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6,7-Coumarin-Heterocyclic Hybrids: A Comprehensive Review of Their Natural Sources, Synthetic Approaches, and Bioactivity
Abstract
The hybridization of heterocycles presents a key opportunity to craft innovative multicyclic compounds with enhanced biological activity. Coumarins, being broadly prevalent natural heterocycles, are extensively utilized in the formulation of diverse biologically and pharmacologically active chemicals. The fusion of various hetero rings with the coumarin ring represents a captivating approach to creating novel hybrid molecules endowed with notable biological activities. In the endeavor of developing heterocyclic-fused coumarins, a diverse array of 6,7-heterocycle-coumarin hybrids has been introduced, showcasing remarkable biological efficacy. The impact of heterocyclic annulation at the 6,7-positions of the coumarin ring on the biological activity of the resultant structures has been examined. This review centers on the natural origins, synthetic methodologies, structural activity relationship investigation, and biological potentials of 6,7-heterocycle-coumarin hybrids. We conducted searches across several databases, including Web of Science, Google Scholar, PubMed, and Scopus. After sieving, we ultimately identified and included 161 pertinent studies published between 1995 and the middle of 2023. This will offer valuable insight to medicinal chemists for the future design and synthesis of biologically active lead compounds based on heterocycle-fused coumarin scaffolds with substantial therapeutic effects.
... This compliance represents how simple it is to insert any substitution(s) at defined positions, excluding positions 1 and 2 [29]. With the same exclusion, various cyclic systems, aromatic or alicyclic, homocyclic or heterocyclic, can connect or fuse with the coumarin framework [30]. The other important characteristics of coumarin are its weak normal cytotoxicity [31], simple aromatic structure [32], low molecular weight [33], solubility in common organic solvents [34], and good oral bioavailability [10]. ...
Despite the up-to-date advancements in its treatment, cancer is still being harvested the lives of millions of people annually; this health threat necessitates exploring more potent agents that can effectively fight it. The class of heterocycles known as coumarin, and its natural and synthetic derivatives are thought to be biomedically valuable. Coumarins have low side effects, outstanding selectivity, a straightforward design for maximum efficiency, and various pharmacological actions. For these characteristics, coumarins are continuously isolated from natural sources and synthesized in laboratories, alongside with examining them for possible bioactivities. In addition to garnering significant attention, coumarin has emerged as a valuable scaffold and a potentially important precursor in the development of innovative anticancer medicines. Researchers are working to create new cancer-fighting coumarins, as well as investigating the old ones. Integration two or more cyclic moieties into a single molecular framework might enhance existing pharmacological effects or perhaps provide entirely new ones. Numerous studies have shown a synergistic or additive impact when various heterocycles are fused with coumarin, where the fusion may occur at coumarin-benzene or coumarin-lactone. The current paper explores in detail how linearly ring-fused coumarins can combat cancer. The derivative with the number 42 was determined to be the best among the fused coumarins that were reviewed. Compared with 5-flourouracil, the IC 50 values of 42 against six cancer cell lines are promising. These values are 25.08, 13.42, 41.45, 28.43, 31.15, and 13.08 μM against SK-OV-3, HeLa, KYSE-30, AMN3, SKG, and MCF-7, respectively. The cancer-fighting attribute of 42 was obvious when compared with those of the reference, which has the following IC 50 values in the same order of cancer cell lines: 22.43, 13.37, 30.72, 24.89, 22.12, and 12.42 μM. The researchers conducted searches across multiple data repositories, such as Scopus, Google Scholar, Web of Science, and PubMed. After conducting a thorough analysis, the authors found and included 59 pertinent publications published by the end of 2023. The reviewed data may help medicinal chemists create and manufacture functionally active leads using the scaffolds that have been mentioned. The knowledge derived from this data may offer substantial medical benefits in the short term for the development of powerful drugs that could boost cancer chemotherapeutics.
... As per a survey conducted in September 2023 and subsequently published in January 2024 (Zeki and Mustafa 2024b), the authors are not cognizant of any published article that synthesizes and examines the linear annulation between coumarin backbone and pentagon ring with four heteroatoms. Therefore, this research can be considered the first investigation in this field. ...
This study revealed the first synthesis of seven novel coumarins annulated with heterocycle composed of four heteroatoms, one sulfur, and three oxygen atoms in a linear pattern. This is an effort to find readily available coumarin frameworks with a broad variety of biological properties that are both adjustable and easy to get. The synthetic annulates' structural framework was confirmed by means of spectroscopic techniques, which included 1H-NMR, 13C-NMR, and FTIR. The synthesized annulates were investigated in vitro for their biomedical potential as antioxidative stress, anti-inflammatory, antidiabetic, anticancer, and antimicrobial agents. In addition, their biosafety toward nontumor cells and commensal bacterial strains was also assessed in vitro. Computer-aided programs were employed to explore the toxicity and pharmacokinetic profiles of the synthesized annulates. Based on the findings that were obtained, the authors stated the following main outcomes. There have been promising and far-reaching biological effects of the synthesized heterocyclic coumarin annulates. HC1 demonstrated strong anti-inflammatory potential through the lipoxygenase-dependent route. Moreover, HC1 exhibited significant antifungal efficacy, surpassing that of nystatin. HC2 held great promise as an antioxidative stress, anticancer, and biosafe candidate. HC3 exhibited a strong antibacterial potential against all tested aerobic bacterial strains, demonstrating a potency equivalent to that of ciprofloxacin. In addition, all of the synthesized annulates, especially HC3, exhibited a noteworthy biosafety profile against the commensal bacterial strains. The strong inhibitory capabilities of HC6 and HC7 toward glucosidase and amylase indicate that they possess great promise as antidiabetic agents. Finally, the synthesized annulates showed favorable toxicity and oral bioavailability properties. It can be inferred that these annulates have the potential to be useful frameworks for developing new drugs with a broad spectrum of bioactivity in the coming years.
... It relies on the principle of combining the different pharmacophoric molecules into new and unique scaffolds with the required activities [37][38][39]. These pharmacophoric molecules offer a dependable route to the discovery and development of new pharmacologically active compounds since they are selected from noteworthy constituents of well-known active pharmaceutical products [40][41][42]. ...
Various pharmacological properties of coumarins brought them under light among the heterocyclics. Also, coumarin derivatives still approve of their importance in the medical field as a valuable building block to elicit further derivatives with diverse, potent, and interesting biological activities. Moreover, the numerous biological actions of thiadiazole-based compounds contribute to the notion of this unique synthesis of linearly fused thiadi-azolocoumarins using the molecular hybridization method. This work reported the novel synthesis of seven linearly fused thiadiazolocoumarins, including Precursor N-III and TDA1-TDA6. These derivatives were characterized by their physicochemical properties and through spectrophotometric tools, including FTIR, 1 H NMR, and 13 C NMR. Also, their pharmacokinetics were predicted using computer-based studies by the SwissADME and PreADMET programs. Furthermore, the derivatives were checked for several biological activities, including anti-cancer, biosafety, anti-oxidative stress, anti-inflammatory, antimicrobial, normal flora safety, and antidiabetic activities. According to the results, TDA3 showed the greatest anticancer activity against the examined cancer cell lines, with the highest cellular biosafety. TDA3 and TDA4 showed higher anti-oxidative stress activity than the other derivatives. All the prepared derivatives showed significant inflammation-inhibitory activity toward the LOX-5 enzyme while showing poor activity towards COX enzymes. According to antimicrobial activity, TDA4 exhibited the greatest anti-gram-negative activity and also showed the best safety toward the examined normal flora. TDA1 exhibited promising activity against anaerobic bacteria, while Precursor N-III, TDA3, and TDA4 showed significant antifungal activity. Finally, TDA1 demonstrated moderate antidiabetic activity, which was the greatest activity among the other derivatives. The authors concluded from the gathered results that the linearly fused thiadiazolocoumarins represent key structures for developing compounds with versatile bioactivities.
... Based on a survey administered in September 2023 and published in January 2024 [43]. the authors have not identified any existing literature that amalgamates and scrutinizes the configuration of a pentagonal ring comprising three heteroatoms linearly fused with a coumarin backbone. ...
