Recent progress in therapeutic applications of chalcones

INTRODUCTION: Chalcones are a group of plant-derived polyphenolic compounds belonging to the flavonoids family that possess a wide variety of cytoprotective and modulatory functions, which may have therapeutic potential for multiple diseases. Their physicochemical properties seem to define the extent of their biological activity. AREAS COVERED: A comprehensive synopsis of recent patent literature (2005 - 2011) describing chalcones and their derivatives on selected activities (e.g., anti-inflammatory, antimitotic, cytotoxic, antioxidant, anti-infection) is provided in this paper. Synthesis, combinatorial techniques, biological evaluation in vitro/in vivo, and new biological assays are discussed. In addition to selected biological data, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized. EXPERT OPINION: Several natural and synthetic chalcones and their derivatives appear as promising anti-inflammatory and anticancer activities. Their clinical evaluation will be critical to assess their therapeutic utility. Those for which the mechanism of action is well defined can serve as lead compounds for the design of new, more promising molecules.     

Coumarin derivatives: an updated patent review (2012 – 2014)

Introduction: Coumarins belong to the benzopyrones family. They are naturally plant-derived and synthetically taken polyphenolic substances, presenting a wide variety of biological activities and behaviours, supporting their use as therapeutic agents for multiple diseases. Their structural characteristics correlated to physicochemical properties seem to define the extent of the biological activity.

Areas covered: Recent patent publications (2012 – 2014), describing coumarins and their derivatives are analyzed. Synthesis, hybridization techniques and biological evaluation in vitro/in vivo, for example, antimitotic, antiviral, anticancer, cytotoxic, anti-acne and antioxidant coumarin macromolecule polymer agents are included. Furthermore, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized.

Expert opinion: Several natural and synthetic coumarins, hybrids and derivatives appear to have promising anticancer-antitumor activities. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules.     

Curcumin analogues and derivatives with anti-proliferative and anti-inflammatory activity: Structural characteristics and molecular targets

ABSTRACT

Introduction: Curcumin (Diferuloylmethane) is a natural phenolic compound, which belongs to the curcuminoid family, presenting pleiotropic activity and low bioavailability. A lot of recent research is focused on the design and synthesis of curcumin analogs as antiproliferative and anti-inflammatory agents improving the bioavailability and target selectivity. Their structural characteristics and functional groups seem to define the extent of the biological activity.

Areas covered: Publications (2008–2018), describing curcumin analogs and curcumin derivatives are analyzed. Structural characteristics, functional groups, modelling studies, structure activity relationships, biological evaluation in vitro/in vivo as antiproliferative and anti-inflammatory agents are included. Furthermore, a wide range of biological results derived from different targets are also summarized.

Expert opinion: Several curcumin analogs and derivatives appear to have a high biological impact as well as promising antiproliferative and anti-inflammatory activities. Their clinical evaluation will be critical to assess therapeutic utility. Compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules.     

The design and development of imidazothiazole–chalcone derivatives as potential anticancer drugs

Introduction: Imidazothiazole derivatives have long been therapeutically used for the treatment of various diseases. In recent years, the imidazothiazole and chalcone moieties have emerged as important pharmacophores in the development of antitumor agents. Imidazothiazole–chalcone conjugates can be accessed by covalently binding these two powerful pharamacophore units. These conjugates are known to exhibit a wide range of biological properties, including anticancer, antimicrobial, anti-inflammatory and immunosuppressive activities. Their promising biological profile and easy synthetic accessibility have triggered investigations directed at the design and development of new imidazothiazole–chalcone conjugate derivatives as potential chemotherapeutics.

Areas covered: The present review focuses on recent reports of the syntheses and anticancer properties of various imidazothiazoles, chalcones and imidazothiazole-linked chalcone conjugates. Furthermore, the authors discuss the structure–activity relationships (SAR) of imidazothiazoles and chalcones and their conjugates as new antitumor agents, as well as in vitro and in vivo evaluation, clinical use and their future therapeutic applications.

