The Role of Chromenes in Drug Discovery and Development

Chromene (benzopyrans) is one of the privileged scaffold molecules that are widely distributed in natural products and possesses a wide variety of pharmacological activities such as anticoagulant, antioxidant, anti-inflammatory, anti-spasmolytic, antitumor, antihepatotoxic, diuretic, estrogenic, antiviral, antifungal, antimicrobial, anthelminthic, anti-HIV, antitubercular, herbicidal, anticonvulsant and analgesic. Their low toxicity combined with their broad pharmacological properties has inspired researchers to obtain new chromenes and derivatives possessing considerable pharmacological action. The present review article attempts to summarize the natural source of chromene and its derivatives along with updated knowledge on its biological activities.

2H/4H-chromenes (2H/4H-Ch) structural scaffolds have been widely employed in the synthesis of many natural products and medicinal agents. 2H/4H-Ch have attracted considerable attention due to their various pharmacological activities, such as anticonvulsant, anticholinesterase, anticancer, anti-tuberculosis, antimicrobial, and inhibitory activity against monoamine oxidase (MAO), and anti-diabetic activities. In literature, the synthesis of 4H-chromenes was performed by one-pot Knoevenagel condensation of resorcinol, aryl aldehydes, and malononitrile in the presence of basic catalysts. Also, 2H-Ch analogs were performed by the Wittig-Horner-Emmons and Suzuki-Miyaura cross-coupling reactions. A description of recent advances in the syntheses of chromenes is presented in this chapter. The strategies for the synthesis of 2H/4H-Ch discussed in this chapter are organocatalysts, organometallic or metal catalysts, heterogeneous base catalysts, enzymatic catalysts, and green chemistry-based approaches. 

Diversity-oriented synthesis (DOS) plays an important role in the construction of various natural products and the development of diverse small molecules of biological significance. In recent years, numerous diversity-oriented approaches have been demonstrated to furnish complex structures with molecular diversity from readily accessible starting materials. This chapter summarizes the recent diversity-oriented approaches based on metal-free, transition metal-catalyzed, and organocatalyzed reactions for the synthesis of chromene derivatives.

 A variety of chemicals were being used by us for the treatment of human and animal diseases from the early beginning of civilization. These chemicals may be from a natural or synthetic source. Here the choice of discussion is being focused on the chemical name Chromene and its derivatives that have a significant effect on various health diseases of human beings. Over the past few years, various natural, as well as synthetic derivatives of chromene, have shown several fascinating features. These chromene derivatives were being used in the treatment of Alzheimer’s disease and Chagas disease. These possess antimicrobial and antiviral properties, used as anticancer agents, showing antileishmanial properties along with antifungal properties. In this review, we have focused on the importance of chromene and its derivatives for the betterment of human beings by finding such studies that describe the use of chromene and derivatives obtained from natural as well as synthetic sources.

Natural products have been used as major sources of therapeutic agents in drug discovery since the ancient eras. Natural products have been widely studied in the physical and biological sciences, including nutrition, health, bio-medical, and other interrelated sciences. Because of their unique chemical diversity and bioactivity, they have continued to offer templates for the development of novel forms of drugs. In the field of traditional medicine, natural products have been used for a very long time in the form of decoctions, medicinal extracts, infusions, or other therapeutic preparations. Chromene is one of the essential chemical constituents, derived from the conversion of multiple biosynthetic pathways present in the plant as well as animal kingdoms, which represents a remarkable group of structurally varied secondary metabolites. The scaffold is considered an important class of oxygenated heterocyclic compounds as two forms of 2H/4H-chromene (2H/4H-Ch) with versatile biological profiles. Chromenes are the basic backbone of various polyphenols, alkaloids, tocopherols, anthocyanins, etc. Crotin, Crotaramine, Dysoline, Malachromone, Oxalicumones A-C, Khellin, Baicalin, Diosmin, etc. are some examples of naturally isolated chromene fused compounds that are reported for the treatment of diverse health ailments. Their unique structure and varied pharmacological activities may provide new leads for the discovery of drugs with their action. In recent years, the need to develop effective and selective methods for the extraction and isolation of new natural products has been increasingly felt. This chapter presents the extraction, isolation, and characterization processes of the chromenes by the natural sources, illumination of the structures of purified chromenes, and their bioactivity.

