Hybrid molecules based on 1,3,5-triazine as potential therapeutics: A focused review

Majority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux-pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5-triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5-triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5-triazine based hybrid molecules in the development of pharmaceuticals.     

Therapeutic significance of quinolines: a patent review (2013-2015)

Introduction: Quinoline is a versatile bicyclic heterocyclic scaffold with immense therapeutic potential. Some of the compounds containing quinoline nucleus are agents of choice for the treatment of various ailments, particularly cancer and malaria. Furthermore, several quinoline derivatives exhibit a broad spectrum of antimicrobial, anti-inflammatory, and antidiabetic activities, quite a few of which are under clinical investigation to combat potentially lethal diseases/disorders.

Areas covered: The present review summarizes inventions developed towards finding new chemotherapeutic agents based on the quinoline skeleton. It presents an outline of patents filed between 2013 and 2015, relating to the anticancer, antimicrobial, anti-inflammatory and other biological activities exhibited by quinoline derivatives.

Expert opinion: Several molecules containing quinoline skeleton are clinically significant drugs, extensively used for the treatment of various human diseases/disorders. The clinical success of some of these compounds and the versatile character of the quinoline nucleus attracted medicinal chemists in the development of newer chemotherapeutic agents. The considerably high number of patents filed in a relatively short period of time indicates the increasing importance of this pharmacophore. The development of facile synthetic strategies is anticipated to facilitate the generation of chemical libraries that could serve as a source of new chemical entities.     

Chemical compositions extracted from Wikstroemia indica and their multiple activities

Context: The rhizome of Wikstroemia indica (L.) C. A. Mey (Thymelaeaceae) is widespread in China which has been widely used in China as folk medicine for the treatment of syphilis, arthritis, whooping cough, and cancer. Due to its multiactivities, its extract has an attractive potential as a promising natural agent in the pharmaceutical industries.

Objective: Aims of this study were to optimize the extraction process of the flavonoids from W. indica, and evaluate its multiple activities.

Materials and methods: An orthogonal test design was employed to optimize the extraction procedure of flavonoids from W. indica. And multichromatography and spectroscopy were used to study the chemical compounds of W. indica, while several bioactivity assays were used to evaluate the antibacterial, anti-inflammatory, and antitumor activities of W. indica.

Results: Optimal extraction conditions were determined: ethanol concentration was 60%; extraction time was 60?min; liquid–solid ratio was 16:1 and the power of ultrasonic instrument was 160?W. Four compounds: daphnoretin, chrysophanol, myricitrime and rutin were purified from W. indica, and chrysophanol was identified from this plant for the first time. The extract of W. indica displayed significant antimicrobial and anti-inflammatory activities. Daphnoretin showed a significant inhibition effect on CNE cells and HeLa cells lines at the concentrations ranging from 15.6 to 125 μg/mL, the tendency of antitumor effect was displayed in a concentration-dependent manner.

Discussion and conclusions: Extracts of W. indica could potentially be used as a promising natural agent in the pharmaceutical industries.     

5个丹皮酚酯的合成和体外抗肿瘤活性研究

丹皮酚与相应的酰氯反应得到5个新的丹皮酚酯,其结构通过光谱法确证.它们的体外抗肿瘤活性通过MTT法和集落形成法进行了评价.初步的体外生物试验结果表明,5-硝基-2-呋喃甲酸的丹皮酚酯对人肿瘤细胞有一定抑制作用,其结果和临床上常用的抗肿瘤药5-Fu相近.     

Anticancer and antiviral activities in indian medicinal plants: A review

This paper reviews the screening studies carried out in India to identify Indian medicinal plants bearing anticancer and antiviral activities. The highlights of the active constituents isolated are described and, based on analysis of screening data, some correlation has been derived on the presence of anticancer and antiviral activities in the taxa belonging to different families.     

