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[Display omitted] • Synthesis of new FePBZPHA, CoPBZPHA, and NiPBZPHA mixed-ligand complexes. • Stoichiometry determination confirming the 1:1:1 (M: PBZ: PHA) ratio; FT-IR spectra comparison elucidating intricate binding modes. • DFT calculations unveiling octahedral coordination geometries and enhanced electron affinity, electronegativity, and reactivity of metal complexes. • Biological evaluation showcasing significantly enhanced efficacy of metal complexes in antimicrobial, anti-inflammatory, and antioxidant activities, with FePBZPHA exhibiting the highest potency. • Molecular docking analysis highlighting potential therapeutic applications, with metal complexation enhancing binding affinity and interaction versatility. This study presents a thorough investigation into the synthesis, characterization, computational analysis, and biological evaluation of FePBZPHA, CoPBZPHA, and NiPBZPHA mixed-ligand complexes. They were synthesized in high yields via reactions between chloride salts of Iron, Cobalt, or Nickel with 2-(pyridin-2-yl)-1H-benzimidazole (PBZ) and Phenylalanine (PHA). They underwent extensive spectroscopic, elemental, conductivity, magnetic, and thermal analysis to confirm their formation. Molar conductivity measurements indicated their non-electrolytic nature, with UV–vis spectra revealing distinct absorption bands for PBZ and PHA ligands, shifting significantly upon metal ion coordination. Stoichiometry determination confirmed the 1:1:1 (M:PBZ:PHA) ratio, while FT-IR spectra comparison elucidated intricate binding modes, supported by mass spectra and elemental analysis. Thermal analysis revealed their thermal stability and decomposition pathways. DFT calculations unveiled octahedral coordination geometries and enhanced electron affinity, electronegativity, and reactivity of metal complexes. Biological evaluation showcased significantly enhanced efficacy of metal complexes in antimicrobial, anti-inflammatory, and antioxidant activities, with FePBZPHA exhibiting the highest potency. Molecular docking analysis highlighted their potential as therapeutic agents, with metal complexation enhancing binding affinity and interaction versatility. Overall, this study provides comprehensive insights into the synthesis, characterization, computational analysis, and biological evaluation of FePBZPHA, CoPBZPHA, and NiPBZPHA mixed-ligand complexes, suggesting promising applications in biomedicine and materials science. [ABSTRACT FROM AUTHOR]

Hyperlipidemia, an elevated level of cholesterol and/or triglycerides, has become a major public health problem worldwide. Although drugs intervention is effective in treating hyperlipidemia, most of them have adverse side effects. Peptides from natural plants with high anti-hyperlipidemic activity and a strong safety profile have emerged as promising candidates to prevent and ameliorate hyperlipidemia. This review summarizes the recent advances in plant-derived anti-hyperlipidemic peptides in terms of their sources, production, purification, identification, and activity evaluation. The focus is extended to their potential anti-hyperlipidemic mechanisms and structure-function relationships. Bioactive peptides derived from various plant sources, especially peptides containing hydrophobic and/or acidic amino acids, have shown remarkable effects in hyperlipidemic treatment. Their anti-hyperlipidemic effects are mediated by various mechanisms, including regulation of cholesterol metabolism and triglyceride metabolism, inhibition of inflammation-related metabolic syndrome, and modulation of the gut microbiota. Further evaluation of the stability, bioavailability, and clinical efficacy of these peptides is recommended. • Various plant-derived peptides have shown significant therapeutic potential for hyperlipidemia. • Most of plant-derived peptides exert anti-hyperlipidemic effects mainly by regulating TC metabolism and TG metabolism. • The peptides containing hydrophobic and/or acidic amino acids contribute to anti-hyperlipidemic activity. • Further evaluation of the stability, bioavailability, and clinical efficacy of anti-hyperlipidemic peptides are needed. [ABSTRACT FROM AUTHOR]

Checkpoint kinase 1 (CHK1) plays a crucial role in the DNA damage response pathway, making it an attractive target for cancer therapy. Herein, we present the synthesis, optimization, and evaluation of selective CHK1 inhibitors with a pyrido[3,2- d ]pyrimidin-6(5 H)-one scaffold. Among them, compound 11 showed single-digit nanomolar potency against CHK1 (IC 50 : 0.55 nM) with good kinase selectivity. Notably, 11 showed anti-proliferative effect in MV-4-11 cells singly (IC 50 = 202 nM) and a synergistic effect in combination with gemcitabine in HT-29 cells (IC 50 = 63.53 nM). Furthermore, the combination of 11 and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Overall, this work provides a strong foundation for the development of selective CHK1 inhibitors and the therapeutic strategy for cancer. [Display omitted] • A series of CHK1 inhibitors by performing a structure-based design approach. • The potent compound 11 showed significant inhibitory against CHK1 (IC 50 = 0.55 nM). • 11 showed superior anti-proliferative activity (IC 50 = 202 nM for MV-4-11). • 11 exhibited synergistic effect in the HT-29 xenograft model with gemcitabine. [ABSTRACT FROM AUTHOR]

• A series of covalent pan-FGFR inhibitors by structure-based design approach. • The compound I-11 showed remarkable enzymatic activity toward FGFR1–4. • I-11 showed superior anti-proliferative activity (IC 50 = 6.35 nM for Huh7). • I-11 exhibited suitable PK properties and induced significant TGI in Huh-7 model. Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of multiple cancer types. Therefore, it is an attractive target for tumor therapy, and many efforts have been directed to the discovery of irreversible FGFR inhibitors over the last decade. Using a quinazoline scaffold, we used structure-based drug design to obtain a series of novel covalent pan-FGFR inhibitors. One of the representative compounds, I-11 , showed remarkable enzymatic activity toward FGFR1–4 (FGFR1/2/3/4, IC 50 = 5.6/2.2/8.5/4.6 nM) and strongly suppressed the proliferation of Huh7 HCC cells (IC 50 = 6.35 nM). Further, I-11 exhibited reasonable PK profiles (F = 57.5 %) and showed significant antitumor effects in the Huh-7 xenograft model without obvious changes in body weight. Overall, I-11 was identified as a potential pan-FGFR inhibitor for cancer therapy and deserved further research. [Display omitted] [ABSTRACT FROM AUTHOR]

Studies have confirmed that tumorigenesis is related to an imbalance of polyamine metabolism and over-expression of oncogenes resulting in the up-regulation of ornithine decarboxylase (ODC, the first rate-limiting enzyme for regulating intracellular polyamines biosynthesis), which has become a target for anti-tumor therapy. In this study, an ornithine derivative, N5-(2-[18F]fluoropropionyl) ornithine (N5-[18F]FPO), has been prepared and its potential utility for tumor PET imaging evaluated. N5-[18F]FPO was successfully prepared via a nucleophilic fluorination reaction and a subsequent efficient deprotection step. The in vitro and in vivo stability were determined by HPLC conducted in fetal bovine serum, saline and rat urine. Cellular uptake studies were conducted in HepG2 cells and the biodistribution and micro-PET/CT imaging performed in normal ICR mice and three tumor-bearing mice models, respectively. Total synthesis time of N5-[18F]FPO was about 80 min with a radiochemical yield of 15% ± 6% (uncorrected, based on 18F−, n = 6) and a high radiochemical stability can be seen in vitro and vivo. The N5-[18F]FPO exhibited fast uptake in HepG2 cells and the cellular uptake ability of N5-[18F]FPO can be inhibited by L-ornithine and DFMO, which indicated that the transport pathway of N5-[18F]FPO is similar to that of L-ornithine, interacting with ODC after being transported into the cell. The biodistribution and micro-PET/CT images demonstrate that N5-[18F]FPO was excreted by the urinary system, and excellent tumor visualization with high tumor-to-background ratios can be observed in the three tumor-bearing mice models studied. All the above results suggest that N5-[18F]FPO has the potential to be a novel radiotracer for imaging ODC expression in solid tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

Alkali/urea, a green dissolution system for chitosan, have been widely used in preparation of chitosan-derived materials. However, there are no related reports detail the structure stability and biocompatibility of chitosan in alkali/urea, which are important for its large-scale application. In this work, chitosan was dissolved in KOH/urea solution and stored at different temperature for different time. The structure, viscosity, molecule weight (Mw), degree of deacetylation (DD), and biocompatibility of chitosan were determined. The Mw of chitosan decreased from 1011 KDa to 827–834 KDa, and DD increased from 76.9% to 85.7–93.5% after been stored at 25 °C and 4 °C for 5 weeks. Incomplete dissolution of chitosan and increase of DD enhanced its thermal stability by forming new crystallization zone. In contrast, chitosan stored in −20 °C for 5 weeks was stable without obvious change of Mw and DD. Moreover, the processed chitosans were no-toxic and safety for the biomedicine applications. • Structure transformation and biocompatibility of chitosan in KOH/urea solution is evaluated. • High storage temperature and concentrated alkaline will change the Mw and DD of chitosan. • Processed chitosans were no-toxic and safety for the biomedicine applications. • This work provides a reasonable reference for long-term storage and large-scale application of chitosan. [ABSTRACT FROM AUTHOR]

• Ultrasonic-assisted synthesis of new sulfonamide schiff base derivatives. • New oxazepine derivatives were synthesized using Microwave-technique. • Low-Cytotoxic, hemolytic Antimicrobial, and antioxidant agents were observed. • Molecular docking and DFT computational analyses have been predicted. • Identification of pharmacokinetic properties, bioactivity scores and pharmacophore site by POM analyses. The eco-friendly sonication and microwave irradiation techniques were used for the straight forward synthesis of the Schiff base platform from sulfathiazole. Herein, Schiff bases were developed and converted to oxazepane derivatives. Compounds were tested for their antimicrobial, antioxidant, in vivo cytotoxicity activity. Moreover, density functional theory (DFT) and molecular docking studies were also carried out to explore the structural prpoperties and interaction of compounds with the receptor molecules. In vitro antimicrobial activity was determined against Gram-positive and Gram-negative strains via microdilution technique, which showed that the synthesized derivatives exhibit significant antimicrobial activity. Furthermore, in vivo cytotoxicity activity of the compounds were carried out via intravenous injection in rats. The results were compared with negative controls and it was observed that most of the synthesized compounds displayed excellent antimicrobial activity and low toxicity in comparison to references and negative controls, respectively. Hemolysis test was carried out for bioactive compounds, and results showed higher hemolysis values of the Schiff bases than the correponding oxazepines and lower hemolytic effects. The free radical inhibittion and antioxidant activity was carried out by using 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH) and ferric reducing antioxidant power (FRAP) methods which suggested that the free radical scavenging activity increases with the presence of hydroxyl group. The Spectral measurements fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), and high resolution electrospray ionization mass spectrometry (HRESIMS) confirmed the structure of the compounds. [Display omitted] [ABSTRACT FROM AUTHOR]

IC 50 = 43 nM, 42 nM and 68 nM (in vitro). Introducing purine bases to P2-ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitory because of the carbonyl and NH groups promoting the formation of extensive H-bonding interactions. In this work, thirty-three compounds are synthesized and evaluated, among which inhibitors 16a , 16f and 16j containing N -2-(6-substituted-9 H -purin-9-yl)acetamide as the P2-ligands along with 4-methoxylphenylsulfonamide as the P2′-ligand, display potent inhibitory effect on the activity of HIV-1 protease with IC 50 43 nM, 42 nM and 68 nM in vitro , respectively. [ABSTRACT FROM AUTHOR]

Abstract The triazolo [4,3- a ]pyrazin analogues are of interest due to their potential activity against various infectious and non-infectious disease. In search of suitable potent drug candidate, we report here the design, synthesis, characterization, biological activities and computation study of novel triazolo [4,3- a ]pyrazin analogues. The synthesized molecules were characterized by various spectroscopic studies such as IR, Mass, 1H NMR, 13C NMR and elemental analysis. The newly synthesized compounds were evaluated for their in vitro biological activities such as anti-malarial, anti-tuberculosis, anti-bacterial and anti-fungal activities against plasmodium falciparum, H 37 Rv, various bacterial and fungal strains, respectively. The molecular docking study was carried out with enzyme aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum to analyze their binding orientation in the active site of the aspartic proteinase enzyme. The best docking complex was subjected to molecular dynamics simulation to illustrate the stability of these complexes and the most prominent interactions during the simulated trajectory. We have also calculated ADMET properties of all the synthesized compounds to predict the pharmacokinetic properties for the selection of the active and bioavailability of compounds. Graphical abstract Image 1 Highlights • Novel triazolo [4,3- a ]pyrazin analogous were synthesized as potential anti-malarial agent. • Compound 12c proves to be hit molecule as anti-malarial agent. • The molecules docked with responsible enzymes i.e. P. falciparum, S. Aureus hydrolase and mycobacterial enoyl reductase (InhA) using PDB ID 1PFZ , 4CJN and 2H7I. • Molecular dynamics study for the structural integrity and stability of the complex. • In silico ADMET prediction of synthesized compounds for good pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Abstract Pityriacitrin is a marine alkaloid with typical β -carboline scaffold, and which has been proven to exhibit diverse biological functions. During the course of our research for highly active compounds from natural products, the pityriacitrin have also been isolated and identified from a Chinese Burkholderia sp. NBF227. So, in order to explore the potential functional molecules, a series of β -carboline analogues derived from pityriacitrin were designed and synthesized, and their in vitro cytotoxic activities against SGC-7901, A875, HepG2, and MARC145 cell lines were evaluated. The results demonstrated that some of these β -carboline derivatives exhibited moderate to good cytotoxic activities, especially, compound 9o with a special sulfonyl group presented the highest inhibitory activities against all tested cell lines with the IC 50 values of 6.82 ± 0.98, 8.43 ± 1.93, 7.69 ± 2.17, 7.19 ± 1.43 μM, respectively, which might be used as lead compound for discovery of novel cytotoxic agents. Graphical abstract Image 1 Highlights • Novel carboline analogues derived from marine alkaloid pityriacitrin. • Good cytotoxic activities compared with the reference drug. • The SARs analyses have been fully investigated. [ABSTRACT FROM AUTHOR]

