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.     

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.     

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.     

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.     

A new approach to encapsulating nonsteroidal antiinflammatory drugs. IV. Effect of cellulose derivatives with different functional groups on the bioavailability and gastric ulcerogenic activity of acidic as well as basic nonsteroidal anti-inflammatory drugs

Abstract

The bioavailability and gastric ulcerogenic activity of oxyphenbutazone and glafenine (acidic and basic nonsteroidal anti-inflammatory drugs), coated with different cellulose derivatives were assessed in albino rats. the cellulose derivatives chosen have different functional groups, acidic (carboxymethyl cellulose), basic (chitosan) and neutral (hydroxypropylmethyl cellulose). the bioavailability was dependent on the drug and polymers. Generally, all the cellulose derivatives chosen dec reased the gastric ulcerogenic activity of the drugs studied.     

Curcumin and neurodegenerative diseases: a perspective

Introduction: Curcumin, a dietary polyphenol found in the curry spice turmeric, possesses potent antioxidant and anti-inflammatory properties and an ability to modulate multiple targets implicated in the pathogenesis of chronic illness. Curcumin has shown therapeutic potential for neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD).

Areas covered: This article highlights the background and epidemiological evidence of curcumin's health benefits and its pharmacodynamic and pharmacokinetic profile. Curcumin's ability to counteract oxidative stress and inflammation and its capacity to modulate several molecular targets is reviewed. We highlight the neuroprotective properties of curcumin including pre-clinical evidence for its pharmacological effects in experimental models of AD and PD. The bioavailability and safety of curcumin, the development of semi-synthetic curcuminoids as well as novel formulations of curcumin are addressed.

Expert opinion: Curcumin possesses therapeutic potential in the amelioration of a host of neurodegenerative ailments as evidenced by its antioxidant, anti-inflammatory and anti-protein aggregation effects. However, issues such as limited bioavailability and a paucity of clinical studies examining its therapeutic effectiveness in illnesses such as AD and PD currently limit its therapeutic outreach. Considerable effort will be required to adapt curcumin as a neuroprotective agent to be used in the treatment of AD, PD and other neurodegenerative diseases.     

Emerging role of nanocarriers to increase the solubility and bioavailability of curcumin

Introduction: Curcumin is a safe, affordable and natural bioactive molecule of turmeric (Curcuma longa). It has gained considerable attention in recent years for its multiple pharmacological activities. However, its optimum pharmaceutical potential has been limited by its lack of aqueous solubility and poor bioavailability. To mitigate the above limitations, recently various nanostructured water-soluble delivery systems were developed to increase the solubility and bioavailability of curcumin.

Areas covered: Major reasons contributing to the low bioavailability of curcumin appear to be owing to its poor solubility, low absorption, rapid metabolism and rapid systemic elimination. The present review summarizes the strategies using curcumin in various nanocarrier delivery systems to overcome poor solubility and inconsistent bioavailability of curcumin and describes the current status and challenges for the future.

Expert opinion: The development of various drug delivery systems to deliver curcumin will certainly provide a step up towards augmenting the therapeutic activity of curcumin thereby increasing the solubility and bioavailability of curcumin. However, the future of such delivery technology will be highly dependent on the development of safe, non-toxic and non-immunogenic nanocarriers.     

Curcumin: a potential candidate for matrix metalloproteinase inhibitors

Introduction: Curcumin, a natural yellow pigment of turmeric, has become focus of interest with regard to its role in regulation of matrix metalloproteinases (MMPs). MMPs are metal-dependent endopeptidases capable of degrading components of the extracellular matrix. MMPs are involved in chronic diseases such as arthritis, Alzheimer's disease, psoriasis, chronic obstructive pulmonary disease, asthma, cancer, neuropathic pain, and atherosclerosis.