Expert opinion: A large number of imidazothiazoles, chalcones and a new series of imidazothiazole–chalcone conjugates possess potent anticancer activity that could be further developed as drug candidates. Imidazothiazole-based conjugates could also display synergistic effect, and still there is a need to use the drug combinations permitting lower dose and development of new generation of drugs. Despite encouraging observed results for their response to tumors in clinical studies, full characterization of their toxicity is further required for their clinical usage as safe drugs for the treatment of cancer.     

Coumarin derivatives: an updated patent review (2015-2016)

Introduction: Coumarins belong to the benzopyrone family. They are naturally plant-derived or synthetically obtained substances, presenting a wide variety of biological activities, offering an extented therapeutic profile. Their structural characteristics correlated to physicochemical properties define their pleiotropic biological responses.

Areas covered in this review: Recent patent publications (2015–2016), describing coumarins and their derivatives are analyzed. Synthesis, biological evaluations in vitro /in vivo e.g. antiviral, anticancer, cytotoxic, antioxidant, anti-inflammmatory protocols are included. Furthermore, several pharmaceutical applications and pharmaceutical compositions are also described.

Expert opinion: Several synthetic coumarins, hybrids and derivatives (azoles, sulfonyl, furazan, pyrazole etc) have been found to possess promising anticancer, antitumor anti-proliferative activities. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules.     

Recent developments in biological aspects of chalcones: the odyssey continues

Introduction: Chalcones are attractive to synthetic chemists because they are easy to prepare, have a large number of replaceable hydrogens, thereby having significant biological potential. Chalcones and their derivatives (carbocyclic as well as heterocyclic) exhibit a range of biological properties including anticancer, antimalarial, antioxidant, anti-inflammatory and anti-tubercular activities. Their promising biological profile, along with their ease of synthetic manipulations, have triggered the design and development of new chalcone derivatives as well as their conjugates with active pharmacophores affording therapeutic templates targeting various diseases.

Areas covered: This review focuses on synthesized substituted chalcones as well as chalcone-based molecular conjugates that have been developed between 2015 and 2018. Furthermore, their structure–activity relationships with an emphasis on their mechanism of action and docking studies along with their future therapeutic applications.

Expert opinion: A recent upsurge in scientific literature encompassing the synthesis of new chalcone-derivatives as well as its role in ameliorating the activity profiles via amalgamation with other pharmacophores has clearly established the importance of chalcones in present-day drug discovery. As a point, we, the authors, believe that new effective scaffolds can be developed from chalcones with an added advantage of being available at a low cost.     

Novel benzopyran derivatives and their therapeutic applications: a patent review (2009–2016)

Introduction: The benzopyran derivatives present a wide variety of biological activity and behaviour. At the same time the benzopyran derivatives support their use as therapeutic agents for multiple diseases. Their structural characteristics correlated to physicochemical properties seem to define the extent of the biological activity.

Areas covered: This review summarizes new patents published on new benzopyran derivatives from 2009 to 2016.

Expert opinion: Many benzopyran derivatives have vivo/vitro biological responses. Their clinical evaluation will be critical to assess therapeutic utility. The compounds containing benzopyran moiety is well defined as lead compounds for design of new more promising molecules.     

Coumarin-based drugs: a patent review (2008 -- present)

INTRODUCTION: Coumarins are a group of plant-derived polyphenolic compounds. They belong to the benzopyrones family and possess a wide variety of cytoprotective and modulatory functions, which may be translated to therapeutic potentials for multiple diseases. Their physicochemical properties seem to define the extent of the biological activity. AREAS COVERED: In this review recent patent publications (2008 – 2011), describing coumarins and their derivatives, are analyzed. Synthesis, combinatorial techniques, biological evaluation in vitro/in vivo/ex vivo, e.g. antimitotic, immunomodulating, antiviral, anticancer and cytotoxic agents, as well as some new biological assays, are included. In addition to selected biological data, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized. EXPERT OPINION: Several natural and synthetic coumarins and derivatives with potent in vivo/in vitro biological responses appear to be promising anticancer activities. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more promising molecules.     