缩胺硫脲类化合物的合成及其抗癌活性研究

合成了16个新型缩胺硫脲类化合物。先由硫酸二甲酯、水合肼与二硫化碳反应,生成肼基二硫代甲酸甲酯（Ⅱ）,产率为60％。取代芳香酮、醛与Ⅱ反应,制备中间体Ⅲ,收率：51％－91％。Ⅲ与N－取代哌嗪反应制备目标代合物Ⅰ,收率：27．3％－85．7％。其结构经IR、^1H-NMR和元素分析等确证。体外抗癌活性测定表明,在适当的基代基匹配下,此类化合物有一定的抗癌活性。     

Cytotoxic effects of extracts obtained from plants of the Oleaceae family: bio-guided isolation and molecular docking of new secoiridoids from Jasminum humile

ContextTraditionally, Oleaceae plants are used to treat many diseases, such as rheumatism, hypercholesterolaemia, or ulcers.ObjectivesTo investigate the cytotoxic potential of Jasminum humile L., Jasminum grandiflorum L., and Olea europaea L. (Oleaceae) extracts against selected human cancer cells lines, followed by a phytochemical investigation of the most potent one.Materials and methodsThe 95% ethanol extracts of aerial parts of three oleaceous plants were examined for their cytotoxicity against HepG-2, MCF-7, and THP-1 cell lines using MTT assay and doxorubicin (positive control). J. humile was bio-selected and submitted to bio-guided fractionation. Chromatographic workup of ethyl acetate and n-butanol fractions afforded two new compounds; 1-methoxyjasmigenin (1) and 1-methyl-9-aldojasmigenin (2), along with five known ones (3–7). Structures were unambiguously elucidated using 1D/2D NMR and ESI-HRMS. Isolated compounds were assessed for their anti-proliferative potential, and both selectivity index and statistical significance were determined. Molecular docking was conducted against the Mcl-1 receptor using (AZD5991) as a standard.ResultsJasmoside (5) was the most potent anticancer compound showing IC₅₀ values of 66.47, 41.32, and 27.59 µg/mL against HepG-2, MCF-7, and THP-1 cell lines, respectively. Moreover, isojasminin (4) exhibited IC₅₀ values of 33.49, 43.12, and 51.07 µg/mL against the same cell lines, respectively. Interestingly, 5 exhibited the highest selectivity index towards MCF-7 and THP-1, even greater than doxorubicin. Molecular docking results were in full agreement with the MTT assay and the proposed SAR.ConclusionIn this study, two new compounds were purified. The biological activity highlighted jasmoside (5) as a lead anticancer drug for further future investigation.     

Natural and synthetic acridines/acridones as antitumor agents: their biological activities and methods of synthesis

Acridine derivatives constitute a class of compounds that are being intensively studied as potential anticancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is limited or even excluded because of side effects. Numerous synthetic methods are focused on the preparation of target acridine skeletons or modifications of naturally occurring compounds, such as acridone alkaloids, that exhibit promising anticancer activities. They have been examined in vitro and in vivo to test their importance for cancer treatment and to establish the mechanism of action at both the molecular and cellular level, which is necessary for the optimization of their properties so that they are suitable in chemotherapy. In this article, we review natural and synthetic acridine/acridone analogs, their application as anticancer drugs and methods for their preparation.     

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

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

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

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

Monoenomycin: A Simplified Trienomycin A Analogue that Manifests Anticancer Activity

Macrocyclic natural products are a powerful class of lead-like chemical entities. Despite commonly violating Lipinski's "rule of 5", these compounds often demonstrate superior drug-like physicochemical and pharmacokinetic attributes when compared to their acyclic counterparts. However, the elaborate structural architectures of such molecules require rigorous synthetic investigation that complicates analogue development and their application to drug discovery programs. To circumvent these limitations, a conformation-based approach using limited SAR and molecular modeling was implemented to design simplified analogues of trienomycin A, in which the corresponding analogues could be prepared in a succinct manner to rapidly identify essential structural components necessary for biological activity. Trienomycin A is a member of the ansamycin family of natural products that possesses potent anticancer activity. These studies revealed a novel trienomycin A analogue, monoenomycin, which manifests potent anticancer activity.     

Discovery of two bombinin peptides with antimicrobial and anticancer activities from the skin secretion of Oriental fire‐bellied toad,Bombina orientalis