This study presents, for the first time, the synthesis of innovative conjugates identified as a five-membered ring integrating three heteroatoms linked linearly to the coumarin framework. Seven conjugates, comprising combinations of 1,3,2-dioxathiole-2-oxide and coumarin derivatives, were made via a three-stage synthetic procedure originating from benzene 1,2,4-triole. Spectroscopic methodologies, encompassing 1 H-NMR, 13 C-NMR, and FTIR, were utilized to validate the structural frameworks of the synthesized conjugates. Their capacity in the biomedi-cine field to act as broad-spectrum antimicrobial agents was evaluated. Furthermore, the biosafety and in silico pharmacokinetic characteristics of the conjugates were also examined. Six pathogenic aerobic bacteriomers, three anaerobic bacteriomers, and two fungiomers were utilized to investigate the broad-spectrum antimicrobial activity of the conjugates. On the other hand, three non-pathogenic bacteriomers were employed to reveal the biosafety profiles of the synthesized conjugates. Finally, two web-based programs were utilized to unveil the pharmacokinetic profiles of the title conjugates. The authors outlined four principal outcomes drawn from the extracted results. The conjugation between 1,3,2-dioxathiole-2-oxide and coumarin derivatives demonstrates biosafety and broad-spectrum antimicrobial implications. Conjugate DOTC5 displayed potent antibacterial activity against the tested aerobic bacteriomers, showing a potency comparable to that of the reference drug. Conjugate DOTC1 demonstrated strong antifungal activity exceeding that of the standard used. The synthesized conjugates , particularly DOTC5, displayed interesting biosafety profiles against the non-pathogenic bacteriomers. It concluded that the conjugates DOTC5 and DOTC1 exhibit the potential to function as valuable scaffolds for developing novel medications with biosafe, broad-spectrum antimicrobial activities in the foreseeable future.
Background: Resveratrol (RVL) is a polyphenol-containing natural product found in a variety of plants, including peanuts, grapes, and berry fruits. The use of RVL is linked in a great deal of research to a number of therapeutic properties. Methods: In an attempt to improve these properties, five RVL-based coumarins, abbreviated YF1-YF5, were synthesized in a structurally constructed pathway. The molecular architecture of our coumarins was confirmed by analyzing their FTIR and NMR spectra. The five biomedical effects of the RVL-based coumarins were investigated and compared with the effects of the precursor. The first is the dual 5-LOX/COX inhibitory effect, which was tested versus three related enzymes. The second is the free-radical neutralizing effects estimated against two radical phenotypes. The third is the apoptotic-inducing effect, evaluated against four tumorous cell lines. The fourth is the high blood-glucose regulatory effect assessed versus two corresponding enzymes. Finally, the bacterial growth-suppressing effect was investigated against four pathogenic bacterial strains. The pharmacoki-netic identifiers of the synthesized compounds were also estimated in silico and matched to RVL to analyze the effect of the chemical functionalization. Results: The findings indicated that the RVL-based coumarins exhibited enhanced biomedical effects compared with their building RVL moiety. The best effects were reported for YF3, and the lowest effects were attributed to YF5. This improvement was coupled with advancements in pharmacokinetic identifiers. Conclusions: According to these outcomes, the authors concluded that the synthesized RVL-based coumarins provide an intriguing chemical modification of RVL for improving its biomedical effects.
Thrombosis is the leading cause of illness and mortality worldwide, posing a serious risk to human health and life. Because antithrombotic drugs can prevent the beginning and progression of thrombotic disorders, they are essential in the management of thrombotic diseases. The substantial side effects and unsatisfactory efficacy of present antithrombotic drugs stimulate the search for novel, effective, and safer antithrombotic therapies. Natural and synthetic coumarins have been shown to have antithrombotic action, specifically anticoagulation, and antiplatelet aggregation. In particular, coumarin-based medications like warfarin, phenprocoumon, and cloricromen have long been used to treat thrombosis in clinical settings. The favored structure for creating novel antithrombotic medications with diverse modes of action is coumarin, which has low toxicity. The goal of the current review is to consolidate recent findings on the development of coumarins as antithrombotic agents, with a focus on the connection between these compounds’ chemical compositions and therapeutic potency. It aims to offer promising suggestions for the identification of new coumarin compounds with potent antithrombotic properties.
Fused coumarins, because of their remarkable biological and therapeutic properties, particularly pyranocoumarins, have caught the interest of synthetic organic chemists, leading to the development of more efficient and environmentally friendly protocols for synthesizing pyranocoumarin derivatives. These compounds are the most promising heterocycles discovered in both natural and synthetic sources, with anti‐inflammatory, anti‐HIV, antitubercular, antihyperglycemic, and antibacterial properties. This review employed the leading scientific databases Scopus, Web of Science, Google Scholar, and PubMed up to the end of 2022, as well as the combining terms pyranocoumarins, synthesis, isolation, structural elucidation, and biological activity. Among the catalysts employed, acidic magnetic nanocatalysts, transition metal catalysts, and carbon‐based catalysts have all demonstrated improved reaction yields and facilitated reactions under milder conditions. Herein, the present review discusses the various multicomponent pyranocoumarin synthesis strategies, potential pharmacological activities of transition metal‐based catalysts, transition metal‐based nanocatalysts, transition metal‐free catalysts, and carbon‐based nanocatalysts.
Background
Kidney stones (KSs), in fact, have been considered one of the most ancient and prevalent medical conditions that impact a significant number of human beings all around the world. Such stones can range greatly in size and can be detected in any part of the urinary system, including the kidneys, ureters, or bladder itself. The development of stones is caused by the mineral’s crystallization, which then interacts with each other and adheres together. Kidney stone formation can represent a prime medical condition for which there are numerous therapies available, among them natural ones. Recurrence of stones after curing is very common, and strategies available to prevent their reoccurrence or even their development for the first time are numerous, with enhanced fluid consumption or avoiding dehydration being the most important one.
Objective
The current review article aims to draw attention to the potential of natural remedies besides lifestyle modification in the management and prevention of KSs. This is not arbitrary but based on real, documented scientific evidence.
Method
The natural remedies mentioned in the context of this manuscript were chosen for their availability in almost all nations, or perhaps even in every home.
Results
The findings of the present article are very promising and exhibit the potential benefit of natural remedies in addition to shifting to a healthy lifestyle in both the treatment and prevention of KSs.
Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound 14b, which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC50 value of 5.32 μM. The anti-inflammatory effects of 14b were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kβ, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The modelling studies revealed that 14b and dexamethasone bind to the same TNF-α pocket, suggesting that 14b has potential as a therapeutic agent superior to dexamethasone for TNF-α.
The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, likely due to the complex biological activities regulated by PKC isoenzymes, often playing ambiguous and protective functions, further driven by the occurrence of mutations. The structure, regulation and functions of PKCs have been extensively covered in other publications. Herein, we focused on PKC alterations mostly associated with complete functional loss. We also addressed the modest yet encouraging results obtained targeting PKC in selected malignancies and the more frequent negative clinical outcomes. The reported observations advocate the need for more selective molecules and a better understanding of the involved pathways. Furthermore, we underlined the most relevant immune mechanisms controlled by PKC isoforms potentially impacting the immune checkpoint inhibitor blockade-mediated immune recovery. We believe that a comprehensive examination of the molecular features of the tumor microenvironment might improve clinical outcomes by tailoring PKC modulation. This approach can be further supported by the identification of potential response biomarkers, which may indicate patients who may benefit from the manipulation of distinctive PKC isoforms.
Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.
Ever since the development of the first vaccine, vaccination has had the great impact on global health, leading to the decrease in the burden of numerous infectious diseases. However, there is a constant need to improve existing vaccines and develop new vaccination strategies and vaccine platforms that induce a broader immune response compared to traditional vaccines. Modern vaccines tend to rely on certain nanotechnology platforms but are still expected to be readily available and easy for large-scale manufacturing and to induce a durable immune response. In this review, we present an overview of the most promising nanoadjuvants and nanoparticulate delivery systems and discuss their benefits from tehchnological and immunological standpoints as well as their objective drawbacks and possible side effects. The presented nano alums, silica and clay nanoparticles, nanoemulsions, adenoviral-vectored systems, adeno-associated viral vectors, vesicular stomatitis viral vectors, lentiviral vectors, virus-like particles (including bacteriophage-based ones) and virosomes indicate that vaccine developers can now choose different adjuvants and/or delivery systems as per the requirement, specific to combatting different infectious diseases.