Abstract Fifteen novel stilbene analogues containing thiazole moiety were designed and synthesized. The structure of the synthesized compounds was confirmed by 1H NMR, 13C NMR and ESI-HRMS. These compounds were screened for their topoisomerase I inhibitory activity using Top1-mediated relaxation assay, and compound 6n displayed promising Top1 inhibitory activity. Molecular docking was established to study the structure-activity relationship of the title compounds and a good correlation was observed between Top1 inhibitory activity and molecular docking study. Furthermore, in vitro antifungal activities of these compounds were evaluated against FusaHum graminearum, Mycosphaerella melonis and Thanatephorus cucumeris respectively. Some compounds possessed moderate antifungal activity at 50 mg/L, while compound 6i displayed 70.1% inhibition against F. graminearum and 6o showed 61.6% inhibition against M. melonis. Graphical abstract A series of novel stilbene analogues containing thiazole moiety have been synthesized and evaluated for their Top1 inhibitory activity and in vitro antifungal activity. The mode of action was also investigated by molecular docking study. Image 1 Highlights • Novel stilbene analogues containing thiazole moiety were designed and synthesized. • Evaluated for their Top1 inhibitory activity and in vitro antifungal activity. • Compound 6n displayed promising Top1 inhibitory activity. • The mode of action was investigated by molecular docking study. • Some compounds possessed moderate antifungal activity at 50 mg/L. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Various 3-amino-, 3-aryloxy- and alkoxy-6-arylpyridazines have been synthesized by an electrochemical reductive cross-coupling between 3-amino-, 3-aryloxy- or 3-alkoxy-6-chloropyridazines and aryl or heteroaryl halides. In vitro antiproliferative activity of these products was evaluated against a representative panel of cancer cell lines (HuH7, CaCo-2, MDA-MB-231, HCT116, PC3, NCI-H727, HaCaT) and oncogenicity prevention of the more efficient derivatives was highlighted on human breast cancer cell line MDA-MB 468-Luc prior establishing their interaction with p44/42 and Akt-dependent signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an important enzyme response for the metabolism or detoxification of toxic aldehydes, in particular acetaldehyde and 4-hydroxynonenal (4-HNE), which were important risk factors for acute alcoholism and stroke respectively. A special variant ALDH2∗2 with reduced enzymatic activity was carried by a high percentage of East Asians, especially Han Chinese, and that could increase the risk of these diseases further. Therefore, ALDH2 activators had important potential clinical values. N -benzylbenzamide compounds represented by Alda-1 were the only ALDH2-specific activators that have been reported so far. In this study, three new classes of compounds were modified from Alda-1 to improve their water-solubility and then drug-like properties. The results showed that all compounds had increased water solubility and two classes of compounds exhibited good activation activity. Among them, compound I-6 showed the best activity. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract As a part of our ongoing research to develop novel URAT1 inhibitors, 19 compounds (1a-1s) based on carboxylic acid bioisosteres were synthesized and tested for in vitro URAT1 inhibitor activity (IC 50). The structure-activity relationship (SAR) exploration led to the discovery of a highly potent novel URAT1 inhibitor 1g , which was 225-fold more potent than the parent lesinurad in vitro (IC 50 = 0.032 μM for 1g against human URAT1 vs 7.20 μM for lesinurad). Besides, 3D-QSAR pharmacophore models were established based on the activity of the compounds (1a-1s) by Accelrys Discovery Studio 2.5/HypoGen. The best hypothesis, Hypo 1, was validated by three methods (cost analysis, Fisher's randomization and leave-one-out). Although compound 1g is among the most potent URAT1 inhibitors currently under development in clinical trials, the Hypo1 appears to be favorable for future lead optimization. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A novel series of fused 1,2,3-triazoles was accessed via an organocatalytic route. • Compounds 14d , 14n , 14q , 18f and 18i are active against coronavirus 229E. • Molecular modelling work flow was developed to identify key molecular interactions. • All active compounds established the key interactions based on molecular modelling. Abstract Synthesis and biological evaluation of a novel library of fused 1,2,3-triazole derivatives are described. The in-house developed multicomponent reaction based on commercially available starting materials was applied and broad biological screening against various viruses was performed, showing promising antiviral properties for compounds 14d , 14n , 14q , 18f and 18i against human coronavirus 229E. Further in silico studies identified the key molecular interactions between those compounds and the 3-chymotrypsin-like protease, which is essential to the intracellular replication of the virus, supporting the hypothesis that the protease is the target molecule of the potential antiviral derivatives. [ABSTRACT FROM AUTHOR]

Some new pyridopyrimidinones derivatives (PPDs) namely (E)-2-(hexadecylthio)-8-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-1,2,3,6,7,8-hexahydro-4H-cyclopenta[5,6] pyrido[2,3-d] pyrimidin 4 -one (Compound I) and (E)-8-(4-methoxybenzylidene)-5-(4-methoxyphenyl) -2-thioxo-1,2,3,6,7,8-hexahydro-4H-cyclopenta [5,6] pyrido [2,3-d] pyrimidin-4-one (Compound II) were synthesized and characterized by IR, 1 H-NMR, 13 C-NMR and mass spectroscopy. The inhibition behavior of these derivatives for the corrosion of API 5L X52 carbon steel in 5% sulfamic acid solutions were considered by various electrochemical methods such as potentiodynamic polarization (PP ), electrochemical impedance spectroscopy (EIS ) and electrochemical frequency modulation ( EFM ) techniques, theoretically by quantum chemical calculations by using DFT method and molecular dynamic simulation (MD) . PP curves presented that the PPDs act as mixed type inhibitors. By increasing PPDs compounds concentrations, the inhibition efficiency increases. The adsorption of PPDs follows Langmuir adsorption isotherm. Excellent agreement was established between the quantum chemical parameters and the experimental data. [ABSTRACT FROM AUTHOR]

• Synthesized 29 compounds containing 9 new skeletons. • 44a and 44b showed the potent inhibitory activity against ASK1, with IC 50 values of 0.15 and 0.31 μM. • The cytotoxicity, flow cytometry cell cycle, oil red O staining, molecular docking, and in silico ADME calculations of them were also carried out. Apoptosis signal regulated kinase 1 (ASK1, also known as MAP3K5) is a member of the mitogen activated protein kinase (MAPK) signaling pathway that participates in cell survival, differentiation, stress responses, and apoptosis. Inhibiting ASK1 is an attractive strategy for treating diseases such as nonalcoholic steatohepatitis and multiple sclerosis. Here, we explored and synthesized a series of new skeleton compounds containing hydrogenated indole, indole, benzimidazole, tetrahydroquinoxaline, benzoxazine, tetrahydroquinoline, phenol, nitrobenzene, pyridine as ASK1 inhibitors. Among them, 44a and 44b containing 2-triazolylpyridine fragment showed the potent inhibitory activity, with IC 50 values of 0.15 and 0.31 μM, respectively. In addition, the cell survival rates of 44a and 44b at different concentrations were greater than 90%, especially at 0.05, 0.1, and 0.8 μM, their cell survival rate is higher than GS-4997 , indicating that they exhibit good safety in human normal liver LO2 cells. The results of flow cytometry showed that 44a and 44b significantly blocked the progression of the G1 phase cycle. Oil red O staining experiments showed that at a concentration of 8 μM for 44a , only slightly swollen cytoplasmic fat droplets were seen in LO2 cells, and there was no significant fusion between the fat droplets. In addition, 44a , as a representative molecule, was used to study the interaction modes with ASK1 protein through molecular docking. These studies and findings provide a good choice for the future development of ASK1 inhibitors. [Display omitted] [ABSTRACT FROM AUTHOR]

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice. Excitingly, 416 effectively overcame ATRA resistance in vitro and in vivo by inducing apoptosis and differentiation. Further mechanistic studies showed that PML/RARα lost the regulation of Bcl-2 and c-Myc in NB4-R1 cells, which probably contributed to ATRA resistance. Notably, 416 maintained its Bcl-2 and c-Myc down-regulation effect in NB4-R1 cells and overcome ATRA resistance by inhibiting DHODH. In conclusion, our study highlights the potential of 416 for APL therapy and overcoming ATRA resistance, supporting the further development of DHODH inhibitors for clinical use in refractory and relapsed APL. [Display omitted] • 416 inhibited the progression of ATRA-sensitive APL in vitro and in vivo. • 416 overcame ATRA resistance in vitro and in vivo. • 416 induced apoptosis and differentiation of NB4 cells by targeting DHODH. • Dysregulation of Bcl-2 and c-Myc by PML/RARα in NB4-R1 cells led to ATRA resistance. • 416 overcame ATRA resistance by downregulating Bcl-2 and c-Myc. [ABSTRACT FROM AUTHOR]

• Syntheses of new Co(II), (C1); Ni(II), (C2); Cu(II), (C3) and Zn(II), (C4) complexes. • Characterization of the new complexes using various physicochemical and analytical techniques. • The free ligand and its metal complexes had been applied as disperse dyes on cotton fabrics. • The free ligand and its metal complexes were in vitro investigated for their antimicrobial activity. • Theoretical studies (DFT and molecular docking) were performed. Four Co(II), (C1); Ni(II), (C2); Cu(II), (C3) and Zn(II), (C4) chelates have been synthesized with 1-(4-((2-amino-5‑methoxy)diazenyl)phenyl)ethanone ligand (L). The produced compounds have been identified by using spectral studies, elemental analysis (C.H.N.O), conductivity and magnetic properties. The produced metal chelates were studied using molar ratio as well as sequences contrast types. Rate of concentration (1 ×10−4 - 3 ×10−4 Mol/L) sequence Beer's law. Compound solutions have been noticed height molar absorptivity. The free of ligand and metal chelates had been applied as disperse dyes on cotton fabrics. Furthermore, the antibacterial activity of the produced compounds against various bacteria had been investigated. For the gained datum, a tetrahedral geometrical structure has been suggested for each primed complex. Molecular docking investigation was carried out to ascertain the inhibitory action of the studied compounds against 1HNJ protein, the target enzyme for the antimicrobial agents. The findings showed that, when compared to other compounds, (C1) has the highest binding affinity. Therefore, these molecules might make good candidates for antimicrobials. The quantum chemical parameters are calculated, and the molecular structure complexes were theoretically optimized. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesized of hexaxaza macroacyclic Schiff base ligand and comlexe. • Characterized the synthesized compounds by elemental analysis, IR, ESI-MS and, NMR spectroscopy and x-ray crystallography of Ni(II) complex. • Investigation of cytotoxicity and antioxidant activities by in vitro. • NBO, HOMO-LUMO studies. A new designed hexaaza Schiff base ligand including the piperazine ring was synthesized by the reaction of 2-(4-(2-aminophenyl)piperazin-1-yl)benzeneamine and pyridine-2-carbaldehyde in a 1:2 ratio and characterized by IR, mass, 13C NMR and 1H NMR spectroscopy. By the direct reaction of the nickel perchlorate with the N 6 ligand (L), in a 1:1 ratio, a novel complex was prepared and characterized by IR and mass spectroscopy as well as by a single crystal x-ray structural analysis, which showed the crystals to be composed of two compounds: [C 28 H 26 N 6 Ni(MeOH)][ClO 4 ] 2 and {[C 28 H 26 N 6 Ni(H 2 O)][ClO 4 ] 2.(H 2 O)} in the ratio 0.85:0.15. In both complexes the nickel is in a distorted octahedral environment coordinated by five nitrogen atoms of the potentially hexadentate ligand with a molecule of MeOH or water occupying the sixth coordination site. The evaluation of anti-cancer activity of the synthesized ligand (L) and the nickel complex was carried out against MCF-7 and AGS cell lines, while the anti-oxidant property was measured using the DPPH method. The binding mode of L to the nickel ion, in the [NiL(MeOH)]2+ cation, was investigated using DFT calculations at the BP86/def2-SVP level of theory. In this super stable complex, the Nickel(II) center adopted a distorted octahedral geometry, while one of the sites was occupied by the methanol as a ligand. The natural bond orbital (NBO) calculations were performed to study the HOMO, LUMO, band gap energies, global descriptors, Wiberg bond indices, atomic charges, polarizabilities as well as charge transfers and related energies. The theoretical and experimental findings are in agreement. [ABSTRACT FROM AUTHOR]

Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing a global public health burden affecting more than 366 million people worldwide. We recently reported the discovery of three series of novel agents showing balanced activity on two metabolic receptors, peroxisome proliferator activated receptor-γ (PPAR-γ) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied on linking the thiazolidinedione head with known GPCR privilege structures. To further investigate this concept, two new scaffolds, the benzhydrol- and indole-based chemotypes, were introduced here in. Our optimization campaign resulted in three compounds; 15a , 15c , and 15d , with affinities in the low micromolar range on both targets. In vivo study of selected test compounds, revealed that 15c possesses a significant anti-hyperglycemic and anti-hyperlipidemic activities superior to rosiglitazone in fat-fed animal models. Molecular docking analysis was conducted to explain the binding modes of both series. These compounds could lead to the development of the unique antidiabetic agent acting as insulin sensitizer as well as insulin secretagogue. [ABSTRACT FROM AUTHOR]