Amphibian skin secretions are known to contain numerous peptides with a large array of biological activities. Bombinins are a group of amphibian‐derived peptides with broad spectrum antimicrobial activities that have been only identified from the ancient toad species, Bombina. In this study, we described the identification and characterization of a novel bombinin precursor which encoded a bombinin‐like peptide (BLP‐7) and a novel bombinin H‐type peptide (named as Bombinin H‐BO) from the skin secretion of Oriental fire‐bellied toad, Bombina orientalis. The primary structures of both mature peptides were determined by combinations of molecular cloning of peptide precursor‐encoding cDNAs and mass spectrometry techniques. Secondary structure prediction revealed that both peptides had cationic amphipathic α‐helical structural features. The synthetic replicate of BLP‐7 displayed more potent antimicrobial activity than Bombinin H‐BO against Gram‐positive and Gram‐negative bacteria and yeast. Also, in vitro antitumour assay showed that both peptides possessed obvious antiproliferative activity on three human hepatoma cells (Hep G2/SK‐HEP‐1/Huh7) at the non‐toxic doses. These results indicate the peptide family of bombinins could be a potential source of drug candidates for anti‐infection and anticancer therapy.     

昆虫抗菌肽抗炎活性及基于信号通路抗炎机制的研究进展

昆虫抗菌肽是昆虫为抵御外界病原微生物感染产生的免疫活性物质的总称,其优异的抗炎活性使其具有广阔的应用前景。综述了不同种类昆虫抗菌肽的抗炎活性及可能涉及的信号通路,介绍了昆虫抗菌肽临床研究现状,以期为昆虫抗菌肽的应用研究提供文献参考。     

Biochemical and pharmacological characterization of isatin and its derivatives: from structure to activity

Isatin, 1H-indole-2,3-dione, is a heterocyclic compound of significant importance in medicinal chemistry. It is a synthetically versatile molecule, a precursor for a large number of pharmacologically active compounds. Isatin and its derivatives have aroused great attention in recent years due to their wide variety of biological activities, relevant to application as insecticides and fungicides and in a broad range of drug therapies, including anticancer drugs, antibiotics and antidepressants. The purpose of this review is to provide an overview of the pharmacological activities of isatin and its synthetic and natural derivatives. Molecular modifications to tailor the properties of isatin and its derivatives are also discussed.     

In vitro anticancer activity of fluphenazine,perphenazine and prochlorperazine. A review

Drug repositioning is an approach that could accelerate the clinical use of compounds in different diseases. The goal is to take advantage of the fact that approved drugs have been tested on humans and detailed information is available on their pharmacology, toxicity and formulation. It can significantly reduce the costs and time needed to implement necessary therapies on the market. In recent years, phenothiazines are being tested for cancer, viral, bacterial, fungal and other diseases. Most research focuses on chlorpromazine as a model drug in this class, but other drugs such as fluphenazine, perphenazine and prochlorperazine have been proven to inhibit the viability of different cancer cell lines. In this study, we performed an extensive literature search to find and summarize all papers on the chosen phenothiazines and their potential in treating different types of cancerin vitro for further animal/clinical trials. Fluphenazine, perphenazine and prochlorperazine possess anticancer activity towards different types of human cancer. The antitumor activity is mainly mediated by an effect of the drugs on the cell cycle, proliferation or apoptosis. Possible molecular targets of phenothiazine derivatives are the drug's efflux pumps (ABCB1 and P‐glycoprotein) and two parallel pathways (AKT and Wnt) regulated by the D₂ receptor antagonists. The drugs have the potential to reduce the viability of human cancer cell lines, fragment the DNA, stimulate apoptosis, inhibit cell migration and invasiveness as well as impair the production of reactive oxygen species. In addition, due to the sedative and antiemetic properties antipsychotics can be used as an adjuvant for the treatment of chemotherapy side effects.     

Cameroonemide A: a new ceramide from Helichrysum cameroonense

From the extracts of all parts of the plant Helichrysum cameroonense, five compounds were isolated and identified. One of them, a ceramide, named cameroonemide A (1), is reported for the first time as a new natural product. Its structure was determined by comprehensive analyses of their 1D and 2D NMR and HR-EI-MS spectral data. The remaining four known compounds were identified by comparing their spectroscopic data with those reported in the literature as kaurenoic acid (2), 3-acetyloxykaurenoic acid (3), β-sitosterol (4), and β-sitosterol glucopyranoside (5). Preliminary studies showed that 3-acetyloxykaurenoic acid (3) inhibited the alga Chlorella fusca, while kaurenoic acid (2) showed strong antibacterial activity against Bacillus megaterium.     

Ethnomedicinal uses,phytochemistry and pharmacological aspects of the genus Premna: a review

Context: The genus Premna (Lamiaceae), distributed throughout tropical and subtropical Asia, Africa, Australia and the Pacific Islands, is used in folk medicine primarily to treat inflammation, immune-related diseases, stomach disorders, wound healing, and skin diseases.

