammatory, anticancer, cardioprotective, and neuroprotective effects, supporting their promise in the treatment of chronic multifactorial disorders. Several recent investigations have revealed that isoquinoline alkaloids (IAs) have multimodal potential, sparking growing interest in the polypharmacological research of these small molecules, particularly in the field of neurological illnesses and cancer. IAs are a broad and diversified category of nitrogenous compounds that are extensively dispersed in living organisms, mostly in plants family. Isoquinolines are known as highly conserved metabolites in early vascular plants at the chemotaxonomic level; moreover, biochemical and molecular phylogenetic investigations have revealed that these alkaloids play an evolutionarily monophyletic role in basal angiosperms.As a result, medicinal chemistry has been experimenting with various ways in order to overcome the constraints of existing paradigms and increase the effectiveness of novel therapeutic molecules. In this context, the search or design of multi-target medications has shown an accelerated breakthrough; in fact, this strategy has sparked the interest of both the scientific community and the pharmaceutical business, allowing several multimodal agents already on the market to be positioned.

 

KEYWORDS: Isoquinoline alkaloids, Plant-based, Ethnopharmacological, Phytochemicals, Medicinal plants.

 

 

INTRODUCTION:

Isoquinoline alkaloids, which have a strong arsenal of proapoptotic, antiproliferative, and cytotoxic properties in a variety of human cancer cells, are one of the most significant classes of natural compounds with a wide range of biological activities and play an important role in cancer research1-5. To thisextend, it is worth highlighting the important contribution of the Isoquinoline alkaloids and their multi targets site in different sites and mechanism and current ongoing clinical trials5-9.

 

Currently, multi-target ligands are searched for and created using rational methodologies, either by screening against distinct targets implicated in disease or by combining pharmacophores in a single molecular entity. To enhance the odds of success of therapeutic drugs capable of preventing or slowing the advancement of various illnesses, a multidisciplinary effort is necessary. As a result, the logical study of the multi-target potential of natural compounds, particularly alkaloids due to their structural similarities with neurotransmitters, represents a significant contribution in the early phases of illness research and development10.

 

Recently, there has been a significant interest in the multi-target properties of natural compounds, with polyphenols and alkaloids being a prospective source of multimodal medicines for the therapy of complicated disorders11-13. Notably, isoquinoline alkaloids have demonstrated a beneficial multimodal profile in cancer, neurological disorders, and infectious illnesses. The usage of plants based isoquinoline alkaloids for therapeutic purposes extends back to ancient times, and many of these herbs have become an important element of ethnobotany in many cultures throughout the world because to their medical, magical, and poisonous properties. For example, extensive archaeological evidence suggests that Opium Poppy (Papaver somniferum) was one of the first herbal medicines utilized by humans for its analgesic effects. Morphine was extracted from P. somniferum in the early 1800s, creating the first plant-alkali natural product and spawning a new field of natural product chemistry14-18.

 

METHODS:

Materials:

The available information on various plants based traditionally used for pharmacological, ethnomedicinal, phytochemical and treatment of disorders was collected through electronic databases searches using PubMed, Scopus, Science Direct, Google Scholar, and Web of Science, as well as a library search for articles published in peer-reviewed journal articles in this review survey19-55

 

Isoquinoline subclasses include a wide range of chemical space, from basic scaffolds like pavines to complicated dimeric structures like bis-benzylisoquinolines. Bisbenzylisoquinolines, pavines, cularines, aporphines, promorphinans, and protoberberines are all produced directly from simple-benzylisoquinolines, as illustrated in Tables. Whereas protropines, benzophenanthridines, phthalides, rhoeadines, and morphinans are derived from previously synthesized isoquinolines, their production is thought to involve more sophisticated and advanced metabolic processes21-28.Morphine was the first nitrogen-containing natural substance with basic characteristics (alkaloid) identified from Papaver somniferum in the beginning of the nineteenth century. More than 2500 additional structures have been identified since then, making isoquinolines one of the most complex and varied groups of alkaloids24-27. Because of their chemical diversity, IAs have been classified into 13 primary subclasses based on distribution, common biosynthetic routes, common scaffold, and oxidation degree.

