Chromone, A Privileged Scaffold in Drug Discovery: Developments in the Synthesis and Bioactivity

Abstract

: Chromones are the class of secondary metabolites broadly occurred in the plant kingdom in a noticeable quantity. This rigid bicyclic system has been categorized “as privileged scaffolds in compounds” in medicinal chemistry. The wide biological responses made them an important moiety in a drug discovery program. This review provides updates on the various methods of synthesis of chromones and biological applications in medicinal chemistry. Various synthetic strategies for the construction of chromones include readily available phenols, salicylic acid and its derivatives, ynones, chalcones, enaminones, chalcones and 2-hydroxyarylalkylketones as starting materials. Synthesis of chromones by using metal, metal free, nanomaterials and different catalysts are included. Details of diverse biological activities such as anti-cancer agents, antimicrobial agents, anti-viral property, anti-inflammatory agents, antioxidants, Monoamine Oxidase-B (MAO-B) Inhibitors, anti-Alzheimer’s agents, anti-diabetic agent, antihistaminic potential, antiplatelet agents of chromone derivatives are diecussed.

Nanocellulose as Convenient Reaction Media for the FeCl3 Mediated Mechanochemical Synthesis of 3-Acylchromones

“…Chromones are benzoannelated γ-pyrone (4 H -chromen-4-one, 4 H -1-benzopyran-4-one) based heterocyclic motifs present in many natural products, pharmaceuticals as well as in the molecules with enriched biological functions. − Chromone and its derivatives have shown numerous biological activities such as anticancer, anti-inflammatory, antidiabetic, antimalarial, and neuroprotective activity. They also showed a potential as tyrosine phosphatases inhibitors, HIV inhibitors, topoisomerases inhibitors, phosphodiesterase inhibitors, leukotriene receptor antagonists, and so on. ,− Therefore, the synthesis of functionalized chromones has received considerable attention owing to their above-mentioned unique biological properties.…”

One-Pot Synthesis of Chromone-2-carboxylate Scaffold: An Important Pharmacophore with Diverse Biological Properties

“…Among the various different functionalizations of chromone core, keeping a carboxylic acid group at 2-position ( 1 , Figure ) has been increasingly gaining the attention of medicinal chemists as the preferred functional group modification, , because chromone-2-carboxylic acids ( 1 ) and their other derivatives (like amides and tetrazoles) have been found to exhibit diverse biological properties with improved physical properties. ,, For example, traditionally, the naturally occurring chromone derivative khellin ( 2 ) has been used as a bronchodilator in the pure form (as a drug) and for other treatments as a plant extract in herbal medicine . But it was found that the pure form of khellin has inherent severe side effects and a poor water-solubility profile.…”

“…Chromone moiety , is the fundamental nucleus present in several phytochemicals (like flavones, isoflavones, and other chromone derivatives) abundant in the diet rich in vegetables, fruits, cereals, etc. , Since ancient times, their applications in herbal medicines for different pharmacological purposes have been well documented. − And numerous chromone-based synthetic compounds have been reported to exhibit diverse biological properties, − such as antiallergic, antioxidant, antitumor activity, antihepatotoxic activity, antispasmolytic, anti-inflammatory, antifungal, antimicrobial, antibacterial activities, and HIV-inhibition properties. Thus, the chromone nucleus has been recognized as one of the privileged heterocyclic scaffolds in the medicinal chemistry. − …”

“…But it was found that the pure form of khellin has inherent severe side effects and a poor water-solubility profile. Therefore, efforts to discover chromone-based small molecules with good bronchodilation properties and better water-solubility profile, but without any inherent severe side effects, led to the discovery of chromone-2-carboxylic acid as the promising scaffold with all desired properties. , As a result, many chromone-2-carboxylic acid derivatives were discovered for the treatment of asthma and allergic rhinitis. − During the 1980–1990 period, the discovery of novel chromone-2-carboxylic acid-based leukotriene receptor inhibitors led to the development of popular drugs like DSCG (or cromolyn), , pranlukast (or ONO-1078), , nedocromil, , and repirinast for the treatment of asthma and allergic rhinitis. Cromoglicic acid is also used in eye drops for chronic allergic conjunctivitis. , Later, several other chromone-2-carboxylic acid derivatives have been developed with diverse pharmacological properties. ,,, …”

“…There are many classical and new synthetic protocols available for accessing such important chromone moieties with diverse functionalization possibilities. ,,− Particularly, for the synthesis of the important chromone-2-carboxylate scaffold, some interesting methods are available, such as Kostanecki–Robinson, Baker–Venkatraman, Ruhemann, Baker–Ollis, and Simon reactions along with few other methods (Scheme a,b). , Also, chromone-2-carboxylic acid scaffold is prepared by modifying other chromone-4-one moieties using various harsh synthetic modifications. ,,− Among them, Kostanecki–Robinson/Baker–Venkatraman reactions, , which use 2-hydroxyacetophenone ( 9 ) as the starting material (Scheme a), are the most reliable and preferred protocols by medicinal chemists as there will not be any regioisomer possibility, as carbonyl and phenoxy groups are pre-fixed in the starting material itself ( 9 ). ,, Ruhemann and other related reactions, which use phenols ( 12 ) as the starting materials, are not preferred because in these reactions, cyclization proceeds on the either side of phenoxy group of intermediate 13 (in case of unsymmetrical phenols) causing regioselectivity issue (Scheme b). , Moreover, these reactions generally need high temperatures (often exceeding 140 °C) for cyclization to occur, although some successful attempts have been made to develop milder reaction conditions. , This could be the probable reason why our careful literature survey revealed that the majority of the reported medicinal chemistry work on the development of biologically active new chromone-2-carboxylic acid derivatives primarily used the two-step Kostanecki–Robinson reaction approach starting from 2-hydroxyacetophenone (Scheme a), ,,− even though it restricts the choice of raw materials to only “2-hydroxyacetophenone” and also requires the use of harsh acidic conditions for cyclization to occur.…”