Therapeutic potential of oxazole scaffold: a patent review (2006–2017)

ABSTRACT

Introduction: Oxazoles are oxygen and nitrogen containing five membered heterocyclic ring systems that are present in various anticancer, antimicrobial, antihyperglycemic, anti-inflammatory agents etc. of natural origin. These pharmacologically active oxazole derivatives have attracted numerous researchers to explore this scaffold for the design and development of newer potential therapeutic agents. A large number of synthetic oxazole containing molecules have been reported over the period that exhibited wide spectrum of pharmacological profiles. Some of them have shown promising therapeutic potential and have qualified for both preclinical and clinical evaluations.

Areas covered: In this review, the patents (published during 2006–2017) focusing on the biological potential of oxazoles have been covered. Therapeutic applications and various techniques/assays employed for the in vitro/in vivo evaluation of patented derivatives have been discussed majorly.

Expert opinion: Chemically oxazole offers three positions for substitution. These substituted oxazole derivatives of natural as well as synthetic origin have numerous pharmacological applications including anticancer, anti-Alzheimer’s, anti-hyperglycemic, anti-inflammatory, antibacterial etc. Their pharmacological actions are mainly mediated through enzyme/receptor involved in the particular disease. The flexible nature of this ligand for various molecular level targets (enzyme/receptor) make this heterocylce an attractive scaffold for development of effective and clinically relevant oxazole containing therapeutic agents.     

Biological evaluation of benzosuberones

Introduction: Several natural products containing benzosuberone moiety are clinically reported as anti-tumor agents. Furthermore, several synthetic benzosuberones cited in this review exhibited wide range of theraputic activities such as bacteriostatic, anti-inflammatory, antidepressants and anti-tumor activities. Our recent review provides an overview of the different methods to synthesize the benzosuberones and their extensive biological activities.

Areas covered: Thirty-two patents among 130 references are cited in this review that covered the recent inhibitory activities of the benzosuberone scaffolds and their broad area of biological applications up to the first quarter of 2017. The areas covered included anti-inflammatory, antimicrobial, antitumor, selective estrogen receptor, anti-obesity, beta-amyloid production, enzymes and HCV inhibitors in addition to anti-Alzheimer and anti-tuberculosis activities as well as several receptors antagonists.

Expert opinion: It is important for medical and pharmaceutical researchers to prepare the first intensive review article concerning the highly biologically active benzosuberone derivatives where they are potent anti-inflammatory, immunosuppressive, antitumor activities and inhibitors of several enzymes. They are useful for treating abnormalities such as sleep disorders, eating disorders and reproductive disorders. Some of these compounds have potential as vascular disrupting agents to selectively target microvessels feeding tumors and some were potential leads for the development of promising therapeutic drugs.     

Oleanolic acid derivatives for pharmaceutical use: a patent review

Introduction: Oleanolic acid belongs to the pentacyclic triterpene family. In China, oleanolic acid has been used as an over the counter (OTC) hepatoprotective drug for decades. Oleanolic acid and its derivatives present a wide variety of biological activities, supporting their pharmaceutical uses for multiple diseases.

Areas covered: Representative patent publications (1971-2015) covering the preparation, pharmaceutical compositions, and medical uses of oleanolic acid and its derivatives are analyzed, with focus on their anticancer, anti-osteoporosis, anti-obesity, anti-diabetic, lipid-lowering, anti-inflammatory, antioxidant, immune-regulatory, and hepatoprotective effects. A large number of Chinese patents have been given particular attention in this review.