Areas covered: Curcumin regulates the expression and secretion of various MMPs. This review documents the matrix metalloproteinase inhibitory activity of curcumin on various diseases viz., cancer, arthritis, and ulcer. Finally, the steps to be taken for getting potent curcuminoids have also been discussed in the structure–activity relationship (SAR) section. From this review, readers can get answer to the question: Is curcumin a potential MMPI candidate?

Expert opinion: Numerous approaches have been taken to beget a molecule with specificity restricted to a particular MMP as well as good oral bioavailability; however, nearly all the molecules lack these criteria. Using quantitative structure–activity relationship (QSAR) modeling and virtual screening, new analogs of curcumin can be designed which will be selectively inhibiting different MMPs.     

Bile acids and bile acid derivatives: use in drug delivery systems and as therapeutic agents

ABSTRACT

Introduction: Bile acids are biological surfactants and signaling molecules with important paracrine and endocrine functions. The enterohepatic organotropism of bile acids turns these facial amphiphiles into attractive drug delivery systems for selective drug targeting to the liver or to enhance drug bioavailability by improving intestinal absorption and metabolic stability.

Areas covered: Bile acid-based amphiphiles, in the form of mixed micelles, bilosomes, drug conjugates and hybrid lipid-polymer nanoparticles are critically discussed as delivery systems for anticancer drugs, antimicrobial agents and therapeutic peptides/proteins, including vaccines. Therapeutic applications of bile acid derivatives as cytotoxic and neuroprotective agents are also addressed.

Expert opinion: Bile acids play an important role in modulating cancer therapy and novel derivatives with cytotoxic activity not restricted to the gastrointestinal tract can be expected. Selective toxicity targeting the bacterial membrane remains an attractive area of research for further development of bile acid-based bactericidal agents. On the other hand, the neuroprotective properties of some bile acids offer therapeutic potential in neurodegenerative disorders. Bile acid-based nanoparticles are also a growing research area due to the unique characteristics and tunable properties of these nanosystems. Therefore, multifaceted pharmaceutical and biomedical applications of bile salts are to be expected in the near future.     

Synthesis and antioxidant activity of curcumin analogs

Numerous biological activities including antioxidant, antitumor, anti-inflammation, and antivirus of the natural product curcumin were reported. However, the clinical application of it was significantly limited by its instability, poor solubility, less body absorbing, and low bioavailability. This review focuses on the structure modification and antioxidant activity evaluation of curcumin. To study the structure–activity relationship (SAR), five series of curcumin analogs were synthesized and their antioxidant activity were evaluated in vitro. The results showed that electron-donating groups, especially the phenolic hydroxyl group are an essential component to improve the antioxidant activity.     

Nanoparticle formulation of 11-keto-β-boswellic acid (KBA): anti-inflammatory activity and in vivo pharmacokinetics

Context: The oleo-gum-resin of Boswellia serrata Roxb. (Burseraceae) is widely used for the treatment of inflammatory diseases such as osteoarthritis, rheumatoid arthritis and cancer. Anti-inflammatory activity of 11-keto-β-boswellic acid (KBA) is impeded by poor oral bioavailability due to its high lipid solubility, rapid phase-1 metabolism and poor intestinal permeability.

Objective: This study developed a poly-dl-lactide-co-glycolide-based nanoparticle formulation of KBA to improve its oral bioavailability and in vivo anti-inflammatory activity.

Materials and methods: KBA was isolated from the oleo-gum resin of B. serrata, and its nanoparticle formulation (KBA-NPs) was prepared by the emulsion–diffusion–evaporation method. Oral bioavailability of KBA and KBA-NPs was studied at 50?mg/kg p.o. dose in Sprague–Dawley rats, and further evaluated for in vivo anti-inflammatory activity in carrageenan-induced rat paw oedema assay at the same dose level.

