Applied Pharmaceutical Practice and Nutraceuticals

Natural Product Development

Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi

• Publisher: Apple Academic Press
• Year: 2021
• ISBN:
  9781000088847
• Edition: 1
• Topic: Medicine
• Subtopic: Alternative & Complementary Medicine

The pharmaceutical industry recognizes the shift to the use of natural products while also considering the serious concerns that have arisen regarding the claimed efficacy, quality, and safety of these products. This volume showcases how pharmaceutical and nutraceutical compounds from natural products can be used to cure or prevent diseases. The chapters explore the connections between agrochemicals and pharmaceuticals and the use of plants and plant products in the formulation and development of new pharmaceuticals and nutraceuticals.

CHAPTER 1
Chalcone (1,3-Diphenyl-2-Propene-1-One) Scaffold Bearing Natural Compounds as Nitric Oxide Inhibitors: Promising Antiedema Agents

DEBARSHI KAR MAHAPATRA^{1 *}, SANJAY KUMAR BHARTI², and VIVEK ASATI³

¹ Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of Pharmacy, Nagpur 440037, India

² Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur 495009, India

³ Department of Pharmaceutical Chemistry, NRI Institute of Pharmacy, Bhopal 462021, India

^* Corresponding author. E-mail: [email protected]

ABSTRACT

Nitric oxide (NO) is a short-lived, small, highly diffusible, reactive, free radical gas, ubiquitous bioactive molecule, and is derived from L-arginine (a well-known amino acid). This constituent was discovered 30 years back as “endothelium-derived relaxing factor.” In mammalian cells, NO acts as a mediator and is believed to play a crucial function in several biological processes. The current chapter comprehensively highlights the emerging perspectives of natural chalcone-based nitric acid inhibitors such as sofachalcone, brussochalcone A, cardamonin, flavokawain B, dimethyl cardamonin (2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone), mallotophilippens, Hidabeni chalcone, okanin, sappanchalcone, 3-deoxysappanchalcone, 2′,4′,6′-tris(methoxymethoxy) chalcone, butein, and licochalcone A which selectively inhibited the production of NO (inducible NO synthase, neuronal NO synthase, and endothelial NO synthase), cytokine, interleukin, TNF-α, MCP-1, and prostaglandins by preventing the phosphorylated IκBα-induced translocation of NF-κB p65 subunit at nuclear milieu, inhibition of NF-κB functions, inhibiting LPS-induced translocation by Erk-1/2 MAP-kinase phosphorylation, restricting the STAT1 expression, and inducing the expression of heme oxygenase-1 (HO-1) by activation of AKT/mTOR pathway in LPS-stimulated RAW 264.7 cells and 3T3-F442A adipocytes.

1.1 NITRIC OXIDE

Nitric oxide (NO) is a short-lived, small, highly diffusible, reactive, free radical gas, ubiquitous bioactive molecule, and derived from L-arginine (a well-known amino acid).¹ This constituent was discovered 30 years back as “endothelium-derived relaxing factor.”² In the NOS-dependent pathway, L-citrulline has been the point toward to be a secondary NO donor and can be converted to L-arginine.³ It is known to play a pivotal role in the host defense mechanisms and is considered as an imperative component in various fungi, parasites, bacteria, and viruses.⁴ NO diffusion occurs across the cellular membrane and no specific mechanism or process is known for its storage.⁵

In mammalian cells, NO acts as a mediator and is believed to play a crucial function in several biological processes such as apoptosis, neurotoxicity, metastasis, cardiovascular homeostasis, mitochondrial respiration, platelet functioning, vasodilatation, angiogenesis, invasion, blood flow, excitatory amino acid release, and neuronal message transmission.⁶ NO has been reported to play a pivotal role in the pathophysiology of cancer (gastric, breast, head, colorectal, neck, and cervical).⁷ The three isoforms: inducible NO synthase (iNOS), neuronal NO synthase (nNOS), and endothelial NO synthase (eNOS) have been seen to exhibit crucial functions in the mediation of imperative biological pathways.⁸ Among these three isoforms: nNOS and eNOS isoforms are expressed constitutively (produced in larger quantities) under appropriate conditions and exclusively need calcium for the activation process while immunologic is not expressed constitutively but induces under immunologic activation (calcium-independent process).⁹ Genes that express both the inducible and immunologic forms are specifically situated on various human chromosomes: viz. eNOS on 7, iNOS on 17, and nNOS on 12.¹⁰

It has recently observed that overexpression of this component leads to precipitation of both acute inflammation and chronic inflammation in tissues.¹¹ For the treatment of such conditions, few natural and synthetic inhibitors have been identified so far which acts as a potent NO production inhibitor by directly modulating the three isoforms.¹² The mediators of the immune system, the macrophages play a critical role in the defense system against various foreign agents and results in the production of NO.¹³ The loss of macrophage activity is found to be associated with cellular activation after treating with endotoxins.¹⁴ The major component of bacterial (gram-negative bacteria) cell walls, lipopolysaccharide (LPS) aggravates the proinflammatory cytokine production by swiftly activating the macrophages.¹⁵ LPS-stimulated NO synthesis has been perceived to enhance the apoptotic process.¹⁶ Glycine propionyl-L-carnitine, a well known dietary supplement has been recently observed clinically in amplifying the levels of NO.¹⁷ NO enhances the Ca²⁺ channel currents by stimulating the guanylate cyclase component present in photoreceptor rod cells.¹⁸ Inhibition of NO in LPS-stimulated cells is considered to be an attractive target in the management of chronic inflammation, platelet count, and thrombosis.¹⁹

1.2 CHALCONES

Chalcones are the chemical scaffold comprising two aromatic groups linked by an α, β-unsaturated carbonyl bridge (often referred to as benzylideneacetophenone or 1,3-diphenyl-2-propene-1-one) and is considered as one of the most privileged scaffolds in medicinal chemistry.²⁰ Kostanecki and Tambor in the 19th century fabricated chalcones for the first time in their laboratory by utilizing acetophenone and benzaldehyde.²¹ They referred to these chalcone products as chromophoric products. They are considered as the precursor of flavonoid and isoflavonoid and are known as intermediate in the aurone synthesis of flavones.²² Specific characteristics such as the presence of replaceable H-atoms, easy ways of computational studies, simple overall chemistry of the compound, and ability to modulate diverse therapeutic targets have made this scaffold attractive among young researchers.²³,²⁴ This gifted scaffold by Mother Nature has been taken into attention owing to multifarious pharmacotherapeutic potential (either singly or in conjugation with benzothiophene, thiadiazole, thiophene, benzodiazepine, piperazine, pyridine, benzothiazepine, thiazole, pyrazine, benzoxazepine, pyrrole, isoxazole, pyrazole, pyrazoline, pyrimidine, furan, pyridazine, etc.) such as bacterial infections, protozoal infections, trypanosomiasis, sleep disorder, gout, anxiety, epilepsy, malaria, reduced immune response, hypertension, tuberculosis, diabetes, ulcer, leishmaniasis, cancer, fungal infections, reactive oxygen species, thrombosis, HIV, inflammation, metastasis, etc.²⁴²⁶

(1)

Chemical reactions play a major role in the journey of chalcones.²⁷ It interchanges into flavonoids in the presence of acid and the reversal into flavanone occurs by base.²⁸ This scaffold serves as a template structure for the elucidation of flavanones, tannins, flavonoids, and chromanochro-manes.²⁹ Nonpharmacological utilization such as insecticides, scintillator, sweeteners in confectionaries, polymerization agents in product development, chemosensor for detection, catalyst in specific reaction...