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Antiproliferative Properties and Structural Analysis of Newly Synthesized Schiff Bases Bearing Pyrazole Derivatives and Molecular Docking Studies
Abstract
New pyrazole Schiff bases containing azo groups were synthesized using the condensation reaction between p-nitrobenzaldehyde and (E)-4-(phenyl)-1-H-pyrazole-3,5-diamine in the molar ratio of 1:2. Characterization of the compounds was performed by spectroscopic techniques, including IR, UV-Vis, ¹H-NMR and ¹³C-NMR. Biological activity of the compounds was evaluated by analyzing DNA protection, antimicrobial and anticancer properties. Compound 4 was effective for Salmonella typhimurium with the MIC concentration of 62.5 µg/mL. Moreover, this compound had the highest protection activity on DNA. Cytotoxic activity of compound 4 was determined on the HeLa cancer cell line with the IC50 concentration of 976.6 µM. The anti-cancer characteristic of compounds 4 and 5 for HeLa cancer was theoretically analyzed by molecular docking study as well. Among the tested compounds, compound 4 possessed significant results due to its in vitro cytotoxic properties. Therefore, it may be considered as a potential bioactive agent for cancer treatment studies. In addition, further in vivo analysis can be performed to indicate its anticancer property.
... Compound 261c exhibited potent anticancer activity with IC 50 = 0.49 ± 0.03 µM than compared to staurosporine. Structure activity relationship revealed that cyclization of chalcone resulted in increase The required compounds were obtained when pyrazole diamine and p-nitrobenzaldehyde were dissolved in THF (1:2) and then adjusting the pH to 4-5 and refluxing it for 24 h (Scheme 28) [118]. Anticancer studies revealed that the compound 289d was effective on the Hela cells. ...
... The most satisfying results that authors found was in the compound 289d where Cl was linked to phenyl ring and in compound 289e, CH 3 linked to the phenyl ring. In addition to this, molecular docking analysis were also studied [118]. Ashraf et al. in 2021 synthesized novel pyrazole-indole hybrids and studied their anti-cancer activities. ...
There is an increase in infectious diseases every year. Heterocyclic compounds have been in use as drugs for a long time. Amongst many heterocyclic derivatives, the drugs containing the pyrazole core has been in limelight because of its relative ease of synthesis and excellent biological activities. Pyrazoles are aromatic compounds consisting of ring structure where two nitrogen atoms are adjacent to each other and contain three carbon atoms. Over the years pyrazoles have been explored for a variety of pharmacological applications. Herein, this review overviews the information related to industrially important pyrazoline scaffolds and their applications, recent literature on synthesizing the pyrazole derivatives, providing an explanation for their biological activity by focusing on their structural activity relationship and hence affording ideas to design the compounds containing pyrazole scaffolds.
Graphical abstract
... It attempts to give a thorough analysis of the synthesis techniques and a broad picture of the numerous applications that have sprung from the latest developments in this exciting field. It is essential to comprehend Schiff bases' historical roots to appreciate their contemporary relevance [7][8][9][10]. Schiff bases have evolved dramatically since Hugo Schiff 's groundbreaking research in the late 1800s when he first described the condensation reaction between amines and aldehydes or ketones. ...
... Structural analysis was performed on all synthesized analogs using 1H, 13C, and LC-HRESI-MS spectroscopy. With IC50 values ranging from 5.26 to 25.17 μM, 12 compounds (10,14,7,9,8,17,12,19,13,15,21, and 11) demonstrated significant activity against α-glucosidase. The move was higher than that of acarbose, which has an IC50 of 873.34 ± 1.67 μM, a standard α-glucosidase inhibitor. ...
Recent advancements in synthesizing Schiff bases, including sustainable and highly customizable approaches, are examined, offering insights into how their structures can be tailored for specific purposes. Schiff bases find applications in various fields, such as materials science, which contribute to developing polymers, metal-organic frameworks, nanocomposites, and medicinal chemistry, which serve as promising drug candidates. Additionally, they play crucial roles in coordination chemistry catalysis and have potential applications in emerging areas like nanotechnology and renewable energy, contributing to the development of nanomaterials and energy storage systems. This chapter provides a comprehensive overview of this synthesis and its applications, catering to researchers, students, and professionals looking to explore the multifaceted landscape of Schiff base compounds in contemporary organic chemistry.
... [8] Further, Schiff bases are mainly blocks in medicinal chemistry due to their biological activities such as anticancer, antiviral, antifungal, anti-HIV infections, and diabetes ( Fig. 1). [9][10][11][12][13][14][15][16] In addition, they have also been used in analytical chemistry and coordination chemistry. [17][18][19] According to the literature, the hydrogen bonding between the active centers of cell components and the imino group of Schiff bases is related to therapeutic efficacy. ...
With the ultimate goal of discovering new anticancer agents, this study involved the design and synthesis of fifteen novel Schiff bases 4a,b, 5, 6a–d, 7a–e, and 8–10 which contain 3-(2-oxo-2H-chromen-3-yl)-
1-(4-phenylthiazol-2-yl)-1H-pyrazole moiety. The synthetic method depended on reaction of 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde (3) with a series of aromatic and heteroaryl amines under ultrasound irradiation to explore the influence of aromatic and heteroaryl rings on biological activity. The chemical structures of these Schiff bases were fully elucidated using various spectral and elemental analyses. The antiproliferative activities of the Schiff bases were studied by the standard SRB method. Among the new 15 Schiff bases, derivatives 4a,b, 5, and 7b have significant
cytotoxic effects against PC3, HepG2, and HCT116 cancer cell lines. These four bioactive Schiff bases significantly increased the late apoptosis of all studied tumor cells. Also, both products 4a and 4b arrested the cell cycle at the G1 phase, while both compounds 5 and 7b arrested the S and G2 phases against PC3 cells. In addition, the products 4a, 4b, 5, and 7b have promising high abilities to arrest the cell cycle at the G2 phase against HepG2 and HCT116 cells. The different substitutions on the aryl ring were the basis for the structure–activity relationship study. The molecular docking study confirmed good binding interactions of these compounds with Cyclin-dependent kinase 8 (CDK-8) receptor, while the absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction supported that these bioactive products can be promising anticancer agents.
... During the last decade, Schiff bases bearing pyrazole scaffold have attracted growing interest in the pharmaceutical and medicinal fields because of their varied biological effectiveness [21]. Schiff base-bearing pyrazole derivative 10 was shown to be an effective antibacterial for Salmonella typhimurium and had anticancer properties against the HeLa cancer cell line [22]. Schiff base-bearing nitroimidazole and pyrazole nuclei 11 demonstrated effective antibacterial activity as an inhibitor against the E. coli FabH receptor [23]. ...
In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to evaluate and study Schiff base–pyrazole molecules as a new class of antioxidant (total antioxidant capacity, iron-reducing power, scavenging activity against DPPH, and ABTS radicals), anti-diabetic (α-amylase% inhibition), anti-Alzheimer’s (acetylcholinesterase% inhibition), and anti-arthritic (protein denaturation% and proteinase enzyme% inhibitions) therapeutics. Therefore, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were designed and synthesized for evaluation of their antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties. The results for compound 22b demonstrated significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer’s (ACE%) activities, while compound 23a demonstrated significant anti-arthritic activity. Prediction of in silico bioinformatics analysis (physicochemical properties, bioavailability radar, drug-likeness, and medicinal chemistry) of the target derivatives (22a, b and 23a, b) was performed. The molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b was measured to determine which parts of the surface are hydrophobic and which are hydrophilic. In addition, the molecular polar surface area (PSA) was measured to determine the polar surface area and the non-polar surface area of the derivatives 22a, b and 23a, b. This study could be useful to help pharmaceutical researchers discover a new series of potent agents that may act as an antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic.
... Pyrazole-based derivatives exhibit various biological activities [8][9][10]. Pyrazole-based Schiff base I possessed significant in vitro cytotoxic properties against HeLa Egyptian Journal of Chemistry http://ejchem.journals.ekb.eg/ cells and antibacterial activity against Salmonella typhimurium Gram (-) (MIC = 62.5 μg/mL) [11]. Oxadiazol-pyrazole derivative II displayed the highest antioxidant assays [12]. ...
The diseases-related complications and causes are threaded. Accordingly, the preparation of one drug with multiple targets is very pressing. In this context, the three series of pyrazole-based derivatives 7a-c, 9a-c, and 11a-c were designed and synthesized by using 5-amino-pyrazoles 3a-c as starting materials. The structures of various products 7a-c, 9a-c, and 11a-c were characterized by using various devices (elemental analysis and spectral tools). The biological activities of pyrazole-based products 7a-c, 9a-c, and 11a-c were estimated as antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic. The estimation results showed that the two products 7c and 11a displayed powerful biological activities. In silico analysis (physicochemical, drug-likeness, and toxicity properties) of the two products 7c and 11a was performed. This research could be valuable for the exploration of one drug with multiple targets.
... Schiff bases can be easily synthesized by a condensation reaction of different amino substituted compounds with versatile aldehydes or ketones [7]. Besides the fact that Schiff bases are important building blocks in medicinal chemistry due to their broad spectrum of biological activity [8][9][10][11], they also have potential applications in coordination chemistry [12] since they can coordinate to metal ions via azomethine nitrogen, in analytical chemistry [13][14], as dyes [15], optical chemosensors [16-17], polymers [18], in catalysis [19], metallurgy [20] and re ning of metals, and as fungicidal and agrochemical compounds. Additionally, the interest of numerous scientists has been focused on evaluating Schiff bases as ligands for transition metals since such complexes possess diverse biological activities including anticancer [21-22], antimicrobial [23-24], antifungal [25] etc. ...
Herein we present the design and synthesis of novel N-substituted benzimidazole derived Schiff bases, and the evaluation of their antiviral, antibacterial and antiproliferative activity. One of the goals was to study the impact on the biological activity of substituents placed at the N atom of benzimidazole nuclei as well as the type of substituents placed at the phenyl ring. The synthesized Schiff bases were evaluated for their in vitro antiviral activity against different viruses, antibiotic activity against a panel of bacterial strains and antiproliferative activity on several human cancer cell lines, thus enabling the study of structure − activity relationships.
Some mild antiviral effects were noted, although at higher concentrations as compared to the included reference drugs. Additionally, some derivatives showed moderate antibacterial activity, with precursor 23 proving broadly active against most of the bacterial strains tested. Lastly, Schiff base 40, a 4-N,N-diethylamino-2-hydroxy substituted derivative bearing a phenyl ring at the N atom on benzimidazole nuclei, displayed strong antiproliferative activity against several cancer cell lines (IC50 1.1–4.4 µM). The strongest antitumoral effect was observed towards acute myeloid leukemia (HL-60).
... [36,37] Thus, their derivatives have continuously been used to design and discover new bioactive molecules. [38,39] These compounds have also been utilized as catalysts, intermediates in organic synthesis, dyes, polymer stabilizers, and corrosion inhibitors. [40,41] Nitro compounds are significant intermediates in synthetic organic chemistry. ...
In this study, a series of novel Schiff base derivatives containing a pyrazolone ring(2a–e) were designed, successfully synthesized for the first time, and characterizedby elemental analysis and some spectroscopic methods. These compounds weretested for their inhibitory activities on acetylcholinesterase (AChE), butyr-ylcholinesterase (BChE), and the human carbonic anhydrase isoenzymes I and II (hCAI and II). All synthesized molecules indicated significant inhibition effects with IC50values ranging from 14.15 to 107.62 nM against these enzymes. Compound2dshowed the most potent inhibitory activity among the tested molecules to-ward AChE and BChE (IC50= 15.07 and 14.15 nM) compared to the standard drugneostigmine. We determined that the IC50values of the tested molecules rangedbetween 16.86 and 57.96 nM for hCA I and 15.24–46.21 nM for hCA II. As a con-sequence, we may say that some of the Schiff base derivatives may be used aspotential drug candidates in later studies.
... Therefore, there is a need to discover and develop more effective and potent radical scavenging antioxidant agents to prevent the harmful influences of free radicals in the human body (Sıcak et al., 2021b) Heterocyclic Schiff base derivatives, synthesized by the condensation of aldehydes with heterocyclic amines, are among the significant compounds in medicinal chemistry (Hashem et al., 2021;Camadan et al., 2021;Orlova et al., 2021). In recent years, compounds of this type have attracted considerable attention due to their remarkable antifungal, antimicrobial, anti-viral, anti-cancer, antihyperlipidemic, anti-inflammatory, and antitumor activities (Şener et al., 2021;Lotlikar et al., 2021;Al-Rubaye et al., 2021;Srinivasan et al., 2021). Nowadays, medicinal chemists studying this subject are constantly synthesizing their novel derivatives and investigating their biological activities (Kavitha, 2021;Mohamed et al., 2021;Naureen et al., 2021) Given the abovementioned findings, this study was carried out to contribute to the continuing researches to design and synthesis new and potent antioxidant agents. ...
In this research work, a series of heterocyclic Schiff base compounds bearing arylsulfonyl ester moiety (2a-i) were designed, synthesized, characterized by spectral techniques such as 1D NMR (1H and 13C), 2D NMR (COSY and HMQC), and FT-IR; and then examined their antioxidant activity was by using four different methods as DPPH, ABTS, CUPRAC, and β-carotenelinoleic acid assays. According to the results obtained, it determined that all synthesized molecules had antioxidant activity. In the DPPH assay, it was found that compound 2e (IC50: 96.23±0.02 μM/mL) demonstrated the antioxidant activity among all synthesized molecules. In ABTS assay, compounds 2e (IC50: 41.88±0.21 μM/mL) and 2g (IC50: 50.75±0.32 μM/mL) were determined to be the molecules with the activity, respectively. Compound 2e (IC50:73.49±0.00 μM/mL) indicated the best antioxidant activity in the CUPRAC assay compared to other synthesize molecules. In the β-carotene-linoleic acid assay, compound 2e (IC50: 58.79±0.58 μM/mL) displayed antioxidant activity than all other synthesized molecules. Compounds 2d (IC50: 74.17±0.22 μM/mL) and 2g (IC50: 66.06±0.13 μM/mL) indicated higher antioxidant activity than the remaining molecules in this series, except for compound 2e. In conclusion, it is thought that this study will contribute to the ongoing studies on the design and synthesis of new antioxidant agents.
Two new complexes, [Co(MPAFA) 3 ](ClO 4) 2 (1) and [Ni(MPAFA) 3 ] (NO 3) 2 �2H 2 O (2), of an 'NN' bidentate Schiff-base ligand, N-(furan-2-ylmethyl)-1-(5-methyl-1H-pyrazol-3-yl)methanimine (MPAFA), have been synthesized and characterized by physicochemical and spectral methods such as elemental analyses, conductance, IR, UV-Vis, and emission spectra. In both complexes, three ligands coordinate with a metal ion to form 1:3 complexes. Both 1 and 2 are distorted octahedral and cationic, behaving as 1:2 electrolytes. IR spectra showed that each of the ligands coordinates via the pyrazolyl ter-tiary nitrogen and the azomethine nitrogen atoms. Single crystal X-ray studies confirmed CoN 6 and NiN 6 coordination for 1 and 2, respectively, and showed that both complexes exhibit p … p stacking and various hydrogen bonding interactions. Both 1 and 2 are fluorescent and participate in DNA binding with calf thymus DNA (CT-DNA) via groove binding.
Herein, we present the design and synthesis of novel N-substituted benzimidazole-derived Schiff bases, and the evaluation of their antiviral, antibacterial, and antiproliferative activity. The impact on the biological activity of substituents placed at the N atom of the benzimidazole nuclei and the type of substituents attached at the phenyl ring were examined. All of the synthesized Schiff bases were evaluated in vitro for their antiviral activity against different viruses, antibacterial activity against a panel of bacterial strains, and antiproliferative activity on several human cancer cell lines, thus enabling the study of the structure−activity relationships. Some mild antiviral effects were noted, although at higher concentrations in comparison with the included reference drugs. Additionally, some derivatives showed a moderate antibacterial activity, with precursor 23 being broadly active against most of the tested bacterial strains. Lastly, Schiff base 40, a 4-N,N-diethylamino-2-hydroxy-substituted derivative bearing a phenyl ring at the N atom on the benzimidazole nuclei, displayed a strong antiproliferative activity against several cancer cell lines (IC50 1.1–4.4 μM). The strongest antitumoral effect was observed towards acute myeloid leukemia (HL-60).
In this study, two chiral Schiff base ligands (L1 and L2) were synthesized from the condensation reaction of (S)-2-amino-3-phenyl-1-propanol with 2-hydroxybenzaldehyde and 2-hydroxy-1-naphthaldehyde as metal precursors for the preparation of transition metal complexes with Pd(II), Fe(II), Ni(II) and Cu(II). The compounds were characterized by using X-ray (for L1-Pd(II)), NMR, FT-IR, UV-Vis, magnetic susceptibility, molar conductivity, and elemental analysis. The in vitro cytotoxic effects of ligands (L1 and L2) and their metal complexes on colon cancer cells (DLD-1), breast cancer cells (MDA-MB-231) and healthy lung human cell lines were investigated by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Among the synthesized compounds, L1-Pd(II) was particularly found to be the most potent anticancer drug candidate in this series with IC50 values of 4.07, and 9.97 µM in DLD-1 and MDA-MB-231 cell lines, respectively. In addition, molecular docking results indicate that Glu122, Asn103, Ala104, Lys126, Phe114, Leu123, and Lys126 amino acids are the binding site of the colon cancer antigen protein, in which the most active complex, L1-Pd(II) can inhibit the current target.
Pyrazoles are five-membered heterocyclic compounds that contain nitrogen. They are an important class of compounds for drug development; thus, they have attracted much attention. In the meantime, pyrazole derivatives have been synthesized as target structures and have demonstrated numerous biological activities such as antituberculosis, antimicrobial, antifungal, and anti-inflammatory. This review summarizes the results of published research on pyrazole derivatives synthesis and biological activities. The published research works on pyrazole derivatives synthesis and biological activities between January 2018 and December 2021 were retrieved from the Scopus database and reviewed accordingly.
Purpose
To develop a system to estimate the risk of herb-drug interactions that includes the available evidence from clinical and laboratory studies, transparently delineates the algorithm for the risk estimation, could be used in practice settings and allows for adaptation and update.
Methods
We systematically searched Drugbank, Transformer, Drug Information Handbook, European and German Pharmacopoeia and MEDLINE for studies on herb-drug interactions of five common medicinal plants (coneflower, ginseng, milk thistle, mistletoe and St. John’s wort). A diverse set of data were independently extracted by two researchers and subsequently analysed by a newly developed algorithm. Results are displayed in the form of interaction risk categories. The development of the algorithm was guided by an expert panel consensus process.
Results
From 882 publications retrieved by the search, 154 studies were eligible and provided 529 data sets on herbal interactions. The developed algorithm prioritises results from clinical trials over case reports over in vitro investigations and considers type of study, consistency of study results and study outcome for clinical trials as well as identification, permeability, bioavailability, and interaction potency of an identified herbal perpetrator for in vitro investigations. Risk categories were assigned to and dynamically visualised in a colour-coded matrix format.
Conclusions
The novel algorithm allows to transparently generate and dynamically display herb-drug interaction risks based on the available evidence from clinical and laboratory pharmacologic studies. It provides health professionals with readily available and easy updatable information about the risk of pharmacokinetic interactions between herbs and oncologic drugs.
Cancer is one of the most serious medical problem and second leading cause of death in the world, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth. The benzimidazole is a heterocyclic moiety found in extensive number of natural and biological active molecules. Benzimidazole derivatives might be considered as auxiliary isosters of nucleotides having attached heterocyclic cores in their structures, cooperate effortlessly with biopolymers and have potential action for chemotherapeutic applications. Benzimidazole and its derivatives displayed a wide range of biological activity because of its structural similarity with the naturally occurring nucleotides. Benzimidazole has established huge alertness in current time and is extremely significant heterocyclic pharmacophore in recent drug innovation and medicinal chemistry. The present review summarizes the chemistry of various substituted benzimidazole derivatives with their antiproliferative significance towards the various cancer cell lines such as HCT116, MCF7, HeLa, HepG2, A549 and A431.
Cervical cancer is the fourth most frequently occurring cancer in women around the world and can affect them during their reproductive years. Since the development of the Papanicolaou (Pap) test, screening has been essential in identifying cervical cancer at a treatable stage. With the identification of the human papillomavirus (HPV) as the causative agent of essentially all cervical cancer cases, HPV molecular screening tests and HPV vaccines for primary prevention against the virus have been developed. Accordingly, comparative studies were designed to assess the performance of cervical cancer screening methods in order to devise the best screening strategy possible. This review critically assesses the current cervical cancer screening methods as well as the implementation of HPV vaccination in Europe. The most recent European Guidelines and recommendations for organized population-based programs with HPV testing as the primary screening method are also presented. Lastly, the current landscape of cervical cancer screening programs is assessed for both European Union member states and some associated countries, in regard to the transition towards population-based screening programs with primary HPV testing.
Cancer cells without mitochondrial DNA (mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox-cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents.
Natural product acquires massive structural and chemical diversity, which cannot be coordinated by any synthetic libraries for small molecules and they are continuing to inspire novel discoveries in health sciences. We have performed the computational calculations for geometry optimization and prediction of electronic and structural properties of some plant phenolic compounds through Gaussian 09 program. Energies of molecular orbitals were computed, to mimic out the stabilities arising from charge delocalization and intramolecular interactions. This process indicated the eventual charge transfer within the molecules. The molecular docking and ADMET properties of these compounds with a novel anticancer (HER2) and anti-inflammatory (COX-2) targets revealed that two molecules were capable to inhibit both the target, and could be used as multi target inhibitors. Furthermore, molecular dynamics simulation studies were performed to elucidate the binding mechanism and the comparison of inhibitor’s binding mode with diverse biological activities as anticancer and anti-inflammatory agents. A high-quality association was reported among quantum chemical, ADMET, docking, dynamics and MMGBSA results.
Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.