 

Table 1 Selected plants containing isoquinoline active alkaloids and their ethnopharmacology relevance11-19

Plant Source

Family

Common name

Pharmacological Uses

Active alkaloids

Argemone mexicana

Papaveraceae

Mexican poppy

Treatment of infectious diseases, pain, inflammation, diarrhea, ulcers, among others

Benzophenanthridines, protoberberines, protopines and benzylisoquinolines

Berberis vulgaris

Berberidaceae

Barberry

Anti-inflammatory, antidiabetic, hypoglycemic, hypotensive, hypolipidemic

Protoberberines such as berberine, berberrubine, columbamine, among others

Carapichea ipecacuanha

Rubiaceae

Ipecac

Emetic, antidiarrheal, antiprotozoal, also to treat coughs and bronchitis

The major constituents of ipecac roots are emetine and cephaeline

Corydalis yanhusuo

Papaveraceae

Yanhusuo

Tubers used in traditional Chinese medicinal as analgesic, pain relief, antidepressant, and antitumor

Benzophenanthridines, protoberberines and Yanhusanines a particular class of isoquinolines

Duguetiapycnastera

Annonaceae

Envirapreta

Used in the Brazilian Amazon as anti-inflammatory and antiparasitic (trypanocidal, leishmanicidal)

Aporphine and oxoaporphine alkaloids, such as anonaine, And liriodenine

Fumaria officinalis

Papaveraceae

Fumitory

Treatment of rheumatism, skin disorders, digestive and Metabolic problems, hypertension and to cleanse blood

Protopines, protoberberines, spirobenzylisoquinolines and benzophenanthridines

Galanthus nivalis

Amaryllidaceae

Snowdrop

Bulbs are used for treatment of neurological conditions such as dementia, Alzheimer

Amaryllidaceae alkaloids (galantamine)

Incarvillea delavayi

Bignoniaceae

Hardy gloxinia

Traditionally used to treat dizziness, anemia and as anti-inflammatory

Isoquinoline terpene alkaloids

Nigella glandulifera

Ranunculaceae

Black cumin

Used in the folk medicine of central Asia to treat amnesia, nervous system disorders, kidney deficiency, alopecia, and bronchial asthma

Isoquinoline terpene alkaloids and protoberberines (berberine)

Thalictrum foliolosum

Ranunculaceae

Meadow-Rue

Traditionally used in the Himalayas for eye disorders and rheumatism, also as diuretic, febrifuge, purgative

Protoberberines, aporphines andbisbenzylisoquinolines

Unonopsisstipitata

Annonaceae

“Carguero”

In Amazon region leaves are used for the treatment of cognitive disorders

Benzylisoquinoline and aporphine alkaloids, mainly reticuline, glaucine, oxoglaucine, stepharine

 

Table 2 Structure, source, and pharmacological effects of some plant based isoquinoline alkaloids22-30

Alkaloid (class)

Botanicalsource

Pharmacological potential

Mechanism and targets

 

Peumusboldus

(Monimiaceae)

Anti-inflammatory agent used for dystrophic myotonia.

Cytotoxic and antiproliferative

·       Inhibit the expression of proinflammatory cytokines(TNF-α, IL-6)

·       ↓ Janus kinase 2 (JAK2) phosphorylation

 

Sinomenium acutum

(Menispermaceae)

Anti-diabetic, anti-inflammatory, antioxidant, immunomodulatory

·       Regulate the production of prostaglandin E2 (PGE2)and pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α)

·       Inhibition of Toll-like receptor 4-mediated NF-κB and MAPK signaling pathways

 

SinomeniumAcutum

(Menispermaceae)

Approved in China for the treatment of arthritis rheumatoidand other inflammatory conditions

·       Regulation de secretion of several proinflammatorycytokines such as, IL-6, IL-12, IL-1α, TNF-α, IL-1β, IL-10, M-CSF, among others

 

Berberis genus

(Berberidaceae)

Pharmacological potential for the treatment ofhyperglycemia and hyperlipidemia activity

·       Antiparasitic,antioxidant, and anti-inflammatory activity↓ of NADPH oxidase expression and activation of Nrf2pathway, Activation of AMPK, PI3K/Akt pathway↓ inflammation blocking AMPK, NF-κB and MAPKsignalling pathways

 

Argemone mexicana

(Papaveraceae)

Antitumoral, cytotoxic, and anti-inflammatory properties

·       Modulation of multiple signaling pathwaysCaspase 3/8/9, PARP, AMPK activation

·       Bcl-2, PI3K, Akt, and mTOR downregulation

 

