Mini Reviews in Medicinal Chemistry - Volume 13, Issue 3, 2013

Coumarins and flavonoids are heterocyclic molecules that have been associated with beneficial effects on human health, such as reducing the risk of cancer, diabetes, cardiovascular and brain diseases. These effects are thought to be related to the radical scavenging effect, due to their antioxidant activities, along with other possible mechanisms, such as anti-inflammatory properties and interaction with several enzymes. Over the past two decades, there have been an increasing number of publications on coumarins and flavonoids, which demonstrate the importance of understanding the chemistry behind the antioxidant activities of both natural and synthesized compounds, considering the benefits from their dietary ingestion as well as pharmacological use. This work aims to review the antioxidant effects of coumarin and flavonoid molecules in humans and the structural aspects that contribute to these effects.

Numerous lines of evidence suggest that heterocyclic compounds used as analgesic, anti-inflammatory and anti-migraine agents can be potent regulators of the nitroxidative stress and targeting free nitrogen and oxygen radicals is a very promising strategy for future pain management. Both classical analgesics (nonsteroidal anti-inflammatory drugs, opioid drugs) and many analgesic adjuvants, including desipramine, duloxetine, fluoxetine, paroxetine, escitalopram, phenytoin or carbamazepine and α-lipoic acid can modulate the balance between pro-oxidant and antioxidant processes in the mammalian tissues and these properties of drugs such as indomethacin, meloxicam, tenoxicam, valdecoxib or some metabolites of analgesic drugs formed by the activity of tissue peroxidases may contribute to their clinical efficacy and drug-related toxic effects, including gastrointestinal ulcers, hepatic failure, agranulocytosis, aplastic anemia, neutropenia, opiate-induced hyperalgesia and tolerance. The antioxidant capacities of novel heterocyclic compounds, including the compounds acting either by prevention of formation or catalyzed decomposition of peroxynitrite anion (ONOO–), namely the peroxynitrite decomposition catalysts or as superoxide (O2 •-)-scavengers which are the functional mimetics of superoxide dismutase (SOD) enzymes (SODm), as well as the derivatives of 6-nitro-3,4-methylenedioxyphenyl-Nacylhydrazone (LASSBio-881) or γ-butyrolactone (LPP1, BM113, BM113A, BM138 and BM138A) are also discussed as potent and promising future heterocyclic analgesics.

Flax is an important crop plant grown mainly for its fiber and seeds, which are also rich in omega-3 fatty acids and valuable antioxidants derived from the terpenoid pathways including carotenoids, tocochromanols and sterols. Many of those components found in flax have been recently shown to positively influence human health. Although terpenes vary greatly in their chemical structure, mainly two mechanisms of their biological activity can be considered: direct antioxidation, and a recently explored one, connected to specific receptor and cell signaling pathway activation. Recent studies show that many of the health promoting agents derived from flax act through both of the mentioned mechanisms, resulting in synergistic physiological effects. The work summarizes the two mechanisms, focusing mainly on the one involving cell signaling, as a promising target for medicine and pharmacotherapy.

Quinoline derivatives constitute an important class of compounds for new drug development. As a large number of experimental and theoretical studies have shown that the quinoline ring system is an important structural unit widely existing in alkaloids, therapeutics and synthetic analogues with exciting biological activities. The present review provides recent antioxidant activities covering in vivo and in vitro studies of natural and synthetic analogues, as well as the proposed mechanisms of action and structure-activity relationships.

Melatonin is an uncommonly widely distributed molecule. It is found throughout the plant and animal kingdoms, i.e., perhaps in every living organism. Within vertebrate organisms, melatonin also has an extremely wide distribution, seemingly being capable of entering every cell and all subcellular compartments. So-called morphophysiological barriers, e.g., the blood-brain barrier, are no impediment to the passage of melatonin and it has a multitude of confirmed functions. We have hypothesized that melatonin originally evolved as a free radical scavenger and during evolution it acquired other important and essential actions. Due to the multi-faceted actions of melatonin and its metabolites as direct free radical scavengers and indirect antioxidants, these agents have been used to abate oxidative damage in a diverse variety of experimental models where free radical destruction is a component. When compared with classic, better-known antioxidants, melatonin is better in terms of limiting destruction of intracellular macromolecules when the damage is a consequence of excessive oxygen or nitrogen-based toxic reactants. Considering the vast array of experimental data that has accumulated which documents melatonin's high efficacy and lack of, or minimal, toxicity over a very wide dose range, it is essential that the usefulness of this agent be more thoroughly tested at the clinical level. The findings from experimental models of numerous diseases overwhelming confirm that this indoleamine would likely have great benefit in aiding humans suffering with conditions that have as their basis tissue and molecular damage resulting from oxygen and nitrogen-based reactants.