Six novel compounds of platinum(II) with pyrazole derivatives PtPz1–PtPz6 were synthesised and characterised (PtPz1 - [Pt2N-hydroksymethyl-3,5-dimethylpyrazole4(berenil)2]Cl4; PtPz2 - [Pt23,5-dimethylpyrazole4(berenil)2]Cl4; PtPz3 - [Pt23,4-dimethylpyrazole4(berenil)2]Cl4; PtPz4 - [Pt2pyrazole4(berenil)2]Cl4; PtPz5- [Pt25-methylpyrazole4(berenil)2]Cl4; PtPz6 - [Pt2N-ethylpyrazole4(berenil)2]Cl4). The cytotoxic activity of these complexes against MCF-7 and MDA-MB-231 breast cancer cell lines was determined using the MTT assay. Evaluation of apoptosis induction was done with the Annexin V-fluorescein isothiocyanate/propidium iodide assay. In addition, using a flow cytometer, we determined the influence of test compounds on the cell cycle and caspase-3, -8, and -9 activity. The obtained results of caspase activity were confirmed by cell imaging. Moreover, using the flow cytometer, the effects of the test compounds on mitochondrial potential change were assessed. The test results showed that novel pyrazole-platinum(II) complexes exhibited stronger anti-proliferative activity against two breast cancer cell lines than reference cisplatin. Compounds PtPz1, PtPz2, and PtPz3 with methyl substituents at the pyrazole ring showed stronger activity than pyrazole or ethylpyrazole containing complexes. Studies have shown that inhibition of cell survival occurs by arresting the G1 cell cycle and inducing apoptosis. Our analysis associated with the response of MCF-7 and MDA-MB-231 cells to treatment with PtPz1–PtPz6 showed that it leads the cells through the external and intrinsic (mitochondrial) apoptotic pathway via indirect DNA damage.
Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o ( N -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1 H -pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, 1o displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy.
This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
The genus Ononis has important value as traditional drugs and foods. In the present work, we aimed to assess the chemical profiles and biological effects of Ononis natrix subsp. hispanica extracts (ethyl acetate, methanol, and water). For chemical profile, total and individual phenolic components were detected. For biological effects, antioxidant (DPPH, ABTS, CUPRAC, FRAP, phosphomolybdenum, and metal chelating assays), enzyme inhibitory (against cholinesterase, tyrosinase, α-amylase and α-glucosidase), antimicrobial, DNA protection and cytotoxic abilities were tested. The predominant phenolics were apigenin, luteolin, and quercetin in the tested extracts. Generally, the ethyl acetate and methanol extracts were noted as the most active in the antioxidant and enzyme inhibitory assays. Water extract with different concentrations indicated high level of DNA protection activity. Methanol and ethyl acetate extracts showed antibacterial effect against to Staphylococcus aureus and Staphylococcus epidermidis strains. The cytotoxic effects of O. natrix subsp. hispanica extracts on the survival of HeLa and PC3 cells were determined by MTT cell viability assay. Water and methanol extracts caused initiation of apoptosis for PC3 cell line. Furthermore, molecular docking was performed to better understand interactions between dominant phenolic compounds and selected enzymes. Our results clearly indicate that O. natrix subsp. hispanica could be considered a potential candidate for designing novel pharmaceuticals, cosmeceuticals and nutraceuticals.
The mammalian digestive tract is home to trillions of microbes, including bacteria, archaea, protozoa, fungi, and viruses. In monogastric mammals the stomach and small intestine harbor diverse bacterial populations but are typically less populated than the colon. The gut bacterial community (microbiota hereafter) varies widely among different host species and individuals within a species. It is influenced by season of the year, age of the host, stress and disease. Ideally, the host and microbiota benefit each other. The host provides nutrients to the microbiota and the microbiota assists the host with digestion and nutrient metabolism. The resident microbiota competes with pathogens for space and nutrients and, through this competition, protects the host in a phenomenon called colonization resistance. The microbiota participates in development of the host immune system, particularly regulation of autoimmunity and mucosal immune response. The microbiota also shapes gut–brain communication and host responses to stress; and, indeed, the microbiota is a newly recognized endocrine organ within mammalian hosts. Salmonella enterica serovar Typhimurium (S. Typhimurium hereafter) is a food-borne pathogen which adapts to and alters the gastrointestinal (GI) environment. In the GI tract, S. Typhimurium competes with the microbiota for nutrients and overcomes colonization resistance to establish infection. To do this, S. Typhimurium uses multiple defense mechanisms to resist environmental stressors, like the acidic pH of the stomach, and virulence mechanisms which allow it to invade the intestinal epithelium and disseminate throughout the host. To coordinate gene expression and disrupt signaling within the microbiota and between host and microbiota, S. Typhimurium employs its own chemical signaling and may regulate host hormone metabolism. This review will discuss the multidirectional interaction between S. Typhimurium, host and microbiota as well as mechanisms that allow S. Typhimurium to succeed in the gut.
Objective: In recent years, enterococci have become increasingly resistant to a wide range of antimicrobial agents. The aim of this study was to identify the species isolated from the urine cultures of hospitalized patients at Cukurova University Medical Faculty Balcalı Hospital, Adana, Turkey. and determine antimicrobial susceptibility rates of enterococcus strains. Materials and
Methods: In this study, a total of 536 enterococcus strains isolated from the urine cultures of the patients hospitalized, and treated in Balcalı Hospital of Çukurova University Faculty of Medicine between January 2012 and April 2014 were typed and antibiotic resistance rates of these isolated were determined Identification and antibiotic susceptibility testing of the enterococci strains were performed using Vitek-2 automated system (BioMérieux, France).
Results: Of these isolated strains 277 (51.6%) were identified as Enterococcus faecalis, 249 (46.4%) as Enterococcus faecium, five (0.9%) as Enterococcus avium, two (0.3%) as Enterococcus durans, two (0.3%) as Enterococcus gallinarum and one (0.1%) as Enterococcus hirae. The rates of resistance were 98.1% to trimethoprim/sulfamethoxazole, 97% to clindamycin, 84.2% to ampicillin, 83.2% to erythromycin, 83.2% to
imipenem, 73.3% to tetracycline, 66.6% to ciprofloxacin, 65.1% to moxifloxacin, 14.7% to vancomycin, 14.3% to teicoplanin, 4.8% to linezolid and 0.3% to tigecycline. High level aminoglycoside resistance was detected as 9.3 % for only gentamicin and 17.5% for only streptomycin.
Conclusion: In this study, glycopeptide resistant enterococcus strains were detected. Thus,resistance to vancomycin and teicoplanin detected in our hospital demonstrates that these antibioticst should be used cautiously in the treatment of enterococcal infections in our center.
In this study, 20 novel disazo dyes containing pyrazole derivatives were synthesized by a convenient method. Diazotized aniline and some aniline derivatives were reacted with malononitrile to give 2-arylazomalononitrile derivatives 1(a-e). The synthesized 2-arylazomalononitrile derivatives were reacted with hydrazine and phenyl hydrazine to afford the corresponding 3,5-diamino-4-arylazo-1 H-pyrazole 2(a-e) and 3,5-diamino-4-arylazo-1-phenylpyrazole 3(a-e). Diazotized compounds of 2(a-e)and 3(a-e) reacted with ethylacetoacetate to give 4-arylazo-3-amino-1 H-pyrazole-5-ylazo-ethylacetoacetate 4(a-e) and 4-arylazo-3-amino-1-phenylpyrazole-5-ylazo-ethylacetoacetate 7(ae). The obtained 4(a-e) and 7(a-e) were reacted with hydrazine and phenyl hydrazine to give disazo dyes 5(a-e), 6(a-e), 8(a-e) and 9(a-e), respectively. The synthesized disazo dyes were characterized by spectroscopic techniques as well as elemental analysis. The solvatochromic behaviours of these dyes in various solvents were examined. Acid-base effects on the absorption maxima of the dyes were also reported. Antimicrobial activities of the synthesized novel disazo dyes were investigated.