Papaver genus

Antitussive, analgesic, and anti-inflammatory

·       Inhibition of histamine H1 receptors (5HT1)

·       ↓MAPK phosphorylation, and NF-κBsignalingpathway

 

Table 3 Structure, biological source, and pharmacological effects of plant based isoquinoline alkaloids29-44

Alkaloid (class)

Botanical source

Pharmacological use (Drugbank Code)

Mechanism and targets

 

Papaver somniferum

(Papaveraceae)

Treatment of chronic, moderate to severe pain (DB00295)

·    Agonist of μ-opioid, κ-opioid and δ-opioid receptors

·    Antagonist of GPCR Calcium channels

 

Papaver somniferum (Papaveraceae)

Analgesic mild or moderate pain, sedative, and antitussive (DB00318)

·    Selective agonist of μ-opioid receptor

 

Papaver somniferum (Papaveraceae)

Muscle relaxant used in the treatment of muscle spasms, impotence and as a vasodilator (DB01113)

·    Selective inhibitor of phosphodiesterase

 

Galanthus genus

Treatment of cognitive decline in mild to moderateAlzheimer’s disease and other memory disorders(DB00674)

·    Competitive inhibitor of the acetylcholinesterase (AChE)

 

Papaveraceae family

Used as antitussive in common cold, also being  investigated for treatment of lymphoma and leukemia(DB06174)

·    Agonist of σ-non-opioid receptor 1.

·    ↓ proinflammatory markers (IL-1β, IFN-c, IL-6)

 

Menispermaceae species

Neuromuscular blocking agent used as an adjunct in anesthesia

(DB01199)

·    Acetylcholinesterase (AChE) inhibitor

·    Acetylcholine receptor antagonist

·    5-hydroxytryptamine receptor 3A (5HTR-A3)antagonist

 

Colchicum Autumnale (Colchicaceae)

Anti-mitotic drug used in the treatment of gout and inflammatory conditions such as Familial Mediterranean Fever (FMF) (DB01394)

·    Microtubule polymerization inhibitor by binding to tubulin.

·    ↓ The inflammasome complex downregulating the interleukin-1β

·    Inhibition of superoxide anion production, RhoA/ Rho effector kinase and the factor κВ (NF-κВ)pathways

 

Table 4 Multi-target activity of plant based isoquinoline alkaloids to treat the different types of cancers39-55

Alkaloid

(class)

Cancer type

Mechanism

Effects and targets

 

(Amaryllidaceae)

Cervix, melanoma, endothelial, prostate

Glioblastoma

BreastGastric

Apoptosis

 

Mitosis-blocking activity, Peptidyl transferase inhibition, Caspase-3 and PARP activation, GTPase RhoA activation, F-actin stress fibers formation, ↓ Migratory capacity, ↑ AMPK and pAMPK, ↓ Phospho-mTORS, Caspase-9, Regulation of AMPK-ULK1 signaling, ↑Bax expression, ↑ Cleaved-PARP, ↑ Caspase-3,8,9, and cyto-c, ↓Bcl-2 expression

 

(promorphinan)

Prostate

Apoptosis

↓ Bcl-2, Bcl-XL, XIAP expression, ↑Bax, Bad, Apaf-1 expression, ↑ cytochrome c and AIF release, Caspase-3 and PARP activation

 

(bisbenzylisoquinoline)

Colorectal

Breast

Cell cycle arrest

Apoptosis

Autophagy/

mitophagy

G2/M phase cell arrest

↑ Cdk1/cyclin B1 activity, ↑Bax expression, Block autophagosome-lysosome, ↑ Mitochondrial fission, DNM1L dephosphorylation

 

(bisbenzylisoquinoline)

Liver

Colorectal, lung and glioblastoma

Apoptosis

Cell cycle arrest

Suppression of PI3K/Akt, G1 phase, ↑ p21, Cyclin D1 inhibition

 

(phthalideisoquinoline)

Colorectal

Apoptosis

↓ mitochondrial membrane potential, Release of cytochrome c, ↑ caspase 3/8/9, ↑ PARP, ↓ Bcl-2 expression, ↑Bax expression

 

(benzophenanthridine)

Gastric

Lung

Renal

Breast, liver, lung, gastric

Apoptosis

Autophagy

Release of cytochrome c, ↑ caspase 3/8/9, ↑ PARP, ↓ Bcl-2 expression, ↑ Bax expression, ↑ JNK phosphorylation, Suppression of PI3K/Akt, ↓ ERK and Akt phosphorylation, ↑Bax and p53 expression, ↑ LC3-II expression, ↑ AMPK activity, ↓ PI3K, Akt, and mTOR expression, ↑ Beclin-1