New 2-oxo-chromene-7-oxymethylene acetohydrazide derivatives 4a-d were designed and synthesized with a variety of bioactive chemical fragments. The newly synthesized compounds were evaluated as acetylcholinesterase (AChE) inhibitors and antioxidant agents in comparison to donepezil and ascorbic acid, respectively. Compound 4c exhibited a promising inhibitory impact with an IC50 value of 0.802 μM and DPPH scavenging activity of 57.14 ± 2.77%. Furthermore, biochemical and haematological studies revealed that compound 4c had no effect on the blood profile, hepatic enzyme levels (AST, ALT, and ALP), or total urea in 4c-treated rats compared to the controls. Moreover, the histopathological studies of 4c-treated rats revealed the normal architecture of the hepatic lobules and renal parenchyma, as well as no histopathological damage in the examined hepatic, kidney, heart, and brain tissues. In addition, an in vivo study investigated the amelioration in the cognitive function of AD-rats treated with 4c through the T-maze and beam balance behavioural tests. Also, 4c detectably ameliorated MDA and GSH, reaching 90.64 and 27.17%, respectively, in comparison to the standard drug (90.64% and 35.03% for MDA and GSH, respectively). The molecular docking study exhibited a good fitting of compound 4c in the active site of the AChE enzyme and a promising safety profile. Compound 4c exhibited a promising anti-Alzheimer's disease efficiency compared to the standard drug donepezil.
This study revealed the design and preparation of new 3-(benzo[d]thiazol-2-yl)-2H-chromen-2-one derivatives 9a-h. The structures of the synthesized products were elucidated by their spectroscopic data and X-ray crystallography for compounds 9a and 9d. The prepared new compounds were measured for their fluorescence, and a good result indicated that the emission efficiency was decreased by increasing the electron-withdrawing groups from the unsubstituted compound 9a to the highly substituted derivative 9h (2 Br heavy atoms). On the other hand, the B3LYP/6-311G** theoretical level of theory was used to optimize the quantum mechanical calculations of the geometrical characteristics and energy of the novel compounds 9a-h under study. The electronic transition was investigated using the TD-DFT/PCM B3LYP approach, which uses time-dependent density functional calculations. Moreover, the compounds exhibited nonlinear optical properties (NLO) and a small HOMO-LUMO energy gap, which makes them easy to polarize. Furthermore, the acquired infrared spectra were compared with the expected harmonic vibrations of the substances 9a-h. On the other hand, binding energy analyses of compounds 9a-h with human corona virus nucleocapsid protein Nl63 (PDB ID: 5epw) were predicted using molecular docking and virtual screening tools. The results showed a promising binding and how these potent compounds were inhibiting the COVID-19 virus. Compound 9h was the most active anti-COVID-19 agent among all the synthesized benzothiazolyl-coumarin derivatives, as it forms five bonds. The presence of the two bromine atoms in its structure was responsible for the potent activity.
Acquired immune deficiency syndrome (AIDS) is a worldwide epidemic caused by human immunodeficiency virus (HIV) infection. Newer medicines for eliminating the viral reservoir and eradicating the virus are urgently needed. Attempts to locate relatively safe and non-toxic medications from natural resources are ongoing now. Natural-product-based antiviral candidates have been exploited to a limited extent. However, antiviral research is inadequate to counteract for the resistant patterns. Plant-derived bioactive compounds hold promise as powerful pharmacophore scaffolds, which have shown anti-HIV potential. This review focuses on a consideration of the virus, various possible HIV-controlling methods and the recent progress in alternative natural compounds with anti-HIV activity, with a particular emphasis on recent results from natural sources of anti-HIV agents. Please cite this article as: Mandhata CP, Sahoo CR, Padhy RN. A comprehensive overview on the role of phytocompounds in human immunodeficiency virus treatment. J Integr Med. 2023; Epub ahead of print.
Parkinson’s disease (PD) as a prevalent neurodegenerative condition impairs motor function and is caused by the progressive deterioration of nigrostriatal dopaminergic (DAergic) neurons. The current therapy solutions for PD are ineffective because they could not inhibit the disease’s progression and they even have adverse effects. Natural polyphenols, a group of phytochemicals, have been found to offer various health benefits, including neuroprotection against PD. Among these, resveratrol (RES) has neuroprotective properties owing to its capacity to protect mitochondria and act as an antioxidant. An increase in the formation of reactive oxygen species (ROS) leads to oxidative stress (OS), which is responsible for cellular damage resulting in lipid peroxidation, oxidative protein alteration, and DNA damage. In PD models, it’s been discovered that RES pretreatment can diminish oxidative stress by boosting endogenous antioxidant status and directly scavenging ROS. Several studies have examined the involvement of RES in the modulation of the transcriptional factor Nrf2 in PD models because this protein recognizes oxidants and controls the antioxidant defense. In this review, we have examined the molecular mechanisms underlying the RES activity and reviewed its effects in both in vitro and in vivo models of PD. The gathered evidence herein showed that RES treatment provides neuroprotection against PD by reducing OS and upregulation of Nrf2. Moreover, in the present study, scientific proof of the neuroprotective properties of RES against PD and the mechanism supporting clinical development consideration has been described.
Eighteen novel functionalized phenyl acetate derivatives of benzo[e]-bispyrone fused hybrids and their three precursors are developed in this study. The precursor acetic acid congeners of benzo[e]-bispyrone fused hybrids (Y1, Y8, and Y15) were created by combining acetone dicarboxylic acid and three resorcinol-based compounds. They were utilized in the preparation of novel functionalized phenyl acetate derivatives of benzo[e]-bispyrone fused hybrids (Y2-Y7, Y9-Y14, and Y16-Y21). Six in vitro biological activities were investigated for the synthesized precursors and their functionalized phenyl acetate derivatives. First, the reactive species-caging activity was tested against DPPH and hydroxyl radicals. Second, the cellular viability-terminating activity was assayed using MTT-visual probing methodology against six common cancerous cell lines. Third, fourth, and fifth activities, collectively termed microbial-shedding potential, were examined using a microdilution broth methodology against six aerobic pathogenic bacterial strains, four anaerobic pathogenic bacterial strains, and two pathogenic fungal strains, respectively. Finally, the blood sugar-dropping activity was assessed against two related enzymes. Moreover, the toxic effects of the twenty-one synthesized compounds were assessed against one normal human cell line and one non-pathogenic bacterial strain. The results showed that the fused hybrids' methoxyphenyl acetate derivatives (Y2, Y9, and Y16) had the greatest reactive species-caging, anaerobic pathogenic bacterial-shooting, and blood sugar-dropping activities. In terms of cellular viability-terminating activity, the fluorophenyl acetate derivatives (Y4, Y11, and Y18) demonstrated the greatest activity against the tested cancerous cell lines while causing the least toxicity to the normal cell line. Chlorophenyl acetate derivatives had the highest aerobic pathogen-shedding activity while causing the least toxicity on normal bacterial strains (Y5, Y12, and Y19). Finally, the precursors and derivatives with flourophenyl or chlorophenyl acetate demonstrated the highest levels of fungal-shooting activity, exceeding the reference. The researchers concluded from these observations that the synthesized precursors and their derivatives provided several biosafe scaffolds with multiple and selective activities.
Significant health issues have lately been brought on by the dramatic increase in pathogenic microbes that are resistant to antibiotics. To manage or fight infections brought on by pathogens, investigators are looking for substitutes for currently used antimicrobial agents. Numerous approaches are being used to create effective antimicrobial agents, with nanotechnol-ogy being one of the most significant. Metal/metal oxide nanocomposite-based antibacterial agents work by evading the bacterial defenses against drug resistance and preventing the growth of biofilms or other critical virulence-related operations. Bacterial cell walls and membranes can be penetrated by nanocomposites, which then act by sabotaging crucial molecular processes. Nanocomposite-based antibacterial agents may exhibit synergy when used in conjunction with the proper antibiotics and aid in halting the growing global emergency of bacterial resistance. Moreover, polymer-derived nanocomposites facilitate the creation of a diverse range of healthcare equipment because of properties like improved biodegradability and biocompatibility. Once nanocomposites are incorporated, packed, or covered into various materials, they have antibacterial applications ranging from medicinal and surgical instruments to antimicrobial artificial fabrics. This review study covers the antibacterial properties of nanocomposites, developments in the understanding of their mechanism of action, and promising applications of nanocomposite-based antibacterial agents in biomedicine.