Paclitaxel, isolated from Taxus brevifolia, is considered to be an efficacious agent against a wide spectrum of human cancers, including human cervical cancer. However, dose-limiting toxicity and high cost limit its clinical application. Curcumin, a nontoxic food additive, has been reported to improve paclitaxel chemotherapy in mouse models of cervical cancer. However, the underlying mechanisms remain unclear. In this study, two human cervical cancer cell lines, CaSki [human papilloma virus (HPV)16-positive] and HeLa (HPV18-positive), were selected in which to investigate the effect of curcumin on the anticancer action of paclitaxel and further clarify the mechanisms. Flow cytometry and MTT analysis demonstrated that curcumin significantly promoted paclitaxel-induced apoptosis and cytotoxicity in the two cervical cell lines compared with that observed with paclitaxel alone (P<0.05). Reverse transcription-polymerase chain reaction indicated that the decline of HPV E6 and E7 gene expression induced by paclitaxel was also assisted by curcumin. The expression levels of p53 protein and cleaved caspase-3 were increased significantly in the curcumin plus paclitaxel-treated HeLa and CaSki cells compared with those in the cells treated with paclitaxel alone (P<0.01). Significant reductions in the levels of phosphorylation of IκBα and the p65-NF-κB subunit in CaSki cells treated with curcumin and paclitaxel were observed compared with those in cells treated with paclitaxel alone (P<0.05). This suggests that the combined effect of curcumin and paclitaxel was associated with the NF-κB-p53-caspase-3 pathway. In conclusion, curcumin has the ability to improve the paclitaxel-induced apoptosis of HPV-positive human cervical cancer cell lines via the NF-κB-p53-caspase-3 pathway. Curcumin in combination with paclitaxel may provide a superior therapeutic effect on human cervical cancer.
In the present study a series of new Schiff bases were synthesized. All the synthesized compounds were characterized by IR, 1H NMR, mass spectral and elemental analyses. Newly synthesized compounds were screened for their antibacterial (Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) activity. The results revealed that, compounds 3f and 3c have exhibited significant biological activity against the tested microorganisms.
Intercalators are the most important group of compounds that interact reversibly with the DNA double helix. Some of them are valuable drugs currently used for the treatment of ovarian and breast cancers and acute leukemias, while many others are in different phases of clinical trials. Intercalating agents share common structural features such as the presence of planar polyaromatic systems which bind by insertion between DNA base-pairs, with a marked preference for 5'-pyrimidine-purine-3' steps. The chromophores are linked to basic chains that might also play an important role in the affinity and selectivity shown by these compounds. Bisintercalators have two potential intercalating ring systems connected by linkers which can vary in length and rigidity. Nowadays it is well accepted that the antitumor activity of intercalators is closely related to the ability of these compounds to stabilize the DNA-intercalator-topoisomerase II ternary complex. In this work we have carried out a revision of small organic molecules that bind to the DNA molecule via intercalation, and exert their antitumor activity through a proven topoisomerase II inhibition. We have tried to give a general overview of the most recent results in this area, paying special attention to compounds that are currently under clinical trials. Among those are naphthalimides, a group of compounds that has been developed in our laboratory since the 70's.
Aqueous and methanol extracts of the leaves of Juniperus oxycedrus were investigated for their in vitro antimicrobial properties. The plant was collected from Pelitli Village of Gebze, Kocaeli, in the Marmara region of Turkey. Juniperus oxycedrus is widely used as traditional folk medicine in Turkey for treatment of different infectious diseases. The antimicrobial activity of the extracts against 143 laboratory strains belonging to 56 bacterial species, and 31 isolates of 5 fungi species were evaluated based on the inhibition zone using the disc-diffusion assay, minimal inhibition concentration (MIC) and minimal bactericidal concentration (MBC) values. The aqueous extract of J. oxycedrus had no antimicrobial effect against the test microorganisms whereas the methanol extract had inhibitory effects on the growth of 57 strains of 24 bacterial species in the genera of Acinetobacter, Bacillus, Brevundimonas, Brucella, Enterobacter, Escherichia, Micrococcus, Pseudomonas, Staphylococcus, and Xanthomonas. In addition 11 Candida albicans isolates at a concentration of 31.25-250 micro g/ml were also inhibited.
Phototherapy involves the irradiation of tissues with light, and is commonly implemented in the forms of photodynamic therapy (PDT) and photothermal therapy (PTT). Photosensitizers (PSs) are often needed to improve the efficacy and selectivity of phototherapy via enhanced singlet oxygen generation in PDT and photothermal responses in PTT. In both cases, efficient and selective delivery of PSs to the diseased tissues is of paramount importance. Nanoscale metal-organic frameworks (nMOFs), a new class of hybrid materials built from metal connecting points and bridging ligands, have been examined as nanocarriers for drug delivery due to their compositional and structural tunability, highly porous structures, and good biocompatibility. This review summarizes recent advances on using nMOFs as nanoparticle PSs for applications in PDT and PTT.
Inspired by the synergistic effects of hetero-aromatic scaffolds on curcumin, a novel array of pyrazoline substituted curcumin analogs was designed. Multi-scale computational studies were carried out to target the proposed analogs on human kinase β (IKK-β), a potential anti-cancer target. In molecular docking analysis, all the eleven molecules were observed to bind the target site and 4-bromo-4’-chloro analog displayed three hydrogen bond interactions with a docking score of –11.534 kcal/mol higher than parent molecule, curcumin (docking score = –7.12 kcal/mol) as the propellant shaped of analogs aided in proper binding with Kinase Domain binding pocket. The molecular dynamics and simulations studies revealed that the stable complexes of lead molecule were developed as the minimal deviations per residue of protein found within the range of 0.11 to 0.92 Å. The proposed compounds were synthesized, characterized and biologically evaluated against human cervical cancer cell line, HeLa, using standard MTT cell assay. Bio-evaluation studies exhibited superior cytotoxic profile for many analogs as Chloro bromo analog with IC50 value (8.7 µg/mL) exhibited fivefolds improvement in the potency in comparison to curcumin (IC50 = 42.4 µg/mL) but was less potent than the standard drug, paclitaxel (IC50 = 0.008µg/mL). The apoptotic effect was evaluated in the terms of caspase-3 enzyme cleavage and exhibited 70.5% of apoptosis significantly (p < 0.05) higher than 19.9% induced by curcumin. In short, 4-bromo-4’-chloro analog was the potent cytotoxic agent in this structural class and must be evaluated further under a set of stringent parameters for transforming in to a clinically viable therapeutic molecule.
Communicated by Ramaswamy H. Sarma
Pyrimidine and purine nucleosides have a remarkable and comprehensive impact on medicinal chemistry and pharmaceutical industries. They become key parts of the growing interdisciplinary area of antimetabolites. The paramount importance of the nucleoside analogs triggered their broader use in treatment of critical diseases such as cancer, malignancies, microbial infection, and autoimmune diseases. Recent advances in their synthetic strategies through microwave-assisted organic synthesis (MAOS) have been reviewed.
Rexinoids, selective ligands for retinoid X receptors (RXR), have shown promise in preventing many types of cancer. However, the limited efficacy and undesirable lipidemic side-effects of the only clinically approved rexinoid, bexarotene, drive the search for new and better rexinoids. Here we report the evaluation of novel pyrimidinyl (Py) analogues of two known chemopreventive rexinoids, bexarotene (Bex) and LG100268 (LG268) in a new paradigm. We show that these novel derivatives were more effective agents than bexarotene for preventing lung carcinogenesis induced by a carcinogen. In addition, these new analogues have an improved safety profile. PyBex caused less elevation of plasma triglyceride levels than bexarotene, while PyLG268 reduced plasma cholesterol levels and hepatomegaly compared with LG100268. Notably, this new paradigm mechanistically emphasizes the immunomodulatory and anti-inflammatory activities of rexinoids. We reveal new immunomodulatory actions of the above rexinoids, especially their ability to diminish the percentage of macrophages and myeloid-derived suppressor cells in the lung and to redirect activation of M2 macrophages. The rexinoids also potently inhibit critical inflammatory mediators including IL6, IL1β, CCL9, and nitric oxide synthase (iNOS) induced by lipopolysaccharide. Moreover, in vitro iNOS and SREBP (sterol regulatory element-binding protein) induction assays correlate with in vivo efficacy and toxicity, respectively. Our results not only report novel pyrimidine derivatives of existing rexinoids, but also describe a series of biological screening assays that will guide the synthesis of additional rexinoids. Further progress in rexinoid synthesis, potency, and safety should eventually lead to a clinically acceptable and useful new drug for patients with cancer.