Results: The prepared KBA-NPs had a particle size of 152.6?nm with polydispersity index of 0.194, 79.7% entrapment efficiency and a cumulative 61.5% release of KBA from KBA-NPs, at 72?h. KBA-NPs showed 60.8% inhibition of rat paw oedema at 5?h as compared to 34.9% as that of KBA. The results of oral bioavailability study and in vivo anti-inflammatory activity showed 7- and 1.7-fold increase in bioavailability and anti-inflammatory activity, respectively, of KBA in KBA-NPs as compared to KBA alone.

Conclusion: The results of improved oral bioavailability and in vivo anti-inflammatory activity of KBA-NPs suggested successful development of KBA nanoparticle formulation.     

Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo

Curcumin, a yellow pigment present in the spice turmeric (Curcuma longa), has been linked with antioxidant, anti-inflammatory, antiproliferative, anticancer, antidiabetic, antirheumatic, and antiviral effects, but its optimum potential is limited by its lack of solubility in aqueous solvents and poor oral bioavailability. We employed a polymer-based nanoparticle approach to improve bioavailability. Curcumin was encapsulated with 97.5% efficiency in biodegradable nanoparticulate formulation based on poly (lactide-co-glycolide) (PLGA) and a stabilizer polyethylene glycol (PEG)-5000. Dynamic laser light scattering and transmission electron microscopy indicated a particle diameter of 80.9 nm. This curcumin, renamed from hereon “as curcumin (NP)”, was characterized for its biological activity. In vitro curcumin (NP) exhibited very rapid and more efficient cellular uptake than curcumin. Estrase staining revealed that curcumin (NP) was at least as potent as or more potent than curcumin in inducing apoptosis of leukemic cells and in suppressing proliferation of various tumor cell lines. When examined by electrophoretic gel shift mobility assay, curcumin (NP) was more active than curcumin in inhibiting TNF-induced NF-κB activation and in suppression of NF-κB-regulated proteins involved in cell proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF). In mice, curcumin (NP) was more bioavailable and had a longer half-life than curcumin. Overall we demonstrate that curcumin-loaded PLGA nanoparticles formulation has enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo over curcumin.     

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.     

Therapeutic potential of boswellic acids: a patent review (1990-2015)

Introduction: Boswellic acids (BAs), a group of pentacyclic triterpenoids, have demonstrated very interesting biological properties that resulted in a number of protocols being developed for their synthesis. During the last twenty-five years (1990–2015), numerous BAs have been prepared. Both natural BAs and their synthetic derivatives can be used to treat various cancers as well as inflammatory diseases.

Areas covered: This review covers patents on therapeutic activities of natural BAs and their synthetic derivatives published in last twenty-five years (1990–2015). Only BA patents to treat cancer and inflammation are available. A discussion about structure-activity relationships (SAR) of these analogs is also included.

Expert opinion: BAs possess excellent anticancer and anti-inflammatory properties. A large number of BAs and their analogues have been prepared through modification at the C₃-OH and C₂₄-CO₂H functional groups. Most importantly, the C-24 amide and amino derivatives demonstrated increased anticancer and anti-inflammatory activity compared with other BA derivatives. Furthermore, BAs have the potential to form conjugates with other anticancer drugs that will synergistically enhance their anticancer effects; and we believe that in order to get lead compounds, there needs to be a greater focus on the synthesis of halo derivatives of BAs.     

Improvement of drug-like properties of peptides: the somatostatin paradigm

Importance of the field: Peptides are promising candidates as therapeutic agents due to their wide involvement in physiological processes. However, their often non-selective activity and their poor drug-like properties, mainly their inherent low stability to enzymatic degradation and poor oral bioavailability, limit their clinical potential. Somatostatin is a peptide hormone involved in many different biological functions. The role of its five different receptor subtypes and their interplay in medicinal processes is only partially understood. In addition, it suffers from poor drug-like properties.

Areas covered in this review: We review several promising chemical modifications, including head-to-tail and backbone cyclization as well as N-methylation, which were applied throughout the years in the development of various somatostatin analogs.

What the reader will gain: These modifications led to enhanced metabolic stability and intestinal permeability. In addition, several analogs exhibited specific receptor subtype activation.