 

(benzophenanthridine)

Renal

Hepatocellular and nasopharyngeal

Breast

Apoptosis

↓Akt and ERK phosphorylation, ↓ MMP-2 and MMP-9, ↓ P53, Bax,

Caspase-3 and PARP activation, Bcl-2 regulation, ↓ JAK1 and STAT3 phosphorylation, ↓ Bcl-2 expression, ↓ cyclin D1 and CDK4, ↑ Bax expression, ↓ c-Src, FAK, MAPK phosphorylation, RhoA, Rac1, and AP-1 activation

 

(benzophenanthridine)

Colorectal

Breast, liver, lung, glioblastoma

Cervical

Apoptosis

Autophagy

Apoptosis

↓ mitochondrial membrane potential, Release of cytochrome c, ↑ caspase 3/8/9, ↑ PARP, ↓ Bcl-2 expression, ↑ Bax expression, ↑ LC3-II expression, ↑ AMPK activity, ↓ PI3K, Akt, and mTOR expression, ↑ Beclin-1, ↓ Bcl-2 expression, ↑ Bax expression, ↑ ROS, Inhibition of STAT3 transcription, Factor, Caspase 3 activation, PARP and phospholipase C-ϒ1 degradation, HIF-1α signaling inhibition, ↓ EMT markers expression, Activation Smad and PI3K-AKT pathways

 

(aporphine)

Ovarian

Apoptosis

Caspase 3/9 induction, ↑ Mitochondrial permeability, ↓ Mitochondrial membrane potential, Cytochrome c release, ↓ Bcl-2 expression, ↑ Bax expression

 

(protopine)

Prostate

Cell cycle arrest

G2/M phase

Cdk1/cyclin B1 activity

↓ Bcl-2 phosphorylation

↓ Mcl-1

 

(protoberberine)

Breast, liver, lung, gastric, glioblastoma

Colorectal

Breast, lung, prostate

Autophagy

Cell cycle arrest

Apoptosis

↑ LC3-II expression, ↑ AMPK activity, ↓ PI3K, Akt, and mTOR expression, ↑ Beclin-1, G2/M phase, Cdk1/cyclin B1 activity, ↓ Mitochondrial membrane potential, ↑ release of cytochrome c, Caspase-3/8/9 activation, ↑ PARP, ↓ Bcl-2 expression, ↑ Bax expression, Apoptotic DNA fragmentation, PI3K/Akt/mTOR pathway, ↑ JNK phosphorylation, ↑ ROS generation, ↑ Bim expression, ↑ FasL expression, ↑ Bax expression, Bad, and Apaf-1 expression, ↑ p38 MAPK phosphorylation,

 

(protoberberine)

Liver and colorectal

Apoptosis

↑ ROS production, Caspase-3/8/9 and PARP activations, ER stress activation, ↑ JNK phosphorylation, PI3K/Akt pathway inhibition

 

(protoberberine)

Colorectal

Apoptosis

↑ ROS production, Caspase-3/8/9 and PARP activations, ER stress activation, ↑ JNK phosphorylation, PI3K/Akt pathway inhibition

 

Table 5 General description of current clinical trials based on plant based isoquinoline alkaloids50-55

Alkaloid

Drug

Title

Therapeutic application

Stage/ Status

Berberine

Berberine hydrochloride

Randomized Trial of Berberine Hydrochloride to PreventColorectal Adenomas in Patients with Previous Colorectal Cancer

Preventive therapy of colorectaladenomas

Phase 1 CompletedPhase 2 Completed

Gefitinib and Berberine sulphate

An Open-label Phase II Trial of Gefitinib and Berberine in Patients with Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations

Multimodal treatment of lung cancer and activating EGFR mutations

Phase 2 Completed without data

Berberine hydrochloride,amoxicillin and rabeprazole

Efficacy and Safety of Berberine Hydrochloride, Amoxicillin and Rabeprazole Triple Therapy in the First Eradication of Helicobacter Pylori

Eradication of H. Pylori for the treatment of chronic gastritis and gastric cancer prevention

Phase I Enrolling by invitation

Berberine, amoxicillin, esomeprazole, and bismuth

Rescue Therapy for Helicobacter Pylori Eradication: A Randomized and Non-inferiority Trail of Berberine Plus Amoxicillin Quadruple Therapy Versus Tetracycline Plus Furazolidone QuadrupleTherapy

Eradication of H. Pylori for the treatment of chronic gastritis and gastric cancer prevention

Phase I Completed

Berberine hydrochloride

The Effect of Berberine Hydrochloride in Familial Adenomatous Polyposis: A Prospective, Randomized, Double Blind, Placebocontrolled, Multicenter Clinical Trial

Chemopreventive effects Berberine hydrochloride on the regression of colorectal adenomas.