Nowadays, cancer has been one of the major threats to human beings throughout the world. Nanomedicines have been demonstrated as a promising candidate for cancer chemotherapy. In this work, we facilely constructed a RGD (Arg-Gly-Asp) modified [email protected] imidazolate framework-8 ([email protected]@ZIF-8) as a novel metal-organic frameworks-based hydrophobic drug delivery system for targeted and enhanced cancer treatment. In our system, the nanoplatform exhibited the superior property of target to the cancer cells due to the function with RGD. More importantly, the [email protected]@ZIF-8 nanoplatform has shown the enhanced cancer cell treatment due to the excellent pH-responsive hydrophobic anticancer drug delivery and intracellular ROS generation. With the excellent targeting and enhanced therapy performance, we envision that the hydrophobic anticancer drug delivery system could become a potential therapeutic agent for targeted cancer treatment.
Amaç: Enterokoklar insan florasında bulunurlar ve oldukça düşük virulansa sahiptirler. Ancak, enterokoklar hastane ve toplum kaynaklı enfeksiyonlara neden olmakta ve son yıllarda bu enfeksiyonlarda antibiyotik direnç oranlarında artış gözlenmektedir. Bu çalışmada en sık izole edilen enterokok türleri olan Enterococcus faecalis ve Enterococcus faecium’un antibiyotik duyarlılıklarının değerlendirilmesi amaçlanmıştır.Gereç ve Yöntem: Çalışmamızda 2012 - 2016 yılları arasında Tıbbi Mikrobiyoloji Laboratuvarımıza gelen çeşitli klinik örneklerden izole edilen 727 enterokok suşu değerlendirmeye alınmıştır. Tür tanımlamaları ve antibiyotik duyarlılık testleri konvansiyonel metodlar ve VITEK®-2 (BioMérieux, Fransa) otomatize identifikasyon cihazı ile yapılmıştır.Bulgular: Bu çalışmada izole edilen 727 enterokok suşunun 450’si (%61,9) E. faecalis, 277’si (%38,1) E. faecium olarak tanımlanmıştır. Enterokok suşlarının izole edildiği hastaların cinsiyet dağılımı; 387 (%53,2) kadın, 340 (%46,8) erkektir. Klinik örneklerin dağılımı; 467 (%64.2) idrar, 110 (%15.1) kan, 77 (%10.6) gaita, 43 (%5.9) yara ve 30 %(4.1) diğer örneklerdir. Enterokok suşları en sık idrar örneklerinden izole edilmiştir. İzole edilen E. faecium ve E. faecalis suşlarının tamamı tigesikline duyarlı olarak saptanmıştır. Vankomisin direnç oranı E. faecium izolatlarında %29,9 (80/268), E. faecalis izolatlarında %8,6 (37/432) olarak belirlenmiştir.Sonuç: Enterokoklarda son zamanlarda giderek artan direnç oranları bu enfeksiyonlara karşı birçok antibiyotiğin kullanımını sınırlandırmaktadır. Her hastanenin kendi sürveyans programını oluşturarak enterokokların tür düzeyinde tanımlanması, antibiyogram duyarlılık testlerini yapılması ve tedavi protokollerinin bu direnç paternlerine göre uygulanmasının enterokok enfeksiyonlarının kontrol altına alınmasında etkili olacağı kanaatindeyiz.
In this work, a novel series of Schiff base has been reported by the reaction of Chitosan with different substituted pyrazole-4-carbaldehydes in acidic media. The synthesized compounds were characterized by Fourier-transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA), X-ray diffraction (XRD) and 13C NMR techniques. Chitosan and the Schiff bases were compared for their antimicrobial activity against the bacteria; Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumonia, Escherichia coli and a fungi, Candida albicans. The results indicated stronger inhibitory effect of the Schiff bases on these microorganisms compared to Chitosan and the extent of inhibition varied with the nature of substitution.
Objective:
Paclitaxel is one of the common anticancer drugs in the treatment of cervical cancer, while the mechanism of restraining and killing cancer cells is still unclear. This study aimed to investigate the molecular mechanism of paclitaxel in regulating proliferation and apoptosis of cervical cancer Hela cells.
Materials and methods:
Paclitaxel at 2 μmol/L was used to treat Hela cells for 48 h. MTT assay and flow cytometry were applied to test Hela cells proliferation and apoptosis respectively. Western blot was adopted to determine the expression of survivin. SiRNA was performed to suppress survivin protein expression in Hela cells.
Results:
Paclitaxel restrained Hela cells growth and induced apoptosis. Also, paclitaxel treatment significantly reduced survivin protein expression in Hela cells. Moreover, survivin siRNA transfection further promoted Hela cells apoptosis after intervention by 2 μmol/L paclitaxel.
Conclusions:
Down-regulation of survivin promoted paclitaxel-induced apoptosis of cervical cancer Hela cells.
New pyrazole Schiff bases containing azo groups, 4-((E)-phenyldiazenyl)-3-(4-nitrobenzylidene)-1-phenyl-pyrazole-5-amine and its series, were synthesized using the condensation reaction between p-nitrobenzaldehyde and (E)-1-phenyl-4-(phenyldiazenyl)-1H-pyrazole-3,5-diamine in the molar ratio of 1:1. The compounds were characterized using IR, UV–Vis, ¹H-NMR and ¹³C-NMR spectroscopies. The UV–Vis spectral data were obtained in ethanol, chloroform, N,N-dimethylformamide (DMF), DMF (pH = 2) and DMF (pH = 12), which have different polarity and pH values. Meanwhile, the experimental spectral analyses were supported by the theoretical calculations based on the density functional theory (DFT) using the B3LYP/cc-pvtz level. Structural analyses, vibrational frequencies, UV, and NMR calculations were performed at the same level of the theory. In addition, via using HOMO-LUMO energies, the electrochemical quantities such as chemical hardness and electronegativity were calculated and analyzed.
Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.
Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5-a]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells. We identified 1-(2'-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole (EFT) as lead cytotoxic agent against MCF7 cell lines with an IC50 value of 1.69 µM. Further evaluation revealed that EFT induces cytotoxicity on Ishikawa, MDA-MB-231 and BT474 cells with IC50 values of 1.97, 4.81 and 4.08 µM respectively. However, EFT did not induce cytotoxicity in normal lung epithelial (BEAS-2B) cells. Previous reports suggested that 1,2,3-triazoles are the inhibitors of VEGFR1 and therefore, we evaluated the effect of EFT on the expression of VEGFR1. The results demonstrated that EFT downregulates the expression of VEGFR1 in MCF7 cells. In summary, we identified a potent cytotoxic agent that imparts its antiproliferative activity by targeting VEGFR1 in breast cancer cells. The novel compound could serve as a lead structure in developing VEGFR1 inhibitors.
Disazo dye containing pyrazole skeleton has been synthesized. The structure of the dye has been confirmed by using FT-IR, ¹H NMR, ¹³C NMR, HRMS spectral technique and elemental analysis. The molecular geometry and infrared spectrum are also calculated by the Density Functional Theory (DFT) employing B3LYP level with 6-311G (d,p) basis set. The chemical shifts calculation for ¹H NMR of the title molecule is done by using by Gauge-Invariant Atomic Orbital (GIAO) method by utilizing the same basis sets. The total density of state, the partial density of state and the overlap population density of state diagram analysis are done via Gauss Sum 3.0 program. Frontier molecular orbitals such as highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and molecular electrostatic potential surface on the title molecule are predicted for various intramolecular interactions that are responsible for the stabilization of the molecule. The experimental results and theoretical values have been compared.