Expert opinion: Detailed efficacy studies are highly worth doing to undoubtedly confirm the clinical potential of oleanolic acid and its derivatives. Based on that, it would be critical to identify the key protein targets of the drugs so as to promote drug development and search for new lead compounds. Together, there is a huge potential for drug-repositioning of oleanolic acid, particularly in the areas of metabolic disease and immunological disorders.     

Indazole derivatives and their therapeutic applications: a patent review (2013-2017)

Introduction: Indazoles are heterocyclic moieties rarely found in nature. They are nitrogen containing chemical compounds composed of a pyrazole ring condensed with a benzene ring. Various indazole derivatives have been described with a wide variety of biological activities. This has aroused great interest in the development of novel indazole based therapeutic agents.

Areas covered: Forty-two patents published within the last 5 years (2013–2017) describing derivatives with the indazole scaffold and their therapeutic applications were analysed.

Expert opinion: The indazole scaffold is of great pharmacological importance as it forms the basic structure of a large number of compounds with potential therapeutic value. Derivatives have been found to possess promising anticancer and anti-inflammatory activity and have also found application in disorders involving protein kinases (aside from cancer) and neurodegeneration. The compounds where mechanism of action is defined can afford new molecules with biological and therapeutic properties.     

Vasopressin V1a and V1b receptor modulators: a patent review (2012 – 2014)

Introduction: The vasopressin V1a and V1b receptors are involved in many crucial physiological, reproductive, behavioral and social functions. Consequently, they are also involved in several pathological conditions, thus the ligands capable of selective stimulation/inhibition of these receptors may present therapeutic benefit in a variety of diseases.

Areas covered: In this review, the author focuses on the vasopressin V1a and V1b receptors, their biological functions and agonists and antagonists patented in the years 2012 – 2014. This paper is divided according to both the target receptor and the applicant and describes the compounds from the patents along with their biological activity.

Expert opinion: In the recent years, pharmaceutical companies have discovered and patented new compounds which act through vasopressin V1a and/or V1b receptors, both peptide and non-peptide. Among the V1bR antagonists published in the last years, the oxindole derivatives appear to be the most promising drug candidates.     

An update on benzofuran inhibitors: a patent review

ABSTRACT

Introduction: Benzofuran is a fundamental unit in numerous bioactive heterocycles. They have attracted chemists and medical researchers due to their broad range of biological activity, where some of them possess unique anticancer, antitubercular, antidiabetic, anti-Alzheimer and anti-inflammatory properties. The benzofuran nucleus is present in a huge number of bioactive natural and synthetic compounds. Benzofuran derivatives have potent applications in pharmaceuticals, agriculture, and polymers. The recent developments considering the biological activities of benzofuran compounds are reported. They have a vital role as pronounced inhibitors against a number of diseases, viruses, fungus, microbes, and enzymes.

Areas covered: This review covers the recent developments of biological activities of benzofurans during the period 2014–2019. The covered areas here comprised antimicrobial, anti-inflammatory, antitumor, antitubercular, antidiabetic, anti-Alzheimer, antioxidant, antiviral, vasorelaxant, anti-osteoporotic and enzyme inhibitory activities.

Expert opinion: In addition to the already commercialized 34 benzofurans-based drugs in the market, this chapter outlines several potent benzofuran derivatives that may be useful as potential pro-drugs. It is also focused on providing details of SAR and the effect of certain functional groups on the activity of the benzofuran compounds. The presence of -OH, -OMe, sulfonamide, or halogen contributed greatly to increasing the therapeutic activities comparing with reference drugs.     

不同干燥方法、贮藏年限及采收时间对青龙衣中胡桃醌的影响

探讨不同干燥方法(自然阴干、自然晒干、40℃烘干、60℃烘干)、贮藏年限(当年、1年、2年)及采收时间(6、7、8、9月)对青龙衣中胡桃醌量的影响.方法 采用HPLC法测定不同干燥方法、贮藏年限及采收时间的青龙衣药材中胡桃醌的量.结果 不同干燥方法对青龙衣药材中胡桃醌量有不同的影响,60℃烘干处理后药材中胡桃醌的量显著低于其他的方法(P＜0.01).青龙衣宜采用阴干或40℃烘干的方法干燥.青龙衣贮藏时间越长,胡桃醌的量越低.青龙衣适宜的采收时间是7～8月份果实未成熟时采收.结论 不同干燥方法、贮藏年限及采收时间对青龙衣药材中胡桃醌的量有一定影响.     