Benzofuran moiety is the main component of many biologically active natural and synthetic heterocycles. These heterocycles have unique therapeutic potentials and are involved in various clinical drugs. The reported results confirmed the extraordinary inhibitory potency of such benzofurans against a panel of human cancer cell lines compared with a wide array of reference anticancer drugs. Several publications about the anticancer potencies of benzofuran-based heterocycles were encountered. The recent developments of anticancer activities of both natural and synthetic benzofuran scaffolds during 2019-2022 are thoroughly covered. Many of the described benzofurans are promising candidates for development as anticancer agents based on their outstanding inhibitory potency against a panel of human cancer cells compared with reference anticancer drugs. These findings encourage medicinal chemists to explore new areas to improve human health and reduce suffering.
Background: Coumarins and their derivatives excel in chemical diversity, coupled with a wide variety of biological potentials, and tend to be beneficial to the health of the human body. One of these derivatives that has sparked the attention of medicinal chemistry specialists in recent decades is benzo-fused coumarins, which have demonstrated their potential as antioxidants, antimicrobials, antidiabetics, antithrombotics, and many more. Objective: This paper discusses the medicinal importance of benzo-fused coumarins derived from natural or synthetic sources. Conclusion: The researchers documented that benzo-fused coumarin's basic structure is a promising framework that opens up the chance of discovering innovative applicants with advanced therapeutic potentials.
Coumarin hybrids have been designed and synthesized as an important new strategy in the field of medicinal chemistry. Coumarin core has been shown to form various compounds to combat several diseases including microbial, cancer, inflammatory, and neurodegenerative disorders. Recently, a number of coumarin-based drugs (e.g., coumadin, acenocoumarol, dicoumarol, phenprocoumon, and novobiocin) have been FDA-approved and are in the clinic, and several coumarin-containing compounds are in clinical trials. Our group classified coumarin-based hybrid compounds into groups showing shared biological activities and discussed their potential therapeutic targets.
Graphical Abstract
The best method of anticoagulation for patients with peripheral artery disease (PAD) is still a topic of interest for physicians. We conducted a meta-analysis to compare the effects of direct oral anticoagulants (DOACs) with those of vitamin-K-antagonist (VKA) anticoagulants in patients with peripheral artery disease. Five databases (Medline (via PubMed), EMBASE, Scopus, Web of Science, and CENTRAL) were searched systematically for studies comparing the effects of the two types of anticoagulants in patients with PAD, with an emphasis on lower-limb outcomes, cardiovascular events, and mortality. In PAD patients with concomitant non-valvular atrial fibrillation (NVAF), the use of DOACs significantly reduced the risk of major adverse limb events (HR = 0.58, 95% CI, 0.39–0.86, p < 0.01), stroke/systemic embolism (HR 0.76; 95% CI 0.61–0.95; p < 0.01), and all-cause mortality (HR 0.78; 95% CI 0.66–0.92; p < 0.01) compared with warfarin, but showed similar risks of MI (HR = 0.81, 95% CI, 0.59–1.11, p = 0.2) and cardiovascular mortality (HR = 0.77, 95% CI, 0.58–1.02, p = 0.07). Rivaroxaban at higher doses significantly increased the risk of major bleeding (HR = 1.16, 95% CI, 1.07–1.25, p < 0.01). We found no significant difference in terms of revascularization (OR = 1.49, 95% CI, 0.79–2.79, p = 0.14) in PAD patients in whom a poor distal runoff was the reason for the anticoagulation. DOACs have lower rates of major limb events, stroke, and mortality than VKAs in PAD patients with atrial fibrillation. Rivaroxaban at higher doses increased the risk of major bleeding compared with other DOAC drugs. More high-quality studies are needed to determine the most appropriate anticoagulation regimen for patients with lower-limb atherosclerosis.
This review summarizes and systematizes the literature on the anti-HIV activity of plant coumarins with emphasis on isolation and the mechanism of their antiviral action. This review summarizes the information on the anti-HIV properties of simple coumarins as well as annulated furano- and pyranocoumarins and shows that coumarins of plant origin can act by several mechanisms: inhibition of HIV reverse transcriptase and integrase, inhibition of cellular factors that regulate HIV-1 replication, and transmission of viral particles from infected macrophages to healthy ones. It is important to note that some pyranocoumarins are able to act through several mechanisms or bind to several sites, which ensures the resistance of these compounds to HIV mutations. Here we review the last two decades of research on the anti-HIV activity of naturally occurring coumarins.
Mammary gland tumors are the most common neoplasms in female dogs, of which 50% are malignant. Esculetin, a coumarin derivative, reportedly induces death in different types of cancer cells. In this study, we explore the anticancer effects of esculetin against CMT-U27 and CF41.mg canine mammary gland tumor cells. Esculetin significantly inhibited the viability and migration of both CMT-U27 and CF41.mg cells in a dose- and time-dependent manner. Flow cytometric analysis and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed increased numbers of annexin-V-positive cells and DNA fragmentation. Furthermore, a cell cycle analysis demonstrated that esculetin blocked the cell progression at the G0/G1 phase and the S phase in CMT-U27 and CF41.mg cells. These results were supported by a Western blot analysis, which revealed upregulated protein expression of cleaved caspase-3, a marker of apoptosis, and downregulated cyclin-dependent kinase 4 and cyclin D1 protein, the cell cycle regulators. In conclusion, this novel study proves that esculetin exerts in vitro antitumor effects by inducing apoptosis and cell cycle arrest in canine mammary gland tumors.
Herein, an efficient and convenient method for the synthesis of 4-(substitutedphenyl)-1,2-dihydro-2-oxo-6-(2-oxo-2H-benzo[g]chromen-3-yl)pyridine-3-carbonitrile derivatives have been reported using ammonium acetate as catalyst. The structures of synthesized compounds were confirmed using FT-IR, 1H, 13C-NMR and LC-MS spectroscopic techniques. The synthesized compounds have been evaluated for antibacterial activity against bacterial strains by agar diffusion method at different concentrations. Further, all the targeted compounds were screened for anti-oxidant and anti-cancer studies by DPPH and MTT assay methods at different concentrations. Compound 4b displayed good antioxidant and anticancer (against MCF-7 cell line) activity. Further, the binding capability for the synthesized compounds (4a–j) was analyzed by molecular docking studies using human peroxiredoxin 5 (PDB ID: 1HD2) and P38 MAP kinase (PDB ID: 1OUK) protein. Further, the physicochemical properties were analysed from ADME studies respectively.
Due to population growth, instability of climatic conditions, and reduction of the areas of natural ecosystems, it becomes necessary to involve modern biotechnological approaches to obtain highly productive plant material. This statement applies both to the creation of plant varieties and the production of new pharmaceutical raw materials. Genetic transformation of valuable medicinal plants using Agrobacterium rhizogenes ensures the production of stable and rapidly growing hairy roots cultures that have a number of advantages compared with cell culture and, above all, can synthesize root-specific substances at the level of the roots of the intact plant. In this regard, special attention should be paid to the collection of hairy roots of the Institute of Plant Physiology RAS, Russian Academy of Sciences, the founder of which was Dr. Kuzovkina I.N. Currently, the collection contains 38 hairy roots lines of valuable medicinal and forage plants. The review discusses the prospects of creating a hairy roots collection as a basis for fundamental research and commercial purposes.
Context: Stachytarpheta jamaicensis (L.) Vahlplant is used for traditional therapy because of its content, including flavonoids, alkaloids, tannins, saponins, terpenoids, and coumarins.
Aims: To determine the antibacterial ability of S. jamaicensis roots extract (SJRE) on some selected mouth bacteria through in vitro and in silico studies.
Methods: Phytochemical analysis and liquid chromatography-high resolution mass spectrometry (LC-HRMS) were done to explore the active compounds on SJRE. Absorption, distribution, metabolism, excretion and toxicity prediction, molecular docking simulation and visualization of luvangetin, and xanthyletin as anti-inflammatory and antibacterial were investigated in silico. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of SJRE against Aggregatibacter actinomycetemcomitans, Enterococcus faecalis, and Actinomyces spp. were calculated.
Results: Luvangetin and xanthyletin are good candidate drug molecules with low toxicity. Xanthyletin has higher binding activity than luvangetin to TNF-α, IL-6, IL-10, peptidoglycan, flagellin, and dectin protein. SJRE exhibited a high antibacterial ability, and MIC. This extract inhibits the growth of A. actinomycetemcomitans, E. faecalis and Actinomyces spp. at various concentrations 2000, 8000, and 8000 µg/mL, respectively, with statistically significant differences (p = 0.0001; p
Scopoletin is a phenolic coumarin isolated from a variety of plants and was originally used to treat various diseases including arthritis as well as bone-related diseases. The goal of this study was to determine scopoletin’s therapeutic potential in an animal model of myocardial infarction induced with ISO. There were five groups of albino male rats. Group I (control) animals were orally treated with olive oil. Group II (scopoletin) animals were pre-treated orally with a 50-mg dosage of scopoletin for 28 days. Group III (ISO-treated) animals were treated with 85 mg/kg of ISO subcutaneously for 2 consecutive days (29th and 30th day). Group IV (scopoletin and ISO) animals were pre-treated orally with 25 mg of scopoletin for 28 days before exposure to ISO. Group V (scopoletin and ISO) animals were pre-treated with 50 mg of scopoletin for 28 days before exposure to ISO. In the ISO-administered animals, a wider heart-to-body weight ratio, a higher heart weight, higher cardiac diagnostic markers, higher MDA levels and related antioxidant levels, inflammatory, and apoptotic markers were observed. Scopoletin pre-treatment with ISO (25 and 50 mg/kg b.wt) significantly reduced heart-to-body weight ratio, cardiac diagnostic markers, MDA, inflammatory markers, and apoptotic markers. Meantime, a pre-treatment with scopoletin increased the levels of antioxidant enzymes. Inflammation and necrosis were observed in the histopathology of heart tissue of ISO-treated animals and these histopathological conditions were reversed by scopoletin pretreatment. The antioxidant and anti-inflammatory properties of ISO-treated rats were shown to be increased by scopoletin, showing its therapeutic potential against cardiovascular diseases. Through the use of its antioxidant and anti-inflammatory properties, scopoletin exhibited anti-myocardial infarction properties. However, further preclinical studies will be required to demonstrate the mechanism of action of scopoletin involved in anti-myocardial infarction.
Coumarins are a structurally varied set of 2H-chromen-2-one compounds categorized also as members of the benzopyrone group of secondary metabolites. Coumarin derivatives attract interest owing to their wide practical application and the unique reactivity of fused benzene and pyrone ring systems in molecular structure. Coumarins have their own specific fingerprints as antiviral, antimicrobial, antioxidant, anti-inflammatory, antiadipogenic, cytotoxic, apoptosis, antitumor, antitubercular, and cytotoxicity agents. Natural products have played an essential role in filling the pharmaceutical pipeline for thousands of years. Biological effects of natural coumarins have laid the basis of low-toxic and highly effective drugs. Presently, more than 1300 coumarins have been identified in plants, bacteria, and fungi. Fungi as cultivated microbes have provided many of the nature-inspired syntheses of chemically diverse drugs. Endophytic fungi bioactivities attract interest, with applications in fields as diverse as cancer and neuronal injury or degeneration, microbial and parasitic infections, and others. Fungal mycelia produce several classes of bioactive molecules, including a wide group of coumarins. Of promise are further studies of conditions and products of the natural and synthetic coumarins’ biotransformation by the fungal cultures, aimed at solving the urgent problem of searching for materials for biomedical engineering. The present review evaluates the fungal coumarins, their structure-related peculiarities, and their future therapeutic potential. Special emphasis has been placed on the coumarins successfully bioprospected from fungi, whereas an industry demand for the same coumarins earlier found in plants has faced hurdles. Considerable attention has also been paid to some aspects of the molecular mechanisms underlying the coumarins’ biological activity. The compounds are selected and grouped according to their cytotoxic, anticancer, antibacterial, antifungal, and miscellaneous effects.
Estrogen and its receptor play a positive role in the development of osteoarthritis (OA). Psoralen is a plant-derived estrogen analog. This study aimed to verify whether psoralen inhibits OA through an estrogen-like effect. First, human primary chondrocytes in the late stage of OA were extracted to complete collagen type II immunofluorescence staining and cell proliferation experiments. Subsequently, estrogen, psoralen and estrogen receptor antagonists were co-cultured with OA chondrocytes, and RT-PCR was performed to detect the gene expression. A rabbit OA model was subsequently made by anterior cruciate ligament transection (ACLT). They were set as Sham group, OA group and Psoralen group, respectively. The articular cartilage samples were taken after 5 weeks of treatment, and the effect was observed by gross observation, histological staining, micro-CT scanning of subchondral bone. The results of cellular experiments displayed that the cultured cells were positive for collagen II fluorescence staining and 12 μg/mL psoralen was selected as the optimal concentration. In addition, psoralen had effects similar to estrogen, promoting the expression of estrogen tar-get genes CTSD, PGR and TFF1 and decreasing the expression of the inflammation-related gene TNF- α, IL-1β and IL-6. The effect of psoralen was blocked after the use of an estrogen receptor antagonist. Further animal experiments indicated that the psoralen group showed less destruction of cartilage tissue and decreased OASRI scores compared with the OA group. A subchondral bone CT scan demonstrated that psoralen significantly increased subchondral bone mineral density (BMD), trabecular thickness and trabecular number and decreased trabecular separation. In summary, psoralen inhibits the inflammatory production of chondrocytes, which is related to estrogen-like effect, and can be used to attenuate the progression of OA.
The goal of targeting drugs to a specific site or organ in the body is to achieve an ideal therapeutic effect with minimal harmful effects on the other components of the human body. In an effort to develop a unique drug delivery system with the capacity to release drugs precisely into the colon in a reproducible and predictable manner, a mutual prodrug design targeting the colon has attracted a great deal of attention in recent years. The colon is an interesting area for both local and systemic medication delivery. A mutual prodrug is made up of two chemotherapeutic drugs: the first is considered as an original drug and the other is regarded as its transporter, both of which have an inherent synergistic or an additive therapeutic activity. Therefore, utilizing a mutual prodrug reduces the necessary dose, minimizing the adverse systemic effects, and consequently producing a more efficient therapy system. The goal of this review is to comprehend the importance of mutual prodrugs in the treatment of colon diseases, and also mention the most significant and efficient prodrugs in this field.
Background
Breast cancer is the most frequent cancer among women. Despite the effectiveness of Doxorubicin (DOX) as a chemotherapeutic for the treatment of breast cancer, the therapy-resistance remains unsolvable. Apigenin is a natural dietary flavonoid with potential anticancer activities. Our study’s intention was to evaluate the effect of Apigenin on DOX resistance in MCF-7 cells.
Methods
DOX-resistant MCF-7 cell line (MCF-7R) was developed by treating MCF-7 cells with increasing concentrations of DOX (0-100 µM). The viability of cell lines was assayed using MTT method. Quantitative polymerase chain reaction method was performed to measure multidrug-resistance 1 (MDR1) gene expression level. The expression of MDR1, Janus kinase 2 (JAK2) and Signal transducer and activator of transcription 3 (STAT3) proteins were determined by western blotting.
Results
MCF-7R cell line showed resistance to DOX in comparison to MCF-7 cells. Apigenin had a significant effect on the reduction of viability of both MCF-7 and MCF-7R cell lines. However, DOX-resistance in the MCF-7 cell line was considerably decreased due to the co-treatment of MCF-7R cells with Apigenin. This natural compound also downregulated the expression of MDR1 at mRNA and protein levels both in resistant and non-resistant cells. Apigenin significantly prohibited the phosphorylation and activation of JAK2 and STAT3 proteins both in MCF-7 and MCF-7R cell lines.
Conclusions
The present results suggested, for the first time, Apigenin as an ideal therapeutic for ameliorating DOX resistance in breast cancer. These data also proposed a novel mechanism for the anti-resistance activity of Apigenin by regulating the JAK2/STAT3/MDR1 axis.
To search a novel lead structure for antiphytopathogenic fungus agent, a series of novel psoralen derivatives possessing sulfonohydrazide or acylthiourea structure were designed and synthesized, and their fungicidal activity against seven phytopathogens was evaluated. Their structures were confirmed by melting points, ¹H NMR, ¹³C NMR and HRMS, and the typical crystal structure was determined by X-ray diffraction for validation. Preliminary fungicidal activity showed that some of the title compounds exhibited certain-to-high fungicidal activity. Compound I-13 exhibited good fungicidal activity against Botrytis cinerea, Cercospora arachidicola and Physalospora piricola with EC50 values of 12.49, 13.22 and 12.12 μg/mL, respectively. Compounds II-9 and II-15 showed over 90% inhibition against B. cinerea at 50 μg/mL in vitro. In particular, II-9 exhibited significant higher fungicidal activity with a lower EC50 value of 9.09 μg/mL than the positive control YZK-C22 (13.41 μg/mL). Our studies found that sulfonohydrazide or acylthiourea-containing psoralen derivatives were promising fungicide leads deserve for further study.
Graphical abstract
Neurotransmitters are molecules that amplify, transmit, and convert signals in cells, having an essential role in information transmission throughout the nervous system. Hundreds of such chemicals have been discovered in the last century, continuing to be identified and studied concerning their action on brain health. These substances have been observed to influence numerous functions, including emotions, thoughts, memories, learning, and movements. Thus, disturbances in neurotransmitters’ homeostasis started being correlated with a plethora of neurological and neurodegenerative disorders. In this respect, the present paper aims to describe the most important neurotransmitters, broadly classified into canonical (e.g., amino acids, monoamines, acetylcholine, purines, soluble gases, neuropeptides) and noncanonical neurotransmitters (e.g., exosomes, steroids, D-aspartic acid), and explain their link with some of the most relevant neurological conditions. Moreover, a brief overview of the recently developed neurotransmitters’ detection methods is offered, followed by several considerations on the modulation of these substances towards restoring homeostasis.
Background
Elevated lipids in umbilical cord blood affect fetal programming, leading to a higher risk of developing cardiovascular disease in later life. However, the causes of changes in the lipid profile of umbilical cord blood are not clear yet. This study aimed for the first time to determine the association of asprosin concentration with TAG, TC, HDL-C, LDL-C concentrations and TAG/HDL-C, TC/HDL-C, LDL-C/HDL-C and non-HDL-C/HDL-C ratio in umbilical cord blood as well as newborn anthropometric indices. This cross-sectional study was based on 450 mother- newborn pairs of a birth cohort study in Sabzevar, Iran. Multiple linear regression was used to estimate the association of lipid concentration and lipid ratios as well as birth weight (BW), birth length (BL), head circumference (HC) and chest circumference (CC) with asprosin in cord blood samples controlled for the relevant covariates.
Result
In fully adjusted models, each 1 ng/mL increase in asprosin was associated with 0.19 (95% CI 0.06, 0.31, P < 0.01), 0.19 (95% CI 0.10, 0.29, P < 0.01), 0.17 (95% CI 0.09, 0.25, P < 0.01), 0.17 (95% CI 0.09, 0.25, P < 0.01), 0.01 (95% CI 0.00, 0.013, P < 0.01), 0.01 (95% CI 0.01, 0.01, P < 0.01), 0.01 (95% CI 0.01, 0.01, P < 0.01) and 0.01 (95% CI 0.01, 0.01, P < 0.01) increase in TAG, TC, LDL-C, TAG/HDL-C, TC/HDL-C, LDL-C/HDL-C and non-HDL-C/HDL-C ratio respectively. Moreover, higher asprosin levels was positively associated with newborn BW, BL, HC and CC; however, these associations were not statistically significant.
Conclusion
Overall, our findings support the positive association between cord asprosin concentration and the development of atherogenic lipid profile in newborns. Further studies are needed to confirm the findings of this study in other populations.
In this research, acetone dicarboxylic acid generated from citric acid was employed in the Pechmann coupling reaction to produce a novel multifunctional benzodipyrone precursor (CSY1). The latter was reacted with a variety of substituted phenols to produce the six CSY1-based derivatives symbolized here as CSY2-CSY7. The chemical structures of the precursor and its based derivative were efficiently recognized by examining the acquired spectral charts. Our compounds' cytotoxic, antimicrobial, and hypoglycemic activities were tested in vitro. The initial activity was evaluated against six tumorigenic cell lines utilizing an IC50 matrix. The antibacterial activity of six aerobic gram-negative bacteria, four anaerobic bacteria, two fungi, and one non-pathogenic bacterial strain was assessed using a broth-dilution test. Furthermore, the hypoglycemic activity on yeast α-glucosidase and porcine α-amylase, two types of blood glucose-controlling enzymes, was calculated. According to the findings of the initial activity, our compounds, notably CSY4, displayed a potent-to-moderate wide-range of cytotoxic properties. This action is accompanied by a low risk of normal cell toxicity. Furthermore, these compounds showed promising antibacterial properties, particularly CSY5 for aerobic gram-negative bacteria, CSY2 for anaerobic bacteria, and CSY1 for pathogenic fungi. This promise is supported by our chemicals relative safety when it comes to the bacteria of the normal flora. The compounds had moderate-to-weak inhibitory effects on the blood glucose-controlling enzymes tested, with CSY2 and CSY3 having the strongest hypoglycemic potential. Our molecules, according to the results, could provide unique bioactive platforms that might open up new avenues for the identification of novel therapeutically active drugs
Microbial infection and microbial resistance to the classical antibiotics have been immense challenges which portend the health of societies. This has directed researchers to straight their attention onto the plants to discover new possible antimicrobial compounds. In this work, 5 solvents were employed to extract the dried seeds powder of quince by ultrasound including ethanol, ethyl-acetate, chloroform, n-hexane, and diethyl-ether. Each extract was subjected to three in vitro antimicrobial tests using the broth-dilution method. The antibacterial effect against the following aerobic bacteria which are Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumonia ATCC 700603, Haemophilus influenzae ATCC 49247, Escherichia coli ATCC 25922, Salmonella typhi ATCC 6539, Shigella dysenteriae ATCC 13313, and non-pathogenic Escherichia coli BAA-1427 applying ciprofloxacin antibiotic as a standard reference, antibacterial study against anaerobic bacteria which include Bacteroides fragilis ATCC 25285, Clostridium perfringens ATCC 13124, Fusobacterium necrophorum ATCC 25286, and Prevotella melaninogenica ATCC 25845 employing metronidazole as a reference, and antifungal study versus Candida albicans ATCC 10231 and Aspergillus niger ATCC 16888, nystatin was the reference. The toxicity against the normal bacterial flora was evaluated to verify the safety profile of the extracts. The results revealed that the extracts have antimicrobial activities with supremacy linked to ethanol extract. In accordance to the activity evidence values, the extracts displayed bactericidal and fungicidal activities, with ethanol extract having the least harmful effect against non-pathogenic microbial strain.
A major global health risk has been witnessed with the development of drug-resistant bacteria and multidrug-resistant pathogens linked to significant mortality. Coumarins are heterocyclic compounds belonging to the benzophenone class enriched in different plants. Coumarins and their derivatives have a wide range of biological activity, including antibacterial, anticoagulant, antioxidant, anti-inflammatory, antiviral, antitumour, and enzyme inhibitory effects. In the past few years, attempts have been reported towards the optimization, synthesis, and evaluation of novel coumarin analogues as antimicrobial agents. Several coumarin-based antibiotic hybrids have been developed, and the majority of them were reported to exhibit potential antibacterial effects. In the present work, studies reported from 2016 to 2020 about antimicrobial coumarin analogues are the focus. The diverse biological spectrum of coumarins can be attributed to their free radical scavenging abilities. In addition to various synthetic strategies developed, some of the structural features include a heterocyclic ring with electron-withdrawing/donating groups conjugated with the coumarin nucleus. The suggested structure−activity relationship (SAR) can provide insight into how coumarin hybrids can be rationally improved against multidrug-resistant bacteria. The present work demonstrates molecular insights for coumarin derivatives having antimicrobial properties from the recent past. The detailed SAR outcomes will benefit towards leading optimization during the discovery and development of novel antimicrobial therapeutics.