Take home message: The results presented in this review suggest a potential use of these chemical modifications in order to achieve required characteristics for a bioactive peptide, mainly for clinical usage.     

Curcumin-loaded solid lipid nanoparticles with Brij78 and TPGS improved in vivo oral bioavailability and in situ intestinal absorption of curcumin

Abstract

Purpose: The present study was to formulate curcumin solid lipid nanoparticles (Cur-SLNs) with P-gp modulator excipients, TPGS and Brij78, to enhance the solubility and bioavailability of curcumin.

Methods: The formulation was optimized by Plackett–Burman screening design and Box–Behnken experiment design. Then physiochemical properties, entrapment efficiency and in vitro release of Cur-SLNs were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of Cur-SLNs on the bioavailability and intestinal absorption of curcumin.

Results: The optimized formulations showed an average size of 135.3?±?1.5?nm with a zeta potential value of ?24.7?±?2.1?mV and 91.09%?±?1.23% drug entrapment efficiency, meanwhile displayed a sustained release profile. In vivo pharmacokinetic study showed AUC_0→t for Cur-SLNs was 12.27-folds greater than curcumin suspension and the relative bioavailability of Cur-SLNs was 942.53%. Meanwhile, T_max and t_1/2 of curcumin for Cur-SLNs were both delayed comparing to the suspensions (p?<?0.01). The in situ intestinal absorption study revealed that the effective permeability (P_eff) value of curcumin for SLNs was significantly improved (p?<?0.01) comparing to curcumin solution.

Conclusion: Cur-SLNs with TPGS and Brij78 could improve the oral bioavailability and intestinal absorption of curcumin effectively.     

Utilizing food effects to overcome challenges in delivery of lipophilic bioactives: structural design of medical and functional foods

Introduction: The oral bioavailability of many lipophilic bioactives, such as pharmaceuticals and nutraceuticals, is relatively low due to their poor solubility, permeability and/or chemical stability within the human gastrointestinal tract (GIT). The oral bioavailability of lipophilic bioactives can be improved by designing food matrices that control their release, solubilization, transport and absorption within the GIT.

Areas covered: This article discusses the challenges associated with delivering lipophilic bioactive components, the impact of food composition and structure on oral bioavailability and the design of functional and medical foods for improving the oral bioavailability of lipophilic bioactives.

Expert opinion: Food-based delivery systems can be used to improve the oral bioavailability of lipophilic bioactives. There are a number of potential advantages to delivering lipophilic bioactives using functional or medical foods: greater compliance than conventional delivery forms; increased bioavailability and efficacy; and reduced variability in biological effects. However, food matrices are structurally complex multicomponent materials and research is still needed to identify optimum structures and compositions for particular bioactives.     

Usnic acid and its derivatives for pharmaceutical use: a patent review (2000–2017)

Introduction: Usnic acid (UA) is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton and is commonly found in lichenized fungi of the genera Usnea and Cladonia. Usnic acid has been incorporated for years in cosmetics, perfumery, and traditional medicines. It has a wide range of bioactivities, including antimicrobial, antiviral, anticancer, anti-inflammatory properties.

Areas covered: This review covers patents on therapeutic activities of UA and its synthetic derivatives published during the period 2000–2017.

Expert opinion: UA demonstrates excellent anticancer and antimicrobial properties. However, its application was withdrawn due to acute liver toxicity reported with chronic consumption. The broad spectrum of its biological activity indicates high the variability of UA’s binding preferences. The main idea to be addressed in the future should include the synthesis of UA derivatives because these might possess increased bioactivity, bioavailability and decreased toxicity. It is noteworthy that UA derivatives possessed better antibacterial, antitubercular, and anticancer activity than the parent compound . Most importantly, UA and its analogs (to a greater extent than UA) can be useful in cancer drug treatment. They have the potential for joint application with other anticancer drugs in order to overcome drug resistance.