Much work has been carried out in the last two decades on the role of oxidative stress and antioxidants deficiency in the pathophysiology of civilization diseases. A considerable amount of chemical, biochemical, epidemiological and clinical evidence indicates that (poly)phenolic compounds widely distributed in the plant kingdom, exhibit a wide range effects on biomolecules. The beneficial effects on human health, many of phenolics have been described to their reactive oxygen (ROS) and nitrogen species (RNS) scavenging and antioxidant capacity. The consumption of vegetables, fruits and flavonoid-rich beverages has been reported to prevent against neurodegenerative diseases, cancer, and ageing. This paper reviews the recent data on (1) the role oxidative stress in the pathology of civilization diseases; (2) the protection against oxidative damage due to the toxicity of ROS/RNS; (3) the cellular and molecular interactions of the (poly)phenolic compounds relevant to the prevention of neurodegenerative diseases and cancer, and (4) the methods for assessing antioxidant capacity.

Benzimidazole ring system is found in many bioactive heterocyclic compounds because of their diverse biological and clinical applications. Furthermore, benzimidazole derivatives are structural isosters of naturally occurring nucleotides, thus they can interact with biological macromolecules such as proteins, enzymes and receptors. This review discusses the benzimidazole derivatives which possess anticancer activity of medicinal efficacy.

Antioxidant compounds can scavenge free radicals and increase shelf life by retarding the process of lipid peroxidation, which is one of the major reasons for deterioration of food, medicine and pharmaceutical products during processing and storage. An antioxidant molecule has been defined as any substance when found in low concentrations compared to that of an oxidizable substrate significantly delays or inhibits the oxidation. The major antioxidant compounds are especially phenolics and flavonoids, which are responsible for their health benefits. Carbonic anhydrase (EC 4.2.1.1., CA) is a pH regulatory/metabolic enzyme in all life kingdoms, being found in organisms all over the phylogenetic tree. It catalyzes the hydration of carbon dioxide (CO2) to bicarbonate (HCO3 -) and the corresponding dehydration of HCO3 -in acidic medium with regeneration of CO2. Also, CA isoforms are found in a variety of tissues where they participate in several important biological processes such as acid-base balance, respiration, carbon dioxide and ion transport, bone resorption, ureagenesis, gluconeogenesis, lipogenesis and electrolyte secretion. On the other hand, the phenyl moiety of phenol was found to lay in the hydrophobic part of the CA active site, where CO2, the physiologic substrate of the CAs, binds in the precatalytic complex, explaining thus the behavior of phenol as a unique CO2 competitive inhibitor. This review consists of two main sections. The first section is devoted to main phenolic antioxidant compounds in the foodstuffs and beverages. The second general section is about some definitions of CA inhibitory effects of the main phenolic compounds used for antioxidant activity. The phenolic compounds and acids had marked especially CA I and CA II inhibitory effects and might be used as leads for generating CA isoenzyme inhibitors. This class of compounds may lead to isoform-selective inhibitors targeting just one or few of the medicinally relevant CAs. In addition, there are given some chemical and kinetic basis and technical details related to phenolic antioxidant compounds and carbonic anhydrase isoenzymes.

This article summarizes the results of using cytokinesis-block micronucleus (CBMN) assay to evaluate the antioxidant potential of heterocyclic compounds. Most studies were carried out with naturally occurring heterocyclic compounds such as plant polyphenols: flavonoids, xanthones, coumarins, and ellagitannins, or plant derived products (juices, extracts, supplements) rich in bioactive heterocyclic compounds. There are also some studies dealing with synthetic heterocyclic antioxidants. CBMN assay is an in vitro study that has been used to evaluate antioxidant and protective effects of heterocyclic compounds on induced chromosome aberration in human lymphocytes.

Mangiferin is a plant natural polyphenol of C-glycosylxanthone structure and various pharmacological activities. It can be found in many plant species, among which the mango tree (Mangifera indica) is one of the primary sources. Mangiferin is also present in some medicinal herbs, influencing their therapeutic and preventive properties, and in honeybush (Cyclopia sp.), a popular South African herbal tea. Mangiferin dissolves well in water, so it can be easily extracted into infusions and decoctions. In the mangiferin molecule, four aromatic hydroxyl groups determine its strong antiradical and antioxidant properties. Mangiferin is also an efficient iron chelator, therefore preventing the generation of hydroxyl radical in Fenton-type reactions. Numerous published in vitro and in vivo pharmacological studies, demonstrated many other activities of mangiferin: analgesic, antidiabetic, antisclerotic, atimicrobial and antiviral, cardio-, hepato-, and neuroprotective, antiinflammatory, antiallergic, MAO inhibiting and memory improving, as well as radioprotective against X-ray, gamma, and UV radiation. Several studies indicated also its ability to inhibit cancerogenesis and cancer cells growth by apoptosis induction in vitro and in vivo. It is also used in cosmetics, due to antioxidant and UV-protecting properties.

Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed.