Flavonoids and Phenolics

Polyphenols and flavonoids represent a group of compounds characterized by a large assortment of phenolic structures, which can be naturally found in vegetables, roots, stems, flowers, grains, and fruits. Thanks to their biological activities, molecules belonging to these classes of compounds, besides their nutritional role, have found applications in several fields such as pharmaceutical, cosmetic, and nutraceutical. In fact, like many natural derivatives from plants, they possess several therapeutic properties, including antitumor, anti-oxidative, anti-neurodegenerative, antimicrobial and anti-inflammatory effects. Nowadays, the growing interest in polyphenolics and flavonoids translates into constant research to better define their pharmacological mechanism of action. Extraction studies in order to obtain pure compounds with a more defined biological activity, as well as pharmacokinetic studies to understand the bioavailability, the involved metabolic pathways and the related active metabolites, are carried out. Molecular docking studies are also continuously in progress to expand the field of application. Moreover, toxicity experiments to clarify their safety and studies about the interaction with other compounds to understand their selectivity of action are continuously forwarded and deepened. Consequently, many recent studies are aimed at introducing polyphenols, more specifically flavonoids, and their semi-synthetic derivatives, in the prevention, management and treatment of several diseases. 

Neurodegenerative diseases (NDs) are characterized by the progressive loss of neurons in different regions of the nervous system, being Alzheimer’s disease (AD) and Parkinson’s disease (PD) the most common NDs. Despite their high incidence, the pharmacological treatments are mainly symptomatic. For this reason, in recent years, the research has been focused on the discovery of new molecules able to target neuropathological pathways involved in NDs. In the last decades, several researchers investigated the neuroprotective actions of naturally occurring polyphenols, such as resveratrol, that has attracted special interest since its ability to interact simultaneously with the multiple targets implicated in NDs. Thanks to the structural simplicity of the stilbene core, the broad spectrum of possible modifications, and the improved synthetic strategies, resveratrol is an attractive chemical starting point for the searching of new entities with extended therapeutic uses in NDs. In this review, a systematic update of the stilbene-based hybrids and derivatives, and SAR analysis were provided for the development of new drugs potentially useful as NDs multitarget directed ligands.

Natural xanthones are a class of secondary metabolites widely distributed in nature and with a broad spectrum of biological activities. Their scaffold is amenable to several modifications and has emerged as a “privileged structure” for drug development, representing a very attractive point for medicinal chemistry optimization. A combination of innovative synthetic methodologies and medicinal chemistry studies have provided several xanthone synthetic derivatives for different therapeutic purposes, including cancer, inflammation, Alzheimer’s disease (AD), cardiovascular and infectious diseases. The aim of this chapter is to give an update on the significance of synthetic xanthones in medicinal chemistry over the last five years (2016-2020), with a focus on their biological activities and structure-activity relationship (SAR).

The combretastatins are a family of stilbene phenolic natural products isolated from the bark of the South African bush willow tree Combretum caffrum. Since their isolation and structural elucidation, these molecules have attracted a lot of interest due to their potent cytotoxic activity against several human cancer cell lines. Combretastatin A-4, a cis-stilbene, is the most potent member of these natural products, has the ability to strongly inhibit tubulin polymerization, resulting in high cytotoxic activity. Indeed, it also displays an additional activity as a potent vascular disrupting agent. This interesting double bioactive profile accounts for the potent antiproliferative and antivascular action in tumors. However, combretastatin A-4, due to the sensitive cis-stilbene moiety, is prone to isomerization giving the less bioactive trans-isomer and exhibits diminished water solubility. Hence, a wide panel of synthetic derivatives were therefore developed with the aim of overcoming these limitations. The development of prodrugs such as fosbretabulin, ombrabulin and Oxi4503 isrepresentative of successful attempts to overcome pharmacokinetic disadvantages, whereas the most recent approaches aim to develop combretastatin prodrugs able to selectively target tumor site, possessing also theranostic properties. Herein, miscellaneous and the most potent synthetic analogues are presented. In addition, a general outlook on combretastatin derivatives and drug delivery approaches based on innovative nanoformulations is also presented.

Tuberculosis is a leading cause of mortality and morbidity worldwide, claiming 1.2 million deaths (including 208 000 people with HIV) and 10 million new cases in 2019. Current treatment suffers from significant shortcomings such as length, dosage regimen, toxicity, and resistance development to currently used medicines. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis is a major concern in controlling the disease. Therefore, there is an urgent need for new antitubercular drugs that are active against resistant strains, less toxic, and that act upon a different mechanism than the current drugs. Natural products can be a great source for the development of new anti-tubercular agents because of their rich chemical diversity with privileged antimicrobial activity. In this chapter, we focus our attention on flavonoids and chalcone scaffolds as leads for the development of new antitubercular agents.

In silico studies or computer-aided drug design (CADD) have led to advancement in drug discovery and development of neurodegenerative disorders (NDDs) and neuropsychiatric disorders. CADD is being increasingly used by universities and industries and provides a clear understanding of molecular interactions. Predicting molecular interactions provides relevant information to extract the potential of bioactive compounds. At present, more interest is on natural entities as therapeutic agents with different heterocyclic categories. Various heterocyclic structures are suggested to show MAO (monoamine oxidase) inhibitory activity by CADD and preclinical studies. Among these, chalcones and flavonoids play a major role in MAO inhibitory action because of the phenolic ring. In this chapter, we discuss in silico studies of natural chalcones and flavonoids with MAO inhibitory by considering the complexity of the brain and the multifactorial nature of neurodegenerative disorders. These in silico studies prove that phytoconstituents from herbal medicine with therapeutic properties can serve as lead drug molecules for the treatment of NDDs.