Radiation resistance of nasopharyngeal carcinoma (NPC) is a joint effect caused by complex molecular mechanisms. The development of multi-target radiotherapy sensitization agents offered a promising method for the treatment of NPC. In this work, the probability of Rhein to be a multi-target radiotherapy sensitization agent was explored through computer aid virtual screening by inverse docking study. In order to validate the accuracy of the computational results, radiotherapy sensitization of Rhein to NPC cells and its effects on the expression of target proteins were evaluated separately by CCK8 assay and Western blotting analysis. Our result demonstrated that Rhein possessed strong binding affinity with RAC1 and HSP90. No cytotoxic concentration of Rhein had radiosensitization effect on nasopharyngeal carcinoma CNE1 cells. After treatment with Rhein and 2Gy radiation, the expression of RAC1 upregulated and the expression of HSP90 down-regulated in cells. Based on the above data, Rhein is likely to become an attractive lead compound for the future design of multi-target radiotherapy sensitization agents. [ABSTRACT FROM AUTHOR]

Hydrogel based matrices and titanium dioxide (TiO 2) nanoparticles (NPs) are well established materials in bone tissue engineering. Nevertheless, there is still a challenge to design appropriate composites with enhanced mechanical properties and improved cell growth. Progressing in this direction, we synthesized nanocomposite hydrogels by impregnating TiO 2 NPs in a chitosan and cellulose-based hydrogel matrix containing polyvinyl alcohol (PVA), to enhance the mechanical stability and swelling capacity. Although, TiO 2 has been incorporated into single and double component matrix systems, it has rarely been combined with a tri-component hydrogel matrix system. The doping of NPs was confirmed by Fourier transform infrared spectroscopy, Raman spectroscopy, scanning electron microscopy and small- and wide-angle X-ray scattering. Our results showed that incorporation of TiO 2 NPs improved the tensile properties of the hydrogels significantly. Furthermore, we performed biological evaluation of scaffolds, swelling degree, bioactivity assessment, and hemolytic tests to prove that all types of hydrogels were safe for use in the human body. The culturing of human osteoblast-like cells MG-63 on hydrogels showed better adhesion of cells in the presence of TiO 2 and showed increasing proliferation with increasing amount of TiO 2. Our results showed that the sample with the highest TiO 2 concentration, CS/MC/PVA/TiO 2 (1 %) had the best biological properties. [ABSTRACT FROM AUTHOR]

A cholic acid-conjugated oxaliplatin, LLC-202, is developed as a novel prodrug for liver cancer. The conjugate is obtained by using 3-NH 2 − cyclobutane-1,1-dicarboxylate as a linker between the oxaliplatin analogue and cholic acid moiety and cholic acid is strongly bonded to the linker via an amide bond. Pharmacokinetic experiment shows that LLC-202 is mainly distributed and accumulated in the liver after intravenous administration to Sprague-Dawley rats, revealing the liver-targeting profile. Compared to oxaliplatin, LLC-202 is more easily taken up by human liver cancer cells than normal human liver cells. LLC-202 exhibits higher in vitro anticancer activity and higher efficacy comparable to oxaliplatin in treating primary hepatocellular carcinoma in C57BL/6 mice. It can significantly prolong the survival time of tumor-bearing mice by inducing apoptosis and inhibiting proliferation of cancer cells. In addition, LLC-202 shows less cytotoxicity toward normal human liver cells than oxaliplatin. Its acute toxicity in healthy Kunming (KM) mice after i.v. administration is comparable to oxaliplatin. Histopathological examination reveals that the main toxicity of LLC-202 in mice is the depression of bone marrow hematopoietic cells. The results suggest that LLC-202 has great potential for further development as a new prodrug specific for liver cancer. Synthesis and biological evaluation of cholic acid-conjugated oxaliplatin as a new prodrug for liver cancer. A novel liver cancer targeting oxaliplatin prodrug LLC-202 is synthesized by conjugating cholic acid as targeting carrier, biologically evaluated by cells, mice models, pharmacokinetics and tissue distribution. [Display omitted] • Novel compound LLC-202 obtained by using 3-NH 2 − cyclobutane-1,1-dicarboxylate as a linker between oxaliplatin analogue and cholic acid moiety. • LLC-202 exhibits higher anticancer activity and efficacy comparable to oxaliplatin in treating primary hepatocellular carcinoma in mice. • LLC-202 mainly distributed and accumulated in the liver after intravenous administration. [ABSTRACT FROM AUTHOR]

2-acetylpyridine-4N- p -chlorophenylthiosemicarbazone ligand (HL) derived from the condensation of 2-acetylpyridine and p -chlorophenylthiosemicarbazide (pClT), and the corresponding Cu(II) complex, [Cu(L)Cl] were synthesized and characterized by different spectroscopic methods. Single crystal X-ray study of [Cu(L)Cl] complex displayed a square-planar coordination geometry around Cu(II) ion. The in vitro antibacterial activities of pClT, HL and [Cu(L)Cl] compounds were studied against a series of gram positive and gram negative bacteria, using the zone inhibition methods. Experimental results revealed that the involvement of pyridine cycle in the ligand backbone enhanced the antibacterial activity of the thiosemicarbazone ligand in comparison with its thiosemicarbazide precursor (pClT). In addition, the [CuLCl] complex had higher antibacterial activity than the free ligand. Further, the investigation of antioxidation properties showed that the thiosemicarbazone ligand (HL) and pClT have considerable in vitro radical scavenging activity over the Cu (II) complex, [CuLCl]. [ABSTRACT FROM AUTHOR]

Collagen products will degrade and evoke certain local tissue reaction after being implanted. ISO 10993.6 is the international standard to evaluate local tissue reaction for biomaterials. However, even in the present version, it does not define the specific view fields for scoring local tissue reaction in the sections, which may influence the fair evaluation for the degradable polymer, such as collagen. In this study, 4 kinds of collagens and 2 kinds of bio-inert products were implanted into the rabbit muscle for 26 weeks, and two different scoring methods (uniform distribution scoring method and area locating scoring method) were applied to evaluate the local tissue reaction for each implant. The results showed that the tissue reaction on the interface was active, but the various scores in the implant and surrounding areas could help us to understand the differences of the degradation process. An area locating scoring method which selected the fields in the implant, interface and surroundings respectively showed a higher total score and offered more detailed information compared to the uniform distribution scoring method. Since the degradation and tissue reaction degree in the different areas are ever changing for the degradable implants, this area locating scoring method is sensitive, effective and applicable for the semi-quantitative evaluating system of ISO 10993.6. [ABSTRACT FROM AUTHOR]