Since 1947, a sterically hindered phenol named 3-(tert-butyl)-4-methoxyphenol, abbreviated here as 3-tBMP, has been widely used as a powerful preservative antioxidant for food, petrochemical, and pharmaceutical packaging. Then, the NIH considered 3-tBMP a human carcinogen based on animal experiments. This work aimed to transform this carcinogen into biosafe, biologically active coumarins using Pechmann condensation and thionyl chloride-promoted reactions. The molecular frameworks of the synthetic coumarins (CBMPa-CBMPd) were confirmed by various spectral detected instruments, including FTIR, 1 H-NMR, and 13 C-NMR. The in silico variables, biosafety, anticancer, antioxidant, and anti-inflammatory assessments regarding these coumarins are determined using two web-mediated free programs, two normal bacteriomers, three non-malignant cellular populations, six malignant ones, two phenotypes of free radicals, and three inflammation-mediated enzymes. The results showed that the synthetic coumarins, in particular CBMPa, showed good physicochemical and drug similarity properties in the computerized analysis. Additionally, despite the high concentrations used, the coumarins displayed biosafety profiles toward the normal bacteriomers and non-malignant cellular populations used. The constructed coumarins also displayed undetected anti-inflammatory traits along with potent antioxidant and anticancer attributes. Based on these findings, the author came to the conclusion that the carcinogenic phenol used in the experiment was converted into a biosafe antioxidant and anticancer agent with no discernible negative effects on the development of normal microbiota and healthy cellular populations. As a result, the coumarin backbone can act as a promising transformer of other phenols that cause malignancies.
Infectious diseases resulting from various strains of pathogenic bacteria are among the leading causes of death and morbidity worldwide. The currently-available antibacterial medications developed from natural or synthetic sources are the cornerstone of bacterial infection intervention, but somehow the mounting spread and expansion of multidrug-resistant harmful bacteria has become a major concern for medical-providing communities and pharmaceutical-releasing companies. The pervasiveness of coumarin-based products in nature and the simplicity of their lab chemical synthesis, in addition to the ability of the coumarin backbone to communicate, may interact with the bacterial DNA gyrase at the B subunit and hinder DNA secondary structure by abolishing ATPase activity ; thus, coumarin-based products and their conjugates may have the potential to act as antibacterial agents. It is conceivable that conjugation of the coumarin chemical nucleus with other heterocyclic-based antibacterial scaffolds may present opportunities for the creation of novel antibacterial drugs. This presentation may be based on the fact that several coumarin-heterocycle conjugates, including clorobiocin, coumermycin A1, and novobiocin, have already been used in medical methods for the treatment of various infectious bacterial diseases. This study explores, during the period of the last 5 years, the relationships between the structure and activity of coumarin-heterocycle conjugates with potential for antibacterial action. This investigation also explored the potential for developing these conjugates into antibacterial medicines.
The seeds of two watermelon cultivars-allsweet and princess-were explored in this study as sources of potential biosafe natural antioxidant and anticancer agents. In the first algorithmic step, the acquired seeds were extracted using four solvents and three different extraction methodologies in each of the three modes. Second, the primary and secondary metabolic extractives were specified in each of the sixty liquid extracts. Third, two liquid extracts were selected based on the detected extractives to isolate natural coumarins depending on their structural characteristics. Fourth, the chemical identities of the seed-isolated coumarins were confirmed by analyzing their physical-chemical properties as well as the charts of various spectrophotometers. Finally, the capacity of the seed-isolated coumarins to capture two radical phenotypes, fight the invasive development of six cancer-derived cell lines, and safeguard the ordinary growth of normal cells was evaluated. The results afforded by the isolation scenario indicated the presence of five coumarins in the seeds of the allsweet cultivar, abbreviated as WA1-WA5, and six in the other cultivar, abbreviated here as WP1-WP6. These seed-isolated coumarins generally exhibited a good ability to capture the two studied radicals, in particular WP2 and WP4. Also, the seed-isolated coumarins showed roughly the same pattern in their potential to fight the abnormal growth of the included cancer-derived cell lines, with privileged activity attributed to WA4, WP6, and WP4. Moreover, the latter three products exhibited the highest biosafety on normal cellular growth, following the same trend. From these findings, the authors concluded that the seed-isolated coumarin WP4 represents a biosafe antioxidant and anticancer mutual agent with a broad spectrum of activity. Moreover, the coumarin WA4 can be regarded as having potent, biosafe, extended range anticancer activity.
The production of harmful free radicals (H-FRs), especially those with oxygen or nitrogen atoms, depends on both internal and environmental causes. The negative effects of H-FRs are greatly alleviated by antioxidant protection. The harmful impact of oxidative stress, or OS, is brought on by a disparity between the defense mechanisms of the body and the creation of H-FRs. Aging is characterized by a slow decline in tissue and organ competence. Age-mediated pathologies start as an aberrant accumulation of H-FRs, which inhibit cells’ capacity to divide, repair, and operate, based on the OS theorem of aging. The natural outcome of this situation is apoptosis. These conditions may include skeletal muscle dysfunction, cancer, cardiovascular, chronic hepatitis, chronic renal, and chronic pulmonary disorders. Given the substantial role that OS plays in the progression of many of these illnesses, antioxidant-based therapy may have a favorable impact on how these diseases progress. To ascertain the true efficacy of this therapy strategy, more research is necessary. The aim of this study is to provide an overview of the literature on this challenging issue that is attracting interest.
Aegle marmelos (L.) Correa is an Indian medicinal plant known for its vast therapeutic activities. In Ayurveda, the plant is known to balance "vata," "pitta," and "kapha" dosh. Recent studies suggest anti-inflammatory, anti-microbial, and anti-diabetic potential but lack in defining the dosage over the therapeutic activities. This study aims to determine the chemical profile of Aegle marmelos fruit extract; identification, enrichment, and characterization of the principal active component(s) having anti-inflammatory and anti-diabetic potential. Targeted enrichment of total coumarins, focusing on marmelosin, marmesin, aegeline, psoralen, scopoletin, and umbelliferone, was done from Aegle marmelos fruit pulp, and characterized using advanced high-throughput techniques. In vitro and in silico anti-diabetic and anti-inflammatory activities were assessed to confirm their efficacy and affinity as anti-diabetic and anti-inflammatory agents. The target compounds were also analysed for toxicity by in silico ADMET study and in vitro MTT assay on THP-1 and A549 cell lines. The coumarins enrichment process designed, was found specific for coumarins isolation as it resulted into 48.61% of total coumarins enrichment, which includes 31.2% marmelosin, 8.9% marmesin, 4% psoralen, 2% scopoletin, 1.7% umbelliferone, and 0.72% aegeline. The quantification with HPTLC and qNMR was found to be correlated with the HPLC assay results. The present study validates the potential use of Aegle marmelos as an anti-inflammatory and anti-diabetic agent. Coumarins enriched from the plant fruit have good therapeutic activity and can be used for Phytopharmaceutical ingredient development. The study is novel, in which coumarins were enriched and characterized by a simple and sophisticated methodology.
Aim: The synthesis of a novel class of compounds bearing a coumarin entity was targeted. They are either iminocoumarins or characterized by the presence of a pyridone ring fused within the iminocoumarin scaffold. Methods & results: The targeted compounds were synthesized through a short method, thanks to microwave activation. The study evaluated the antifungal activity of 13 newly synthesized compounds against a new fungal strain of Aspergillus niger. The most active compound showed activity comparable to the widely used reference drug, amphotericin B. Conclusion: The conditions and the ease of synthesis warrant high potential of the method for diversity-oriented synthesis, very useful within the drug discovery area.