Lignins and lignans as natural polyphenols exhibit a rather broad variety of common physico-chemical features that can be of interest with respect to their use in the pharmaceutical sector. While polyphenol types have antioxidant, antiinflammatory, antibacterial and eventually antiviral activities in common, structural features beyond the polyphenol aspect differ enormously: isolated lignins are oligomers and/or polymers of monolignol C9-building blocks, while lignans are based on dimers thereof. The structural differences caused lignin to be exploited in the pharmaceutical sector mainly as material for the generation of matrices and carrier for drug delivery, while lignans are tested for the suitability as APIs. The chapter gives an overview of this situation, including the biological backgrounds of the two interesting natural polyphenols, isolation and methods for their characterisation.

Structural modifications of the resveratrol scaffold are valuable tools in order to develop new derivatives with potential biomedical and pharmacological applications. The investigation of the biological properties of resveratrol-derived semisynthetic systems and the study of their structure-activity relationships are attracting growing interest from medicinal chemists and biologists. In this context, the synthesis of novel resveratrol-derived systems characterisaed by elevated molecular complexity is highly sought after. Over the past years, a wide variety of resveratrol derivatives have been prepared and studied for their biological properties. Therefore, a number of stilbenoid-related potential anticancer, antioxidant, antiviral, analgesic, and anti-neurodegenerative systems have been investigated. This chapter focuses on recent studies related to the preparation and the study of semisynthetic resveratrol-derived systems.

Continuous efforts in the development of monoamine oxidase inhibitors prompted the search for effective strategies for the design of novel drugs candidate. Thankfully, nature often provides scaffolds useful for the promotion of novel exploitable chemical entities. In this regard, aurones (a class of uncommon flavonoids) and their structural related analogues may play an important role in the development of monoamine oxidase inhibitors. The target prediction of the simplest aurone (2- benzylidenebenzofuran-3(2H)-one) clearly suggests that this compound probably affects MAO (monoamine oxidase) enzymes, which is in accordance with the recently reported literature. The current chapter reports the recent discoveries involving aurones and their structurally related analogues as MAO inhibitors, describing detailed structure-activity relationships (SARs) for each subgroup of compounds.

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes and relevant drug targets with many medicinal chemistry applications. Their classes of inhibitors are in clinical use as diuretics, or drugs for the management of glaucoma, epilepsy, obesity, tumors and infectious diseases. Among the inhibitors discovered so far, coumarins constitute an interesting class. They undergo CA-catalyzed hydrolysis and act as “prodrug inhibitors”, forming 2-hydroxy-cinnamic acids, which bind at the entrance of the enzyme active site, which has a relevant variability of amino acid residues among the different CA isoforms present in mammals, humans included. Coumarins act as isoform-selective CA inhibitors against pharmacologically relevant enzymes, such as the tumor-associated CA IX and XII. Coumarins present as metabolites in many species of bacteria, fungi, plants and ascidians showed relevant CA inhibitory properties and were used as leads for obtaining synthetic derivatives with enhanced enzyme inhibitory action belonging to a variety of classes, such as polysubstituted coumarins on both rings, thiocoumarins, thioxocoumarins, sulfocoumarins, etc.

Thousands of phenolic derivatives have been identified in the plant kingdom, which exert crucial roles in plant physiology. Many such derivatives were shown to produce pharmacological effects in humans which address their use in medicine as antiaging, anti-inflammatory, antioxidant, antidiabetic, and antiproliferative agents among others. Numerous such pharmacological activities are likely to derive from the inhibition of human carbonic anhydrase (CAs, EC 4.2.1.1) isoforms. Phenols, in fact, are able to anchor to the zinc-bound nucleophile present in the enzyme active site, blocking the catalytic action of CAs in humans and/or encoded in various microorganisms. This chapter discusses natural, semisynthetic and synthetic phenol derivatives that exhibited a CA inhibitory action. The discussion over the CA inhibition profiles is categorized as the inhibition of human CAs and inhibition of CAs from microorganisms. Multiple types of inhibition mechanisms by phenolic derivatives are discussed according to X-ray crystallographic resolutions and in silico studies.

The importance of diet in determining the incidence of chronic illnesses such as diabetes, cardiovascular disorders, neurodegenerative diseases, and cancer has inspired extensive research on the role of individual dietary components in chemoprevention. Flavonoids and (poly)phenols have often been identified as the ideal candidates for these types of studies, as they represent large classes of natural products that are widely available in fruit and vegetables. In this chapter, we will discuss the antiproliferative properties of flavonols, flavanols, flavones, isoflavones, anthocyanins, curcuminoids and resveratrol derivatives, with a particular focus on their ability to interfere with epigenetic processes and modulate gene expression. We will look at the challenges encountered during the optimisation of the pharmacokinetic and pharmacodynamic properties of these natural products and, where possible, we will define structure-activity relationships.