Phase II and III Completed without data

 

DISCUSSION:

The extensive survey of literature revealed that the medicinal plants are an important source of many pharmacologically and medicinally important. Given the expanding burden of diseases such as cardiovascular and cancer, as well as gastrointestinal disorders, which pose a danger to global public health, it is vital to investigate several avenues for the discovery and development of more effective and safe therapeutic agents. Natural products are a cornerstone in drug development because they provide leads, candidates, and privileged scaffolding templates53-55. Isoquinoline alkaloids, in particular, cover a broad chemical spectrum ranging from simple nitrogenous metabolites to complex nitrogenous metabolites with great polypharmacological potential as anti-inflammatory, neuroprotective, analgesic, and anticancer drugs. Based on their ability to inhibit neurological enzymes, block key receptors, activate pro-apoptotic cascades, as well as their antioxidant and anti-inflammatory properties, several in vitro studies have suggested the multi-target potential of IAs for the treatment of complex pathologies such as Parkinson's and Cancer. Berberine, nitidine, sanguinarine, boldine, and narciclasine, for example, have a useful polypharmacological profile. However, further preclinical, pharmacokinetic, toxicologic, and clinical research is needed to confirm the druggability potential of isoquinoline alkaloids with promise multimodal action in vitro and those that have been proven to generate epigenetic modifications. Furthermore, in order to have alternative sources of new bioactive compounds, it is critical to encourage focused chemical and pharmacological investigations for the discovery of multimodal IAs in hitherto undiscovered plant species.

 

CONFLICT OF INTEREST:

The author has no conflicts of interest.

 

ACKNOWLEDGMENTS:

The authors would thank you NCBI database for the free database services for their kind support during this study.

 

REFERENCES:

1.      World Health Organization. WHO traditional medicine strategy: 2014-2023. World Health Organization, 2013.

2.      World Health Organization. WHO global report on traditional and complementary medicine 2019. World Health Organization, 2019.

3.      Qi, Zhang. "Who traditional medicine strategy. 2014-2023." Geneva: World Health Organization 188 (2013).

4.      World Health Organization. "The regional strategy for traditional medicine in the Western Pacific (2011-2020)." (2012).

5.      World Health Organization. Regional strategy for traditional medicine in the Western Pacific. Manila: WHO Regional Office for the Western Pacific, 2002.

6.      Kasilo, Ossy MJ, and Jean‐Baptiste Nikiema. "World Health Organization perspective for traditional medicine." Novel Plant Bioresources: Applications in Food, Medicine and Cosmetics (2014): 23-42.

7.      Zhang, Qi, Aditi Sharan, Stéphane Alexandre Espinosa, Daniel Gallego-Perez, and John Weeks. "The path toward integration of traditional and complementary medicine into health systems globally: The World Health Organization report on the implementation of the 2014–2023 strategy." The Journal of Alternative and Complementary Medicine 25, no. 9 (2019): 869-871.

8.      Hajare, Ashok A, Sachin S Mali, Sonali S Gorde, Jyoti D Thorat, and Sachin S Salunkhe. “Narrative Review: A Rational Approach to Needle Free Insulin Technology,” 2014, 11.

9.      Lakshmi, K. “Effectiveness of Nursing Care of Antenatal Mothers with Gestational Diabetes Mellitus.” Asian Journal of Nursing Education and Research 10, no. 3 (2020): 286.

10.    Raju, Vidya, Jasmine Joy Bell, N. J. Merlin, and Shaiju S Dharan. “Ethno Pharmacological Uses of Artocarpus Altilis -A Review.” Asian Journal of Pharmaceutical Research 7, no. 4 (2017): 239.