Brine shrimp lethality assay ‘an effective prescreen’: Microwave-assisted synthesis,BSL toxicity and 3DQSAR studies-based designing,docking and antitumor evaluation of potent chalcones

Abstract

Context: In the course of searching potential antitumor agents from a library of chalcones synthesized under microwave irradiations, the brine shrimp lethality (BSL) assay and a 3D structure–activity relationship (3DQSAR) studies were followed by the antitumor evaluation of most potent analogues.

Objective: The objective of the current study was to effectively use the BSL assay for the identification of potential cytotoxic analogues from a set of compounds.

Methods: We applied the comparative molecular field analysis (CoMFA) and devised 3DQSAR on 33 synthesized chalcones leading to prediction of five related compounds with improved activity. The scope of BSL assay for the prediction of antitumor potency was tested through the in vitro antitumor studies against six human tumor cell-lines, docking studies and the tubulin-polymerization assay.

Results: The newly designed compounds 34–38 displayed very promising cytotoxic potency. From our results, the BSL toxicity, antitumor efficacy and docking outcomes could be easily co-related.

Conclusion: The study draws a very good relationship between a simple, inexpensive, and bench-top BSL assay and the antitumor potential of the cytotoxic compounds. Devising the CoMFA analysis helped in designing chalcones with improved cytotoxic potential as displayed through their BSL and cytotoxic activity against human tumor cell lines. The studies are noteworthy as such comprehensive studies were never performed before on the BSL assay. The present studies widen the scope of the BSL model that may prove quite helpful as a preliminary screen in the antitumor drug designing and synthesis expeditions.     

Pyrazine derivatives: a patent review (2008 – present)

Introduction: Pyrazines derivatives are well-known and important two-nitrogen-containing six-membered ring aromatic heterocyclic compounds and can carry substituents at one or more of the four ring carbon atoms. Pyrazines are a class of compounds that occur in nature and various methods have been worked out for their synthesis. A large number of pyrazine derivatives have been found to possess diverse pharmacological properties, which has caused an increasing interest by researchers in this core.

Area covered: This review provides a comprehensive review of the pyrazines derivatives patented between the years 2008 to 2012 as potential active compounds. The patent databases SciFinder and esp@cenet were used to locate patent applications that were published between 2008 to present. Information from articles published was also included.

Expert opinion: The diversity of pyrazines derivatives found in organisms in nature with different applications began to arouse the interest of research in this nucleus. The pyrazines derivatives have numerous prominent pharmacological effects, such as antibacterial, antifungal, antimycobacterial, anti-inflammatory, analgesic, anticancer for different types, antidiabetic, treatment for arteriosclerosis, antiviral. It's the time to conduct further studies aimed at rationalizing the biological activities found in order to develop more effective and clinically interesting compounds.     

Foetithiophenes C-F,thiophene derivatives from the roots of Ferula foetida

Abstract

Context: Ferula foetida Regel (Apiaceae) is an Iranian medicinal plant with various biological activities including antispasmodic and anthelmintic.

Objective: The sulfur compounds from the roots of F. foetida were isolated and characterized to test their cytotoxic and antimicrobial activities.

Materials and methods: The methanolic extract of the roots of F. foetida was fractionated using silica column chromatography. The components of each fraction were further purified using RP-HPLC. Their structures were elucidated by 1- and 2-D NMR spectroscopy as well as HREIMS. Their cytotoxic and antimicrobial activities were evaluated using Alamar Blue assay and broth microdilution method, respectively.