Nutraceuticals have received tremendous interest in the treatment or prevention of multiple diseases in modern times. Chromenes (Benzopyran), phytochemicals that are polyphenolic secondary metabolites, are one of the privileged scaffolds that occur in various natural products as essential structural components and also have beneficial nutraceutical properties. Chromenes are more correctly referred to as ‘nutraceuticals' due to their variety of pharmacological activities in the mammalian body. A better understanding of their mechanisms and biological activities suggests their ability as therapeutic agents and also for predicting and monitoring food quality due to their significance in food organoleptic properties and human health. In this chapter, the discussion will be on the diverse therapeutic actions of chromenes as well as the probable mechanisms of action that are responsible for their therapeutic activity. The origins of these chromenes, their extraction from these sources, and their use as nutraceutical components in various food items will also be discussed. The pharmacological relevance of chromenes, which may be added to staple foods to create various nutraceutical products, will also be discussed. As shall be evident after reading this chapter, chromenes as pharmacological agents have a wide range of targets. As a result, medicinal chemistry and quantitative structure-activity relationships should be used to focus on their specific biological action when developing new congeners of chromenes to be used as drugs. 

Unfavourable pharmacokinetics is the major hurdle for the new chemical entity (NCE) to become a drug during the drug discovery and development process. Early evaluation of absorption, distribution, metabolism, and excretion (ADME) characteristics for the promising candidates not only speed up the drug development stages but also lower the attrition rate in clinical phases which can save resource and time. Furthermore, pharmacokinetic behavior is helpful for a better understanding of efficacy, toxicity, and safety. The present chapter deals with ADME information on chromene-based molecules, which have gained significant importance nowadays due to their wide range of pharmacological actions, including anticancer activities. Comprehensive ADME data based on the available information on in-vitro and in-vivo profiles will pave the way towards understanding for discovery and development of new therapeutics in this scaffold from bench to bedside.

Coronavirus pandemics are characterizing the 21st century in itself. In 2002- 03, the first coronavirus SARS-CoV caused Severe Acute Respiratory Syndrome (SARS); in 2012, the Middle East Respiratory Syndrome (MERS-CoV) made its appearance, and in 2019, a new human beta coronavirus strain, the SARS-CoV-2 led to COVID-19 pandemic that took over the entire globe under its rollout. The scientific research and medical challenges to save lives have revealed the biochemistry and genetic evolution of an important cycle of the new pathogen, which has steered us to new preventive and therapeutic approaches to treat SARS-CoV-2. Until now, there is a scant resource of vaccines available, and therefore, it is very challenging to dose huge mass around the world. Moreover, there are other various difficulties in producing, distributing, and storing vaccines; the allopathic drug is always a thrust in this situation. Various in-silico and in-vitro studies have helped to prove that natural molecules containing chromene have shown their effectiveness in the treatment of SARS-CoV-2. Pleiotropic activities and the absence of systemic toxicity of natural chromene and its derivatives represent potential target compounds in clinical trials to enrich the drug armament against coronavirus infections. In this chapter, efforts are being made to discuss the recent investigation of the progress of chromenes in treating SARS-COV-2 virus infection and various treatments involving the possible use of poly-substituted chromene compounds of modern and natural medicines for the treatment of COVID-19.

Heterocyclic compounds hold an important place in the realm of medicinal chemistry due to their vast pharmacological and therapeutic significance. Worldwide, cancer is the leading cause of death, and developing an appropriate treatment for the management of cancer is a challenge. Efforts are being made continuously to search for a suitable medicinal agent to treat cancer. Chromene (benzopyran) is an important scaffold and is also considered a privileged pharmacophore. This scaffold also appears as an important structural component in various natural products. The various substituted and fused chromenes display propitious activity against various types of cancer. This chapter highlights the latest advancements from the year 2015 to date on chromene-based molecules that have anticancer activities. A subpart briefing natural chromenes containing anticancer potential is also incorporated. 