11.    Somwanshi, Sachin B., Punam D. Bairagi, and Kiran B. Kotade. “Study of Gestational Diabetes Mellitus: A Brief Review.” Asian Journal of Pharmaceutical Research 7, no. 2 (2017): 118.

12.    Yousaf, Aqsa, and Sammia Shahid. “The Study of Anethum Graveolens L. (Dill) in the Case of Diabetes Mellitus (DM).” Asian Journal of Research in Pharmaceutical Science 10, no. 4 (2020): 248–56.

13.    Chanda D, Prieto-Lloret J, Singh A, Iqbal H, Yadav P, Snetkov V, et al. Glabridin-induced vasorelaxation: Evidence for a role of BKCa channels and cyclic GMP. Life Sciences. 2016 Nov 15; 165:26–34. https://doi.org/10.1016/j.lfs.2016.09.018.

14.    Gautam Y, Dwivedi S, Srivastava A, Hamidullah, Singh A, Chanda D, et al. 2-(3′,4′-Dimethoxybenzylidene)tetralone induces anti-breast cancer activity through microtubule stabilization and activation of reactive oxygen species. RSC Adv. 2016 Apr 5; 6(40):33369–79. https://doi.org/10.1039/C6RA02663J.

15.    Hamid AA, Hasanain M, Singh A, Bhukya B, Omprakash, Vasudev PG, et al. Synthesis of novel anticancer agents through opening of spiroacetal ring of diosgenin. Steroids. 2014 Sep; 87:108–18. https://doi.org/10.1016/j.steroids.2014.05.025.

16.    Hamid AA, Kaushal T, Ashraf R, Singh A, Chand Gupta A, Prakash O, et al. (22β,25R)-3β-Hydroxy-spirost-5-en-7-iminoxy-heptanoic acid exhibits anti-prostate cancer activity through caspase pathway. Steroids. 2017 Mar; 119:43–52. https://doi.org/10.1016/j.steroids.2017.01.001.

17.    Jain S, Singh A, Khare P, Chanda D, Mishra D, Shanker K, et al. Toxicity assessment of Bacopa monnieri L. grown in biochar amended extremely acidic coal mine spoils. Ecological Engineering. 2017 Nov; 108:211–9. https://doi.org/10.1016/j.ecoleng.2017.08.039.

18.    Khwaja S, Fatima K, Hasanain M, Behera C, Kour A, Singh A, et al. Antiproliferative efficacy of curcumin mimics through microtubule destabilization. European Journal of Medicinal Chemistry. 2018 May; 151:51–61. https://doi.org/10.1016/j.ejmech.2018.03.063.

19.    Kumar BS, Ravi K, Verma AK, Fatima K, Hasanain M, Singh A, et al. Synthesis of pharmacologically important naphthoquinones and anticancer activity of 2-benzyllawsone through DNA topoisomerase-II inhibition. Bioorganic and Medicinal Chemistry. 2017 Feb; 25(4):1364–73. https://doi.org/10.1016/j.bmc.2016.12.043.

20.    Mishra D, Jyotshna, Singh A, Chanda D, Shanker K, Khare P. Potential of di-aldehyde cellulose for sustained release of oxytetracycline: A pharmacokinetic study. International Journal of Biological Macromolecules. 2019 Sep; 136:97–105. https://doi.org/10.1016/j.ijbiomac.2019.06.043.

21.    Sathish Kumar B, Kumar A, Singh J, Hasanain M, Singh A, Fatima K, et al. Synthesis of 2-alkoxy and 2-benzyloxy analogues of estradiol as anti-breast cancer agents through microtubule stabilization. European Journal of Medicinal Chemistry. 2014 Oct; 86:740–51. https://doi.org/10.1016/j.ejmech.2014.09.033.

22.    Sathish Kumar B, Singh A, Kumar A, Singh J, Hasanain M, Singh A, et al. Synthesis of neolignans as microtubule stabilisers. Bioorganic & Medicinal Chemistry. 2014 Feb; 22(4):1342–54. https://doi.org/10.1016/j.bmc.2013.12.067.

23.    Singh A, Kumar BS, Alam S, Iqbal H, Shafiq M, Khan F, et al. Diethyl-4,4ʹ-dihydroxy-8,3ʹ-neolign-7,7ʹ-dien-9,9ʹ-dionate exhibits antihypertensive activity in rats through increase in intracellular cGMP level and blockade of calcium channels. European Journal of Pharmacology. 2017 Mar; 799:84–93. https://doi.org/10.1016/j.ejphar.2017.01.044.