Schiff bases synthesised from the condensation of 2-(hydroxy)naphthaldehyde and
sulfonamides (sufathiazole (STZ), sulfapyridine (SPY), sulfadiazine (SDZ), sulfamerazine
(SMZ) and sulfaguanidine (SGN)) are characterized by different spectroscopic data (FTIR,
UV-Vis, Mass, NMR) and two of them, (E)-4-(((2-hydroxynaphthalen-1-
yl)methylene)amino)-N-(thiazol-2-yl)benzenesulfonamide (1a) and (E)-N-
(diaminomethylene)-4-(((2-hydroxynaphthalen-1-yl)methylene)amino)benzenesulfonamide
(1e) have been confirmed by single crystal X-ray structure determination. Antimicrobial
activities of the Schiff bases have been evaluated against certified and resistant Gram positive
(S. aureus, E. facelis) and Gram negative (S. pyogenes, S. typhi, Sh dysenteriae, Sh. flexneri,
K. pneumonia) pathogens. Performance of Schiff base against the resistant pathogens are
better than standard stain and MIC data lie 32 – 128 µg/ml while parent sulfonamides are
effectively inactive (MIC >512 µg/ml). The DFT optimized structures of the Schiff bases
have been used to accomplish molecular docking studies with DHPS (dihydropteroate synthase) protein structure (downloaded from Protein Data Bank) to establish the most
preferred mode of interaction. ADMET filtration, Cytotoxicity (MTT assay) and haemolysis
assay have been examined for evaluation of druglike character.
Three disperse azo dyes having the same 4-nitrobenzene/azo/4-Aminobenzene skeleton but different color have been structurally and spectrally characterized and compared in this paper. X-ray single-crystal diffraction analysis of compound 3 reveals that it has a planar molecular conformation between the azo and the nitrobenzene units. However, severely twisted aminoazobenzene structures in compounds 1 and 2 are observed because of the steric hindrance effect of ortho chloro and bromo groups. Electronic spectra of 1-3 are closely related to their molecular structures, which demonstrate that the presence of different substituted groups and the spatial crowding effect in the aminoazobenzene backbone leads to the significant alterations of bathochromic and hypochromatic shifts. In addition, theoretic computational studies as well as solvatochromisms for three azo dyes have been included.
The Schiff bases of chitosan were synthesized by the reaction of chitosan with 3-(4-substituted-phenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde. The structure of the prepared chitosan derivatives was characterized by FTIR spectroscopy, elemental analysis, and X-ray diffraction studies and thermogravimetric analysis (TG). The results show that the specific properties of Schiff bases of chitosan can be altered by modifying the molecular structures with proper substituent groups.TG results reveal that the thermal stability of the prepared chitosan Schiff bases was lower than chitosan. The activation energy of decomposition was calculated using Coats-Redfern model. The antimicrobial activity of chitosan and Schiff bases of chitosan were investigated against Streptococcus pneumonia, Bacillis subtilis, Escherichia coli (as examples of bacteria) and Aspergillus fumigatus, Geotricum candidum and Syncephalastrum recemosum (as examples of fungi). The results indicated that the antimicrobial activity of the Schiff bases was stronger than that of chitosan and was dependent on the substituent group. The activity of un-substituted arylpyrazole chitosan derivative toward the investigated bacteria and fungi species was better than the other derivatives.
Copyright © 2015. Published by Elsevier B.V.
In continuation of our efforts to find new biologically active agents, regioselective synthesis of a series of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-arylethanones 4a-k has been achieved under facile, extremely mild and greener reaction conditions with excellent yields. Moreover, one pot multicomponent reaction has also been reinvestigated under previously reported solvent conditions to prepare 4a-b and found that the reaction generates significant amount of side products. The chemical structures of 4a-k were established on the basis of a combined use of IR, NMR ((1)H, (13)C) spectroscopy, mass spectrometry and elemental analysis. All the compounds were evaluated for their antibacterial, DNA photocleavage and anticancer activities. Among all, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-(naphth-2-yl)ethanone 4j displayed good inhibitory profile against Escherichia coli and Staphylococcus aureus which was about 50% and 25% of the Ampicillin (standard drug), respectively. The compounds, 4a and 4f showed relatively moderate inhibition against Psuedomonas aeruginosa and E. coli. In DNA photocleavage study, compounds 4c and 4d were found to be highly active and completely degraded both forms of DNA (SC and OC), even at a very low concentration of 1 μg (4c) under irradiation of UV light. However, 4h and 4f resulted in complete DNA degradation at 30 μg concentration. Moreover, 4h showed fluorescence at 15 μg concentration and increased the intensity of both bands of DNA (SC and OC) as compared to control. On the other hand, to valorize the biological potential, the compounds were screened for their cytotoxic activity on colon (HCT116 and HT29), prostate (DU145), ovarian (SKOV3) and lung (A549) cancer cell lines. The compound 4j was found to be cytotoxic to all the cancer cell lines, except SKOV3, with more selectivity towards the colon cancer cell lines (HCT116, HT29) and A549 lung cancer cell line. On A549 lung cancer cell line, 4j and 4k exhibited similar potency as carboplatin in inhibiting cell viability.
To identify the most active antimicrobial fraction of Folium Syringae, four common pathogens were used in an in vitro screening. The results indicated that the combination of the 30% and 60% ethanol fraction (FSC) obtained from the water extraction was the most active fraction with a minimal inhibitory concentration of 0.65 mg mL(- 1). FSC was also found to be able to protect mice from a lethal infection of Staphylococcus aureus at clinical dosage (0.2 g kg(- 1)) with a survival rate of 83.3%. The antibacterial activity of FSC was then tested using the serum pharmacology method which revealed that FSC exhibits a more long-lasting activity than the positive control (levofloxacin hydrochloride). The main components were confirmed to be iridoid glycosides and flavones by HPLC-MS analysis.
The interactions of small molecules with nucleic acids have provoked considerable interest in the field of anticancer drug design over the past three decades; however, critical information linking the physical-chemical properties associated with these complexes with their biological effectiveness remains unclear. Significant progress has been made towards unraveling the structural and dynamic properties of many ligand-DNA complexes which has provided pivotal insight into the design and development of more effective second and third generation chemotherapeutic agents for the successful treatment of many types of cancer. Interactions of ligands with DNA are studied by a variety of physical and biochemical methods in an effort to determine the chemical and physical basis of novel binding phenomena such as DNA base sequence selectivity, correlation of structure-activity relationships, linkages between the geometry and thermodynamic properties describing drug-DNA complexes, and influences of substituent modifications on the physical, chemical, and biological properties of the drug-DNA complex.
We report on a test of FLEXX, a fully automatic docking tool for flexible ligands, on a highly diverse data set of 200 protein–ligand complexes from the Protein Data Bank. In total 46.5% of the complexes of the data set can be reproduced by a FLEXX docking solution at rank 1 with an rms deviation (RMSD) from the observed structure of less than 2 Å. This rate rises to 70% if one looks at the entire generated solution set. FLEXX produces reliable results for ligands with up to 15 components which can be docked in 80% of the cases with acceptable accuracy. Ligands with more than 15 components tend to generate wrong solutions more often. The average runtime of FLEXX on this test set is 93 seconds per complex on a SUN Ultra-30 workstation. In addition, we report on “cross-docking” experiments, in which several receptor structures of complexes with identical proteins have been used for docking all cocrystallized ligands of these complexes. In most cases, these experiments show that FLEXX can acceptably dock a ligand into a foreign receptor structure. Finally we report on screening runs of ligands out of a library with 556 entries against ten different proteins. In eight cases FLEXX is able to find the original inhibitor within the top 7% of the total library. Proteins 1999;37:228–241. ©1999 Wiley-Liss, Inc.