Chromene is a heterocyclic compound that contains oxygen in its ring. It is widely obtained naturally from both animals and plants, and it is an integral part of alkaloids, tocopherol, anthocyanins, and flavonoids. The 2-oxo-2H-chromene is called coumarins, and coumarins have excellent antioxidant potential due to the presence of the phenol group, more than 1300 coumarins have been identified to date. The chromene scaffold in coumarins has the structural modification ability that makes it the structure of choice for medicinal purposes. Various medicines can be synthesized by using a chromene scaffold e.g. asthma, hypertension, antifungal, and antimicrobial. Chromene shows a good antioxidant potential that depends on its hydrogen ion releasing capacity and stabilizes hydrogen with the help of a high resonating structure. The bond length between bonds also enhances the free radical scavenging function. In this chapter, we have discussed some chromene derivatives and their antioxidant potential, and the effect of cyclic structure on the antioxidant’s function. 

Chromene is a heterocyclic scaffold and can be obtained from the natural origin (from different fractions of the plant extracts), synthetic origin as well as mineral origin. The nucleus of the scaffold possesses the ability to interact with different biological targets and thus is medicinally active. Chromene derivatives obtained from different origins are reported to possess pharmacological activities such as antitumor, antibacterial, anti-inflammatory, antithrombotic, and antipsychotic activities. Many chromene-based admixtures are reported to possess different bioactivities. Many derivatives of chromene, such as isomiroestrol, deoxymiroestrol, and miroestrol have been investigated as phytoestrogens. Along with therapeutic potencies, chromene glycosides have safety, efficacy, and stability in the form of herbal drugs and cosmetics. So, the chapter focuses on chromene derivatives, their biological sources, respective bioactivities, and recent advancements. 

This overview depicts the voltage-regulated potassium channel, which is found in the CNS, and the emerging therapeutic applications of potassium channel modulators. It also discusses the recent developments in our understanding of the mechanisms, that control the activity of a series of channels, that are selective for potassium ions. It has been long recognized that the excitability of cells is mediated by proteins, which can modulate the ability of potassium ions to travel across the cell membrane. Going back ten years, it has become increasingly clear that, potassium ion channels represent an excellent target for novel drug design. Investigating the role of potassium channels in treating human diseases continues to be a growing field of research. The ability of potassium channels to regulate membrane potential accords a central role in varied cellular processes that govern excitability, action potential characteristics, stimulus secretion coupling, cell volume regulation, and epithelial electrolyte transport. Attention from medicinal chemists to potassium channels as drug targets has grown with the realization that a variety of potassium channel openers offer significant therapeutic opportunities in cardiac, smooth muscle, neuronal, immune, and secretary systems. Progressive improvements in molecular biology have enabled regular cloning of potassium channels of interest, and defined families of these channels have facilitated a comprehensive understanding of their function. Importantly many families of increasingly selective small molecules have emerged as target validation and clinical proof of principle. Many reviews have appeared summarizing the synthesis and therapeutic potential of these channels. The scope of this report is to make you aware of potassium channel biology, which leads to a more expedient identification of agents for the treatment of CNS disorders, emphasizing developments in medicinal chemistry based on potassium channels where modulators would have considerable clinical potential. While every effort has been made to include all relevant reports in this discussion, any omission is inadvertent and we apologize for the same.

Chromenes (Benzopyran) comprise a major class of pharmacophores widely distributed in various natural products, synthetic drugs, and therapeutic leads. They have been able to fascinate scientists due to the diverse pharmacological activities they possess and the variety of interesting chemical reactions they exhibit. This chapter critically reviews and highlights the general spectroscopic characteristics of chromenes, the diversity of naturally available chromenes as well as various strategies and mechanisms to develop synthetic chromenes. Recent biological application of chromenes of both natural and synthetic origin is also summarized here.