24.    Singh A, Kumar BS, Iqbal H, Alam S, Yadav P, Verma AK, et al. Antihypertensive activity of diethyl-4,4’-dihydroxy-8,3’-neolign-7,7’-dien-9,9’-dionate: A continuation study in L-NAME treated wistar rats. Eur J Pharmacol. 2019 Sep 5; 858:172482. https://doi.org/10.1016/j.ejphar.2019.172482.

25.    Singh A, Mohanty I, Singh J, Rattan S. BDNF augments rat internal anal sphincter smooth muscle tone via RhoA/ROCK signaling and nonadrenergic noncholinergic relaxation via increased NO release. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2020 Jan 1; 318(1):G23–33. https://doi.org/10.1152/ajpgi.00247.2019.

26.    Singh A, Rattan S. BDNF rescues aging-associated internal anal sphincter dysfunction. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2021 Jul 1; 321(1):G87–97. https://doi.org/10.1152/ajpgi.00090.2021

27.    Singh, A., Singh, J., Rattan, S., 2021. Evidence for the presence and release of BDNF in the neuronal and non‐neuronal structures of the internal anal sphincter. Neurogastroenterology& Motility. 2021 Feb 7; 00; e14099. https://doi.org/10.1111/nmo.14099

28.    Singh A, Fatima K, Singh A, Behl A, Mintoo MJ, Hasanain M, et al. Anticancer activity and toxicity profiles of 2-benzylidene indanone lead molecule. European Journal of Pharmaceutical Sciences. 2015 Aug 30; 76:57–67. https://doi.org/10.1016/j.ejps.2015.04.020.

29.    Singh A, Fatima K, Srivastava A, Khwaja S, Priya D, Singh A, et al. Anticancer activity of gallic acid template-based benzylidene indanone derivative as microtubule destabilizer. Chem Biol Drug Des. 2016 Nov; 88(5):625–34. https://doi.org/10.1111/cbdd.12805.

30.    Yadav P, Iqbal H, Kumar K, Kumar P, Mishra D, Singh A, et al. 2-Benzyllawsone protects against polymicrobial sepsis and vascular hyporeactivity in swiss albino mice. European Journal of Pharmacology. 2022 Feb; 917:174757. https://doi.org/10.1016/j.ejphar.2022.174757.

31.    Manmohan, S., Arjun, S., Khan, S. P., Eram, S., &Sachan, N. K., 2012. Green chemistry potential for past, present and future perspectives. International Research Journal of Pharmacy, 2012 Feb; 3, 31-36. https://doi.org/10.1016/j.ejphar.2022.174757.

32.    Singh A, Kumar BS, Alam S, Iqbal H, Shafiq M, Khan F, Negi AS, Hanif K, Chanda D. Corrigendum to "Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate exhibits AH activity in rats through increase in intracellular cGMP level and blockade of calcium channels" Eur J Pharmacol. 2017 Jul 5; 806:111. doi: 10.1016/j.ejphar.2017.04.033.

33.    Singh, A., R. Sharma, K. M. Anand, S. P. Khan, and N. K. Sachan. "Food-drug interaction." International Journal of Pharmaceutical & Chemical Science 2012 Feb; 1(1) 264-279. doi: 10.1016/j.ejphar.2017.04.033.

34.    Thanh-Hoang, N.-V.; Loc, N.; Nguyet, D.; Thien-Ngan, N.; Khang, T.; Cao, H.; Le, L. Plant Metabolite Databases: From Herbal Medicines to Modern Drug Discovery. J. Chem. Inf. Model. 2020, 60, 1101–1110.

35.    Kumar, S.; Malhotra, R.; Kumar, D. Euphorbia hirta: Its chemistry, traditional and medicinal uses, and pharmacological activities. Pharmacogn. Rev. 2010, 4, 58–61.

36.    Ramu,F.A.; Kumar,S.R.ScientificevaluationoftraditionallyknowninsulinplantCostusspeciesforthe treatment of diabetes in human. Int. J. Curr. Res. Biosci. Plant Biol. 2016, 3, 87–91.

37.    Jayasri,M.A.; Gunasekaran,S.; Radha,A.; Mathew,T.L. Antidiabetic effect of Costuspictus leaves in normal and streptozotocin-induced diabetes rats. Int. J. Diabetes Metab. 2008, 16, 117–122.