Hypericin (Hyp) is a natural photoactive pigment utilized in the treatment of different types of cancer and antimicrobial inactivation using photodynamic therapy (PDT). Hyp is poorly soluble in water leading to problems of administration, getting close contact with the site, and bio-availability. Therefore, this study aimed to develop bioadhesive thermoresponsive system containing Hyp for local PDT. Carbomer 934P, poloxamer 407, and Hyp were used to prepare the thermoresponsive bioadhesive formulations. They were characterized for sol-gel transition temperature, mechanical, mucoadhesive, rheological (continuous flow and oscillatory) and dielectric properties, syringeability, in vitro Hyp release kinetics, ex vivo permeability, and photodynamic activity. The formulations displayed suitable gelation temperature and rheological characteristics. The compressional, mechanical and mucoadhesive properties, as well the syringeability showed the easiness of administration and the permanence of the system adhered to the mucosa or skin. The dielectric analysis helped to understand the Hyp availability, and its release presented an anomalous behavior. The system did not permeate the pig skin nor rat intestine and showed good biological photodynamic activity. Therefore, data obtained from the bioadhesive system indicate a potentially useful role as a platform for local hypericin delivery in PDT, suggesting it is worthy of in vivo evaluation. [ABSTRACT FROM AUTHOR]

5-Methylphenanthridium derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cell division inhibitory activity against various Gram-positive and -negative bacteria. Among them, compounds 5A2 , 5B1 , 5B2 , 5B3 , 5C1 and 5C2 displayed the best on-target antibacterial activity with an MIC value of 4 µg/mL against B. subtilis ATCC9372 and S. pyogenes PS, showing over 2-fold better activity than sanguinarine. The SARs showed that the 5-methylphenanthridium derivatives with the alkyl side chains at the 2-postion, especially the straight alkyl side chains exerted better on-target antibacterial activity. [ABSTRACT FROM AUTHOR]

In this study, we synthesized the series of novel azole derivatives and evaluated for enzyme inhibition assays, corresponding kinetic analysis and molecular modeling. Among the investigated bioassays, the oxadiazole derivatives 4a-k were found potent α-glucosidase inhibitors while the Schiff base derivatives 7a-k exhibited considerable potential toward urease inhibition. The inhibition kinetics for the most active compounds were analyzed by the Lineweaver–Burk plots to investigate the possible binding modes of the synthesized compounds toward the tested proteins. Moreover, the detailed docking studies were performed on the synthesized library of 4a-k and 7a-k to study the molecular interaction and binding mode in the active site of the modeled yeast α-glucosidase and Jack Bean Urease, respectively. It could be inferred from docking results that theoretical studies are in close agreement to that of the experimental results. The structure of one of the compound 7k was characterized by the single crystal X-ray diffraction analysis in order to find out the predominant conformation of the molecules. [ABSTRACT FROM AUTHOR]

The endogenous oxysterol 22( R )-hydroxycholesterol (22RHC, 1 ) is an LXR agonist which upregulates genes of critical involvement in human cholesterol- and lipid metabolism. In contrast, its synthetic epimer 22( S )-hydroxycholesterol (22SHC, 8 ) has shown specific antagonistic effects in recent studies, avoiding unwanted side effects provided by potent LXR agonists. In terms of LXR modulation, the aim of this study was to compare 22SHC ( 8 ), 22RHC ( 1 ) and synthesized ligands with keto- and amide functionality in the 22nd position of the cholesterol scaffold. 22SHC ( 8 ) and 22RHC ( 1 ) performed as expected while 22-ketocholesterol (22KC, 10) revealed an attractive in vitro profile for further investigation in terms of anti-atherosclerotic properties as selective upregulation of the ATP-binding cassette transporter ABCA1 was observed. A new synthesized amide derivate, Fernholtz cyclohexylamide ( 13 ) was shown to reduce lipogenesis in a dose-responsive manner and abolish the effect of the potent LXR agonist T0901317 when administered simultaneously. [ABSTRACT FROM AUTHOR]

Citronellyl- and solanesyl-based dolichol linked oligosaccharide (DLO) analogs were synthesized and tested along with undecaprenyl compounds for their ability to inhibit the release of [ 3 H]OSP from [ 3 H]DLO by mammalian liver DLO diphosphatase activity. Solanesyl (C45) and undecaprenyl (C55) compounds were 50–500 fold more potent than their citronellyl (C10)-based counterparts, indicating that the alkyl chain length is important for activity. The relative potency of the compounds within the citronellyl series was different to that of the solanesyl series with citronellyl diphosphate being 2 and 3 fold more potent than citronellyl-PP-Glc N Ac 2 and citronellyl-PP-Glc N Ac, respectively; whereas solanesyl-PP-Glc N Ac and solanesyl-PP-Glc N Ac 2 were 4 and 8 fold more potent, respectively, than solanesyl diphosphate. Undecaprenyl-PP-Glc N Ac and bacterial Lipid II were 8 fold more potent than undecaprenyl diphosphate at inhibiting the DLODP assay. Therefore, at least for the more hydrophobic compounds, diphosphodiesters are more potent inhibitors of the DLODP assay than diphosphomonoesters. These results suggest that DLO rather than dolichyl diphosphate might be a preferred substrate for the DLODP activity. [ABSTRACT FROM AUTHOR]

Liver X Receptor (LXR) modulators have shown potential as drugs since they target genes affecting metabolism and fatty acid synthesis. LXR antagonists are of particular interest since they are able to reduce the synthesis of complex fatty acids and glucose uptake. Based on molecular modeling, five new cholesterol mimics were synthesized, where four contained a hydroxyl group in the 22-S-position. The new compounds were screened in vitro against several genes affecting lipid metabolism. The compound that performed best in vitro was a dimethylamide derivative of 22( S )-hydroxycholesterol and it was chosen for in vivo testing. However, the blood plasma analysis from the in vivo tests revealed a concentration lower than needed to give any response, indicating either rapid metabolism or low bioavailability. [ABSTRACT FROM AUTHOR]

99m Tc–tricarbonyl–vardenafil was specifically radiosynthesized for diagnostic evaluation of erectile dysfunction with a radiochemical yield ~97.2%. It was stable in saline up to 15 h and in serum for more than 6 h. The radiocomplex was lipophilic with a partition coefficient ~1.32 and plasma protein binding 72–76%. Its structure was determined using molecular mechanics and confirmed by NMR. In-silico docking to its target PDE 5 enzyme was performed. The radiocomplex inhibitory activity was assessed and its IC 50 was 0.7 nM. Biodistribution in normal rats and biological evaluation in rat models of erectile dysfunction were performed. The results strongly suggested that 99m Tc–tricarbonyl–vardenafil is a good candidate to image erectile dysfunction in humans. [ABSTRACT FROM AUTHOR]