Comparisons of the effects of clinically relevant concentrations of the anticancer agent paclitaxel on growth, viability, and apoptosis were determined using in vitro human cell cultures. Growth of the cervical cancer cell line, HeLa-S3, was significantly reduced, and apoptotic index was significantly increased, after 24 h in cultures treated with 12 nM paclitaxel. In contrast, hepatic carcinoma (HEpG2) cells capable of detoxifying paclitaxel were only affected at paclitaxel concentrations ge120 nM. The previously uncharacterized non-cancerous human microvessel endothelial cell line HMEC-1, was more sensitive to paclitaxel treatment than both HeLa-S3 and HEpG2 cells, demonstrating decreased growth and increased apoptosis with 1.2 nM paclitaxel. These results are significant in the design of in vitro cell culture systems to study drug metabolism and toxicity.
Antibacterial and antifungal activities of six plant-derived flavonoids representing two different structural groups were evaluated against standard strains of Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecalis, Bacillus subtilis and their drug-resistant isolates, as well as fungi (Candida albicans, C. krusei) using the microdilution broth method. Herpes simplex virus Type-1 and Parainfluenza-3 virus were employed for antiviral assessment of the flavonoids using Madin-Darby bovine kidney and Vero cell lines. Ampicillin, gentamycin, ofloxacin, levofloxacin, fluconazole, ketoconazole, acyclovir, and oseltamivir were used as the control agents. All tested compounds (32–128 μg/ml) showed strong antimicrobial and antifungal activities against isolated strains of P. aeruginosa, A. baumanni, S. aureus, and C. krusei. Rutin, 5,7-dimethoxyflavanone-4′-O-β-d-glucopyranoside and 5,7,3′-trihydroxy-flavanone-4′-O-β-d-glucopyranoside (0.2–0.05 μg/ml) were active against PI-3, while 5,7-dimethoxyflavanone-4′-O-[2″-O-(5‴-O-trans-cinnamoyl)-β-d-apiofuranosyl]-β-d-glucopyranoside (0.16–0.2 μg/ml) inhibited potently HSV-1.
Aniline derivatives were diazotized and coupled with 3-aminocrotononitrile to give the corresponding 2-arylhydrazono-3-ketiminobutyronitriles. Cyclization of these arylhydrazono derivatives with hydrazine monohydrate afforded 5-amino-4-arylazo-3-methyl-1H-pyrazoles which were subsequently diazotised and coupled with malononitrile to yield a series of pyrazolylhydrazonomalononitriles. These compounds were then reacted with hydrazine monohydrate to provide 10, novel, heterocyclic disazo dyes, which were characterized by elemental analysis and spectral methods. The antimicrobial activity and absorption characteristics of the dyes were also examined in detail.
Despite the remarkable thermochemical accuracy of Kohn–Sham density-functional theories with gradient corrections for exchange-correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact-exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange-correlation functional containing local-spin-density, gradient, and exact-exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first- and second-row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
It is important to develop new antibiotics aimed at novel targets. The investigation found that the leaf extracts from five maples (Acer platanoides, Acer campestre, Acer rubrum, Acer saccharum and Acer truncatum Bunge collected in Denmark, Canada and China) and their component tannic acid displayed antibacterial ability against 24 standard bacteria strains with the minimum inhibitory concentration of 0.3-8.0 mg/mL. Unlike the standard antibiotic levofloxacin (LFX), these samples inhibited Gram-positive bacteria more effectively than they inhibited Gram-negative bacteria. These samples effectively inhibited two antidrug bacterial strains. The results show that these samples inhibit bacteria by a different mechanism from LFX. These samples potently inhibited b-ketoacyl-ACP reductase (FabG), which is an important enzyme in bacterial fatty acid synthesis. Tannic acid showed the strongest inhibition on FabG with a half inhibition concentration of 0.78 microM (0.81 microg/mL). Furthermore, tannic acid and two maple leaf extracts showed time-dependent irreversible inhibition of FabG. These three samples also exhibited better inhibition on bacteria. It is suggested that FabG is the antibacteria target of maple leaf extracts and tannic acid, and both reversible and irreversible inhibitions of FabG are important for the antibacterial effect.
A correlation-energy formula due to Colle and Salvetti [Theor. Chim. Acta 37, 329 (1975)], in which the correlation energy density is expressed in terms of the electron density and a Laplacian of the second-order Hartree-Fock density matrix, is restated as a formula involving the density and local kinetic-energy density. On insertion of gradient expansions for the local kinetic-energy density, density-functional formulas for the correlation energy and correlation potential are then obtained. Through numerical calculations on a number of atoms, positive ions, and molecules, of both open- and closed-shell type, it is demonstrated that these formulas, like the original Colle-Salvetti formulas, give correlation energies within a few percent.
We have quantified the effects of the regiochemical distribution of positive charges along the polyamine moiety in lipopolyamines for DNA molecular recognition. High affinity binding leads to charge neutralisation, DNA condensation and ultimately to lipofection. Binding affinities for calf thymus DNA were determined using an ethidium bromide displacement assay and condensation was detected by changes in turbidity using light scattering. The in vitro transfection competence of cholesterol polyamine carbamates was measured in CHO cells. In the design of DNA condensing and transfecting agents for non-viral gene therapy, the interrelationship of ammonium ions, not just their number, must be considered.
Thirty Schiff bases of hydroxysemicarbazide (Ar-CH=NNHCONHOH) have been synthesized and tested against L1210 murine leukemia cells. The IC(50) values were found to be in a range from 2.7 x 10(-6) to 9.4 x 10(-4) M. A total of 17 out of the 30 compounds had higher inhibitory activities than hydroxyurea (an anticancer drug currently used for the treatment of melanoma, leukemia, and ovarian cancer) against L1210 cells. Six compounds with IC(50) values in micromolar range were 11- to 30-fold more potent than hydroxyurea (IC(50) = 8.2 x 10(-5) M). The partition coefficient (log P) and ionization constants (pK(a)) of a model compound [1-(3-trifluoromethylbenzylidene)-4-hydroxysemicarbazide, 1] were measured by the shake-flask method, and the measured log P was used to derive Hansch-Fujita pi constant of -CH=NNHCONHOH. On the basis of the newly derived pi and those of other moieties, the partition coefficients (SlogP) of the other 29 compounds were calculated by the summation of pi values. Quantitative structure-activity relationship (QSAR) analysis showed that, besides the essential pharmacophore (-NHCONHOH), hydrophobicity (SlogP), molecular size/polarizability (calculated molar refractivity), and the presence of an oxygen-containing group at the ortho position (I) were important determinants for the antitumor activities. In conclusion, the results obtained in this study show that several Schiff bases of hydroxysemicarbazide are potent inhibitors of tumor cells and warrant further investigation as cancer chemotherapeutic agents.
Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Because free radicals can also inflict cellular damage, several defences have evolved both to protect our cells from radicals--such as antioxidant scavengers and enzymes--and to repair DNA damage. Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis.
We have developed a novel method to protect DNA from cleavage using bioconjugated nanoparticles. Positively charged amino-modified silica nanoparticles have been directly prepared using water-in-oil microemulsion. Plasmid DNA can be easily enriched onto the positively charged nanoparticle surface, and the DNA strands are well protected from enzymatic cleavage. When incubated with nuclease enzyme for enzymatic cleavage, free plasmid DNA strands are completely cleaved, while those on the nanoparticle surfaces are intact. Our results clearly demonstrate unique properties of nanomaterials when combined with biomolecules. Our simple bionanotechnology will be highly useful in DNA separation, manipulation, and detection, and possibly in genetic engineering and gene therapy, as plasmid DNA can be protected in cellular environments without any change in its property.