38.    Sidhu, A.K.; Wani, S.; Tamboli, P.S.; Patil, S.N. In Vitro Evaluation of Anti-Diabetic Activity of Leaf and Callus Extracts of Costus pictus. Int. J. Recent Sci. Res. 2014, 3, 1622–1625.

39.    Prakash,K.; Harini,H.; Rao,A.; Rao,P.N. A review on Isulin plant(CostusigneusNak). Pharmacogn.Rev. 2014, 8, 67–72.

40.    Radha Devi, G.M. A Comprehensive Review On CostusPictusD. Don. Int.J.Pharm.Sci.Res.2019, 10, 3187–3195.

41.    Dhar, M.L., Dhar, M.M., Dhawan, B.N., Mehrotra, B.N., Ray, C. 1968. Screening of Indian plants for biological activity. Indian Journal of Experimental Biology 6 (4), 232-247.

42.    Dhawan, B.N., Dubey, M.P., Mehrotra, B.N., Rastogi, R.P., Tandon, J.S. 1980. Screening of Indian plants for biological activity. Part 9. Indian Journal of Experimental Biology 18, 594-606.

43.    Chattopadhyay RR. A comparative evaluation of some blood sugar lowering agents of plant origin. J Ethnopharmacol. 1999; 67(3):367-372. doi:10.1016/s0378-8741(99)00095-1

44.    Joglekar, G.V., Chaudhary, N.Y., Aiaman, R. 1959. Effect of Indian medicinal plants on glucose absorption in mice. J Clin BiochemNutr. 2007 May; 40(3):163-73. doi: 10.3164/jcbn.40.163.

45.    Panlasigui LN, Panlilio LM, Madrid JC. Glycaemic response in normal subjects to five different legumes commonly used in the Philippines. Int J Food Sci Nutr. 1995; 46(2):155-160. doi:10.3109/09637489509012544

46.    Marles RJ, Farnsworth NR. Antidiabetic plants and their active constituents. Phytomedicine. 1995; 2(2):137-189. doi:10.1016/S0944-7113(11)80059-0

47.    Rao, P.V., Ushabala, P., Seshiah, V., Ahuja, M.M., Mather, H.M. 1989. The Eluru survey: prevalence of known diabetes in a rural Indian population. Diabetes Res Clin Pract. 1989; 7(1):29-31. doi:10.1016/0168-8227(89)90041-7

48.    Bading TB., Bouckandou, M., Souza, A., BourobouBourobou, H.P., MacKenzie, L.S., Lione, L., An overview of anti-diabetic plants used in Gabon: Pharmacology and toxicology. Journal of Ethnopharmacology 2018 Apr 24; 216:203-228. doi: 10.1016/j.jep.2017.12.036.

49.    Chin, Y., Balunas, M., Chai, H., Kinghorn, A., 2006. Drug Discovery From Natural Sources. AAPS J. 2006; 8(2):E239-E253. Published 2006 Apr 14. doi:10.1007/BF02854894.

50.    Choudhury H, Pandey M, Hua CK, et al. An update on natural compounds in the remedy of diabetes mellitus: A systematic review. J Tradit Complement Med. 2017; 8(3):361-376. Published 2017 Nov 29. doi:10.1016/j.jtcme.2017.08.012

51.    Cornwell T, Cohick W, Raskin I. Dietary phytoestrogens and health. Phytochemistry. 2004; 65(8):995-1016. doi:10.1016/j.phytochem.2004.03.005

52.    Newman, D.J., Cragg, G.M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016. 79, 629–661.

53.    Newman, D.J., Cragg, G.M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 2012. 75, 311–335. doi:10.1016/j.phytochem.2010.03.009

54.    Rao, M.U., Sreenivasulu, M., Chengaiah, B., Reddy, K.J., Chetty, C.M., n.d. Herbal Medicines for Diabetes Mellitus: A Review 11.doi:10.1016/j.phytochem.2004.03.005

55.    Ward, R.S. Lignans, neolignans and related compounds. Nat. Prod. Rep. 1999.16, 75–96.doi:10.1016/j.phytochem.1999.03.005

 

 

 

 

 

Received on 17.03.2022                    Modified on 23.08.2022

Accepted on 04.12.2022                   ©AJRC All right reserved

Asian J. Research Chem. 2023; 16(1):43-48.

DOI: 10.52711/0974-4150.2023.00008