Prostate carcinoma is a malignant situation that arises from genomic alterations in the prostate, leading to changes in tumorigenesis. The NF-κB pathway modulates various biological mechanisms, including inflammation and immune responses. Dysregulation of NF-κB promotes carcinogenesis, including increased proliferation, invasion, and therapy resistance. As an incurable disease globally, prostate cancer is a significant health concern, and research into genetic mutations and NF-κB function has the efficacy to facilitate the introduction of novel therapies. NF-κB upregulation is observed during prostate cancer progression, resulting in increased cell cycle progression and proliferation rates. Additionally, NF-κB endorses resistance to cell death and enhances the capacity for metastasis, particularly bone metastasis. Overexpression of NF-κB triggers chemoresistance and radio-resistance, and inhibition of NF-κB by anti-tumor compounds can reduce cancer progression. Interestingly, non-coding RNA transcripts can regulate NF-κB level and its nuclear transfer, offering a potential avenue for modulating prostate cancer progression.
Among many industries, the textile industry is the oldest industry of human civilization. Cloth is the second most important human need after food. Textile processing includes several steps in which wet processing is the most important. As wet processing involves an extensive amount of water and chemicals, an enormous volume of textile effluent generates during wet processing. Textile effluents is disposed of on bare land or on water bodies, which causes soil and water contamination. Improper disposal of textile effluents causes severe soil and water contamination. Textile effluents contain dyes, heavy metals, inorganic salts, surfactants, organic contaminants, oil, and grease. Textile effluents cause contamination in water bodies. The colour present in effluents hinders the photosynthesis of aquatic plants. Inorganic salts cause the degradation of water quality and soil excellence. Heavy metals enter the food chain and cause severe health impacts on human life. Various physical, chemical, bailogical and hybrid methods are used to treat textile effluents. Textile processing has been explained in brief in this study. The current research deals with different textile processing steps, various pollutants generated in textile processing and their ecotoxicity, various ecological crises associated with textile processing, and numerous treatment methods for the remediation of textile effluents.
Antibacterial resistance is one of the greatest threats to human health. The development of new therapeutics against bacterial pathogens has slowed drastically since the approvals of the first antibiotics in the early and mid-20th century. Most of the currently investigated drug leads are modifications of approved antibacterials, many of which are derived from natural products. In this review, we highlight the challenges, advancements and current standing of the clinical and preclinical antibacterial research pipeline. Additionally, we present novel strategies for rejuvenating the discovery process and advocate for renewed and enthusiastic investment in the antibacterial discovery pipeline.
A new coumarin derivative, 7-((8-(4-benzylpiperidin-1-yl) octyl)oxy)-4-methyl-2H-chromen-2-one (C3), was synthesized by two-step alkylation reaction of 7-hydroxy-4-methyl coumarin. The structure and purity of the compound were characterized by its ¹H and ¹³C-NMR, FT-IR and LC-MS spectral data. The DNA binding interaction of C3 was evaluated using UV-vis spectrophotometric and viscosimetric methods. These experiments showed that C3 was bound in intercalative mode. The antioxidant activity of C3 was evaluated by the DPPH method, the antioxidant activity results displayed that C3 had DPPH radical scavenging effect. The possible mechanism of antioxidant and anticancer activity of C3 was investigated via molecular docking by using two enzymes CyP450 and EGFR as receptors. The C3 also tended a good antioxidant ability based on the result of the molecular docking analysis, with good binding affinity values (-7.82 kcal/mol) and binding site interactions. Molecular Dynamics (MD) simulation was implemented to elucidate the interactions with the protein-ligand complex in 20ns. The ADMET analyzes which paved the way for us to predict C3 as a drug candidate were also performed. All experimental and theoretical results showed that the compound C3 was a potential drug candidate as an antioxidant and anticancer agent.
Unique coumarin aminophosphonates as new antibacterial agents were designed and synthesized to combat severely bacterial resistance. Bioactivity assessment identified that 3-hydroxylphenyl aminophosphonate 6f with low hemolytic activity not only exhibited excellent inhibition potency against Staphylococcus aureus at low concentration (0.5 μg/mL) in vitro but also showed considerable antibacterial potency in vivo. Meanwhile, the active compound 6f was capable of eradicating the S. aureus biofilm, thus alleviating the development of S. aureus resistance. Furthermore, the drug combination of compound 6f with norfloxacin could enhance the antibacterial efficacy. Mechanistic explorations manifested that molecule 6f was able to destroy the integrity of cell membrane, which resulted in the leakage of protein and metabolism inhibition. The cellular redox homeostasis was interfered through inducing the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to the reduction of glutathione (GSH) activity and lipid peroxidation. Furthermore, compound 6f could intercalate into DNA base pair to hinder normal biological function. The above results provided powerful information for the further development of coumarin aminophosphonates as antibacterial agents.
Over the last seven decades, a significant scientific contribution took place in the delineation of the implications of vascular endothelial-derived growth factor (VEGF) in the processes of angiogenesis. Under pathological conditions, mainly in response to hypoxia or ischemia, elevated VEGF levels promote vascular damage and the growth of abnormal blood vessels. Indeed, the development of VEGF biology has revolutionized our understanding of its role in pathological conditions. Hence, targeting VEGF or VEGF-mediated molecular pathways could be an excellent therapeutic strategy for managing cancers and intraocular neovascular disorders. Although anti-VEGF therapies, such as monoclonal antibodies and small-molecule tyrosine kinase inhibitors, have limited clinical efficacy, they can still significantly improve the overall survival rate. This thus demands further investigation through the development of alternative strategies in the management of VEGF-mediated pathological angiogenesis. This review article focuses on the recent developments toward the delineation of the functional biology of VEGF and the role of anti-VEGF strategies in the management of tumor and eye pathologies. Moreover, therapeutic angiogenesis, an exciting frontier for the treatment of ischemic disorders, is highlighted in this review, including wound healing.
Free radicals, usually containing one or more unpaired electrons, are extremely unstable and highly reactive with other biological molecules. Recently, there has been increasing interest and substantial progress in exploring the double-edged roles of free radicals in biological systems. Particularly, nanotherapeutics based on free radical regulation have emerged as a new treatment modality against various diseases. Herein we provide a state-of-the-art review on free radicals as a double-edged sword in various disease treatments, which derives new opportunities for future nanotherapeutics. In this review, the major sources, types, and physiological functions of free radicals are firstly introduced. A specific focus is placed on the emergence of free radical generation-based nanotherapeutic approaches, including photodynamic therapy (PDT), sonodynamic therapy (SDT), radiation therapy (RT), chemodynamic therapy (CDT), ferroptosis therapy, and other nanotherapeutics involving free radical generation strategies. Subsequently, free radical depletion-based nanotherapeutics for alleviating molecular damage and related diseases are presented with emphasis on the treatment of inflammatory diseases, neurodegenerative disorders, cardiovascular and cerebrovascular diseases, acute kidney/liver injury, diabetes and diabetic complications, tumorigenesis and so on. Finally, some ongoing challenges and insightful perspectives of the currently developed nanotherapeutics based on regulating free radicals in biomedicine are discussed. We believe that this review would appeal to the researchers from interdisciplinarity fields of nanoscience, chemistry, biology, material science, pharmaceutical science, as well as clinical medicine to push the development of related nanotherapeutic technologies.
Pyridine (py) is one of the important heterocyclic compounds and an internal part of several natural products. There are various medicines containing pyridine ring system being available in the market to combat different human ailments. Many drugs have been approved by FDA for the treatment of cancer in recent years like Omeprazole (1998), Netupitant (2014), Abemaciclib (2015), Apalutamide (2018), Lorlatinib (2018), and Ivosidenib (2019), and natural products including nicotine, niconine, and nucleic acid. Various methods have been reported for the synthesis of pyridine derivative and also several reactions offer the great scope in the division of organic and medicinal chemistry. From this review, we have summarized in medicinal and nonmedicinal advantages of numerous pyridine scaffolds. Pyridine analogues have been reported for diverse biological activity profiles and numbers of compounds are used in clinical trials. Pyridine scaffolds have also increasing importance for modern medicinal implementation and are expected to deliver several applications in day-to-day life.