Fifteen stereoisomers of boswellic acid analogues bearing 2-OH, 24-OH, 3-keto or 2-OH, 3-OH, 24-OH groups were synthesised and their structures were confirmed using 1 H NMR, 13 C NMR, 2D NMR and HRMS. The cytotoxic activities of these compounds toward three human tumor cell lines, K562, PC3 and A549, were evaluated. Preliminary biological evaluation indicated most of these compounds exhibited cytotoxic activity comparable to that of 3- O -acetyl-11-keto-β-boswellic acid (AKBA). Notably, several analogues exhibited relatively stronger cytotoxicity, with IC 50 values less than 10 μM against A549 and PC3 cell lines. For the 24-OH series of BAs analogues, structure-activity relationship (SAR) analysis indicated that the stereochemical configurations of compounds incorporating 2-OH, 3-keto or 2-OH, 3-OH group pairs could not predictably or markedly impact cytotoxic activity, except when 2β-OH and/or 3β-OH were present. Esterification of 2-OH, 3-OH and 24-OH groups tended to decrease cytotoxicity. [ABSTRACT FROM AUTHOR]

• Synthesis of 2-((3-phenylisoxazol-5-yl) methoxy) benzamide derivatives. • Not all chlorination on phenyl ring in benzaldehyde oximes with electronic donator following Friedel - Crafts substitution. • Excellent inhibiting HBV than 3TC. A series of 2-((3-phenylisoxazol-5-yl) methoxy) benzamides derivatives were designed and synthesized, and their anti-hepatitis B virus (HBV) activities were evaluated with HepG2.2.15 cells. The results showed that compounds 10a, 10c, 10d and 10f strongly inhibited secretion of HBeAg (IC 50 = 0.20, 0.07, 0.30 and 0.12 μM, respectively, 3TC in 119.87 μM). Compounds 8a, 8b, 10c, 10f effectively inhibited HBV DNA replication with IC 50 in 7.61, 8.92, 0.10 and 1.49 μM, respectively and were more effective than 3TC (IC 50(DNA) = 13.02 μM). Result of docking studies indicated that compounds interacted to HBV core protein and coincided to their inhibitions on HBV. This work provided new compounds with significant inhibition on HBV for further optimization and development as potential non-nucleoside anti-virus agents. Meanwhile, chlorination on phenyl ring of dimethoxybenzaldehyde oxime occurred and did not follow Friedel - Crafts substitution when the oxime reacted with excess NCS. [Display omitted] [ABSTRACT FROM AUTHOR]

( d )-Glucosamine and other nutritional supplements have emerged as safe alternative therapies for osteoarthritis, a chronic and degenerative articular joint disease. N -acetyl-( d )-glucosamine, a compound that can be modified at the N position, is considered to improve the oral bioavailability of ( d )-glucosamine and has been proven to possess greater in vitro chondroprotective activity compared with the parent agent. In this study, to further utilize these properties, we focus on the modification of the N position with a benzenesulfonyl and different isoxazole formyl groups. Among these compounds, the 3-(2-chlorobenzene)-5-methyl-isoxazole formyl chloride and p -methoxybenzenesulfonyl chloride modifying structures proved to be the most active of the series and efficiently processed the chondrocytes in vitro. These novel N -position substitution compounds may represent promising leads for osteoarthritis drug development. [ABSTRACT FROM AUTHOR]

With an intention to find more potent antibacterial agents, four halogen disubstituted thiazolineone derivatives ( 2a – d ), five halogen monosubstituted thiazolineone derivatives ( 2e – i ), and eleven 2-arylimino-3-pyridin-thiazolineone derivatives ( 2j – t ) were synthesized and screened for their antibacterial activity, bactericidal activity, cytotoxicity, and erythrocyte hemolysis. Most of the synthesized derivatives showed antibacterial activity in inhibiting the growth of S. epidermidis and MRSA, and exhibited safety in the cytotoxicity study on the Vero cells and hemolytic activities test on healthy human erythrocytes. 2-Arylimino-3-pyridin-thiazolineone derivatives not only improved the c log P , but also showed potent antibacterial activity in inhibiting the growth of S. epidermidis and MRSA. In particularly, several compounds ( 2f , 2i , 2r and 2t ) showed bactericidal activity, in which compound 2r displayed the best inhibitory capacity among the synthesized compounds, and further druggability research is on going. [ABSTRACT FROM AUTHOR]

In this study, we disclose the design and synthesis of novel 4-susbtituted nipecotic acid derivatives as inhibitors of the GABA transporter mGAT1. Based on molecular modeling studies the compounds are assumed to adopt a binding pose similar to that of the potent mGAT1 inhibitor nipecotic acid. As substitution in 4-position should not cause an energetically unfavorable orientation of nipecotic acid as it is the case for N -substituted derivatives this is expected to lead to highly potent binders. For the synthesis of novel 4-substituted nipecotic acid derivatives a linear synthetic strategy was employed. As a key step, palladium catalyzed cross coupling reactions were used to attach the required biaryl moieties to the ω-position of the alkenyl- or alkynyl spacers of varying length in the 4-position of the nipecotic acid scaffold. The resulting amino acids were characterized with respect to their binding affinities and inhibitory potencies at mGAT1. Though the biological activities found were generally insignificant to poor, two compounds, one of which possesses a reasonable binding affinity for mGAT1, rac - 57 , the other a notable inhibitory potency at mGAT4, rac - 84 , both displaying a slight subtype selectivity for the individual transporters, could be identified. [ABSTRACT FROM AUTHOR]

A series of novel morpholinoquinoline based conjugates with pyrazoline moiety were synthesized under microwave irradiation. The newly synthesized compounds were screened for their preliminary in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, antituberculosis activity against Mycobacterium tuberculosis H 37 Rv and antimalarial activity against Plasmodium falciparum . Most of them exhibited significant antibacterial activity as compared to the first line drugs. Compounds 6a and 9d were found to possess excellent antibacterial activity potency as compared to ampicillin (286 μM), chloramphenicol (154 μM) and ciprofloxacin (150 μM). In antifungal screening, against Candida albicans , compounds 6c , 7c , 8a , 8b , 8c and 9b showed significant activity as compared to griseofulvin (1147 μM). Compounds 8b , 6b , 9d, 6a, 9b , 7b and 8a displayed brilliant activity against P. falciparum strain as compared to chloroquine (IC 50 0.062 μM) as well as quinine (IC 50 0.826 μM). Compounds 6d , 7b , 8b , 9c and 9d exhibited superior antitubercular activity. Among them 8b was found to be equipotent to rifampicin with 95% inhibition. The cytotoxicity of the synthesized compounds was tested using bioassay of Schizosaccharomyces pombe cells at cellular level. [ABSTRACT FROM AUTHOR]