Results: Four new thiophene derivatives, namely foetithiophenes C-F (3–6), together with four known compounds, foetithiophenes A (1) and B (2), coniferaldehyde, and sinapic aldehyde, were isolated from the roots of F. foetida. Antimicrobial activities were observed in particular against the Gram-positive bacteria. The best antimicrobial activity was observed for compound 6 against B. cereus with a MIC value 50?µg/mL. The tested compounds did not show cytotoxic properties against MCF-7 and K562 cells.

Conclusion: Four new thiophene derivatives including foetithiophenes C-F (3–6) were characterized from the roots of F. foetida. Foetithiophene F (6) exhibited the most potent activity against the Gram-positive bacteria B. cereus.     

Chemical reactivity and biological activity of chalcones and other α,β-unsaturated carbonyl compounds

Abstract

1. Chalcones are structural analogues of benzalacetophenone (BAP). Several derivatives have been identified in plants and anticarcinogenic and anti-inflammatory properties were attributed to the compounds, probably related to their direct antioxidant activity or stimulatory effects on the expression of endogenous defence enzymes like hemeoxygenase-1 (HO-1). HO-1 expression is triggered by the Nrf2-Keap1 signalling pathway, initiated by the addition of chalcones to thiol groups of Keap1 via Michael-type reaction.

2. The present study used a model system estimating the reactivity of different synthetic chalcones and other α,β-unsaturated carbonyl compounds with thiols and compared the chemical reactivity with the biological activity, measured by HO-1 expression in human dermal fibroblasts.

3. Chemical reactivity with the thiol group of N-acetylcysteine was determined with 5,5′-dithiobis-(2-nitrobenzoic acid) and followed chemical principles of structure–reactivity relationship. Most reactive were sulforaphane, dimethylfumarate, chalcone 3 ((2E)-1-phenyl-3-pyrimidin-2-ylprop-2-en-1-one) and chalcone 7 (1,3-diphenylprop-2-yn-1-one). This result demonstrates that α,β-unsaturated carbonyl derivatives react with thiols differently. All compounds were also biologically active; however, expression of HO-1 was not only related to the chemical reactivity but also to the lipophilicity of the molecules which likely affected transmembrane uptake. Most efficient inducers of HO-1 expression were BAP, 4-hydroxynonenal and chalcone 1 (4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]benzonitrile), chalcone 5 ((2E)-1-phenyl-3-[4-(trifluoromethyl)-phenyl]prop-2-en-1-one) and chalcone 7.     

Recent advances in the therapeutic applications of pyrazolines

INTRODUCTION: Pyrazolines are well-known and important nitrogen-containing five-membered ring heterocyclic compounds. Various methods have been worked out for their synthesis. Several pyrazoline derivatives have been found to possess diverse biological properties, which has stimulated research activity in this field. AREAS COVERED: The present review sheds light on the recent therapeutic patent literature (2000 - 2011) describing the applications of pyrazolines and their derivatives on selected activities. Many of the therapeutic applications of pyrazoline derivatives have been discussed, either in the patent or in the general literature areas in this review. In addition to selected biological data, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized. EXPERT OPINION: Pyrazoline derivatives have numerous prominent pharmacological effects, such as antimicrobial (antibacterial, antifungal, antiamoebic, antimycobacterial), anti-inflammatory, analgesic, antidepressant and anticancer. Further pharmacological effects include cannabinoid CB1 receptor antagonists, antiepileptic, antitrypanosomal, antiviral activity, MAO-inhibitory, antinociceptive activity, insecticidal, hypotensive, nitric oxide synthase inhibitor, antioxidant, steroidal and antidiabetic. Lastly, they also effect ACAT inhibition, urotensin II and somatostatin-5 receptors, TGF-β signal transduction inhibitors and neurocytotoxicity inhibitors activities. Many new pyrazoline derivatives have been synthesized and patented, but there are still new aspects to explore and work on.