Objectives: This review exhaustively gathers available information on ethnopharmacological uses, phytochemistry, and bioactivity studies on more than 20 species of Premna and critically analyzes the reports to provide the perspectives and directions for future research for the plants as potential source of drug leads and pharmaceutical agents.

Methods: A literature search was performed on Premna species based on books of herbal medicine, major scientific databases including Chemical Abstract, Pubmed, SciFinder, Springerlink, Science Direct, Scopus, the Web of Science, Google Scholar, and ethnobotanical databases.

Results: More than 250 compounds have been isolated and identified from Premna species, comprising of diterpenoids, iridoid glycosides, and flavonoids as the most common secondary metabolites, followed by sesquiterpenes, lignans, phenylethanoids, megastigmanes, glyceroglycolipids, and ceramides. Many in vitro and in vivo studies have been conducted to evaluate the biological and pharmacological properties of the extracts, and isolated compounds of Premna species with antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, antihyperglycaemia, and cytotoxic activities.

Conclusion: The bioactive compounds responsible for the bioactivities of most plants have not been well identified as the reported in vivo pharmacological studies were mostly carried out on the crude extracts. The isolated bioactive components should also be further subjected to more preclinical studies and elaborate toxicity study before clinical trials can be pursued.     

萘酰亚胺-多胺缀合物的合成及体外抗癌活性

合成了6个萘酰亚胺-多胺缀合物, 化合物的结构经元素分析、¹H NMR、¹³C NMR和MS确证。经MTT法对白血病细胞 (K562)、人乳腺癌细胞 (MB-231) 和前列腺癌细胞 (Ln cap cell) 进行了体外活性测试, 结果表明大多数化合物的体外抗肿瘤活性优于对照品氨萘非特 (amonafide), 其中化合物6d、6e和6f对正常人肝上皮细胞 (QSG-7701) 和肝癌细胞 (BEL-7402) 具有良好的选择性。     

Novel indole hydrazide derivatives: Synthesis and their antiproliferative activities through inducing apoptosis and DNA damage

A series of novel indole hydrazide derivatives was synthesized and evaluated for their anticancer activities. Compound 12 exhibited the highest antiproliferative activity against the MCF-7 cell line, with an IC₅₀ value of 3.01 µM. Treatment of MCF-7 cells with compound 12 led to cell cycle arrest at the G0/G1 phase and also displayed a significant annexin V binding pattern, indicating that compound 12 is effective in apoptotic cell death. The Western blot analysis showed that compound 12 increased the expression of proapoptotic Bax and decreased the levels of the antiapoptotic Bcl-2 protein. It was also observed that MCF-7 cells treated with compound 12 showed reduced levels of procaspase-3 and -9 proteins. Moreover, compound 12 treatment induced a significant DNA damage in MCF-7 cells by increasing H2AX and ATM phosphorylation.     

苯并咪唑类衍生物的合成及其抗炎活性和致胃溃疡作用研究

合成了10个苯并咪唑类衍生物,经质谱,红外光谱和核磁共振氢谱等确认了这些化合物的结构和组成,其中5个为未见文献报道的新化合物,对部分化合物进行了抗炎活性筛选和致胃溃疡作用研究,药理实验结果表明,2种苯并咪唑类衍生物经灌胃给药（200mg/kg)对二甲苯所致小鼠耳肿胀具有显著抑制作用。     

A perspective on rational drug design with cyclopentenone: targeting the proteome with the cyclopentenone chemical moiety

The biological activity of cyclopentenone prostaglandins, of members of clavulones, and of other natural and synthetic compounds is strongly related to the presence of a conjugate cylcopentenone (CP) chemical moiety in their structure. CP reactivity is specifically directed toward the proteome, to covalent binding of crucial sulphydril groups on targeted proteins. In the literature it has been shown that directing this special CP biochemical reactivity by means of additional orienting constituents is a feasible strategy for inactivating specific enzymes in a cell. The introduction of a CP moiety into anticancer molecules, such as jasmonates and chalcones, has been shown to greatly boost their activity, probably due to the stable covalent chemical interaction with their targets. In general, similar strategies could lead to the development of a novel repertoire of therapeutic molecules targeted against specific pathogenetic anomalies of the proteome of diseased cells.