[Display omitted] A series of pyrazolo[3,4- d ]pyrimidin-4-one scaffold were designed and synthesized as novel CDK2 inhibitors. By analyzing the common motifs of various known inhibitors, the designed compounds 1 were virtually screen for their inhibitory activity by docking into the active pocket of CDK2. The influence of different substitutes on the docking results was investigated. A total of 15 pyrazolo[3,4- d ]pyrimidin-4-ones 1 were synthesized by Paal-Knorr reaction, pyrimidine ring closure, bromination, Suzuki coupling reaction, amide formation and Knoevenagel condensation. The Cell Counting Kit-8 (CCK-8) was used to evaluate the inhibitory activity of pyrazolo[3,4- d ]pyrimidin-4-ones 1 in the breast cancer cell line MCF-7 in vitro using Etoposide as a reference control substance. The screening results demonstrated that the designed compounds have significant antiproliferative activity, and compounds 1e and 1j were the most active compounds with IC 50 values of 10.79 μM and 10.88 μM, respectively, being better than that of Etoposide (IC 50 = 18.75 μM). The enzyme inhibition assay was carried out against CDK2, the results indicated that the compounds 1e and 1j significantly inhibited CDK2 with IC 50 values of 1.71 μM and 1.60 μM. [ABSTRACT FROM AUTHOR]

Stigmatellin A, a natural product with a chromone ring structure, is a specific inhibitor of the mitochondrial respiratory chain cytochrome bc 1 complex at the Q o site. In the last two decades, researchers have carried out extensive and in-depth organic synthesis studies and biological evaluations of this molecule. Herein, we review the recent progress on the synthesis and structural modification of stigmatellin A and its application in fungicide discovery. This review is expected to provide valuable clues for the synthesis of natural products that contain the chromone motif. Stigmatellin A, a natural product bearing a chromone moiety as the core skeleton, has been identified as a representative inhibitor that binds to the Q o site of the cytochrome bc 1 complex. Due to its unique structure and diverse biological activities, numerous researchers have conducted systematic and extensive investigations. This paper mainly described the development and biological activities of stigmatellin A, and then summarized the recent results of its synthesis and structural modifications. [Display omitted] [ABSTRACT FROM AUTHOR]

All-trans-retinoic acid (ATRA) as a physiological metabolite of vitamin A is widely applied in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. CYP26A1 enzyme, induced by ATRA in liver and target tissues, metabolizes ATRA into 4-hydroxyl-RA. Inhibition of CYP26A1 metabolic enzyme represents a promising strategy for discovery of new specific anticancer agents. Herein, we describe the design, synthesis and biological evaluation of a series of new amide imidazole derivatives as retinoic acid metabolism blocking agents (RAMBAs) toward CYP26A1 enzyme. First, based on the recent theoretical models (Sun et al., J. Mol. Graph. Model. , 2015 , 56 , 10–19) a series of RAMBAs with novel scaffolds were designed using fragment-based drug discovery approach. Subsequently, the new RAMBAs were synthesized and evaluated for their biological activities. All the compounds demonstrated appropriate enzyme activities and cell activities. The promising inhibitors 20 and 23 with IC 50 value of 0.22 μM and 0.46 μM toward CYP26A1, respectively, were further evaluated for CYP selectivity and the metabolic profile of ATRA. Both compounds 20 and 23 showed higher selectivity for CYP26A1 over other CYPs (CYP2D6, CYP3A4) when compared to liarozole. They also showed better inhibitory activities for the metabolism of ATRA when also compared to liarozole. These studies further validated the pharmacophore and structure–activity relationship models obtained about CYP26A1 inhibitors and highlighted the promising activities of the new series of CYP26A1 inhibitors designed from such models. They also paved the way for future development of those candidates as potential drugs. [ABSTRACT FROM AUTHOR]

Objective This study was designed to evaluate the biocompatibility and osteointegrative activity of hydroxyapatite (HA)-CaTiO 3 , titanium substrate, traditional HA coating and CaTiO 3 coating via an animal experiment. Method Four types of screws (type 1: coated with HA; type 2: coated with CaTiO 3 ; type 3: coated with HA-CaTiO 3 ; type 4: untreated titanium screws) were implanted into femur bone of 48 New Zealand rabbits. Histological and mechanical investigations were employed at the end of 2, 4, 8 and 12 weeks to evaluate the material osteointegration. Results (1) All of the experimental rabbits were healthy during the experiment process. (2) Histological investigation showed fully regenerated and well integrated bone tissue surrounding the screws coated with HA, HA-CaTiO 3 and CaTiO 3 . (3) Mechanical investigation showed that the bonding strength of HA-CaTiO 3 coating was significantly higher than that of CaTiO 3 coating or titanium materials without coating, but was lower than those coated with HA. Conclusion HA-CaTiO 3 coating possesses similar admirable biocompatibility and osteointegration activity with HA coating, indicating a promising coating material for implants in orthopedics. [ABSTRACT FROM AUTHOR]

Two novel coordination polymer {[Cu(Cip)]·2H 2 O} n ( 1 ) and {[Cu 2 (Cip) 2 ClO 4 (CH 3 OH)]·0.5H 2 O} n ( 2 ) (HCip = ciprofloxacin, Cip = deprotonated ciprofloxacin) have been synthesized and characterized by elemental analysis, infrared spectra and single-crystal X-ray diffraction. Both complexes 1 and 2 exhibit good binding propensity to human or bovine serum albumin protein (HSA or BSA) with relatively high binding constant values. UV and circular dichroism (CD) spectroscopies studies of the interaction of ciprofloxacin and its complexes with calf-thymus DNA (CT DNA) show that complex 2 exhibits higher binding constant to CT DNA ( K b = 3.32 × 10 6 ) and the results indicate they interact with DNA mainly via intercalation. Fluorescence competitive studies with ethidium bromide (EB) reveal that the complexes could compete with EB and displace it to bind to DNA using the intercalative binding site. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) are zinc-dependent or NAD + dependent enzymes and play a critical role in the process of tumor development. Herein a series of indoline-2,3-dione derivatives have been designed and synthesized as potential HDACs inhibitors. The preliminary biological evaluation showed that most compounds synthesized have exhibited moderate Hela cell nuclear extract inhibitory activities, among which compound 25a (IC 50 = 10.13 nM) has shown the best efficacy. The anti-proliferative activities of some of these compounds were also discussed. [ABSTRACT FROM AUTHOR]

HSP70 is a potential target for tumour treatment. HSP70 plays significant roles in several biological processes, including the regulation of apoptosis. In this study, piperidine derivatives were designed as novel HSP70 inhibitors based on virtual fragment screening performed in Dock 4.0, Discovery Studio 2.5 and SYBYL 6.9. A total of 67 novel piperidine derivatives were synthesized. Cell viability assays were performed in 16 cancer cell lines. The emphasis was placed on lapatinib-resistant breast cancer cells (BT/Lap R 1.0, MDA-MB-361, SK/Lap R 1.0, and MDA-MB-453). The compounds HSP70-36/37/40/43/46 significantly inhibited the proliferation of human breast cancer cells. Compound HSP70-36 inhibited the growth of BT474 and BT/Lap R 1.0 cells with IC 50 values of 1.41 μM and 1.47 μM, respectively. The binding affinity of HSP70-36/HSP70 was evaluated by surface plasmon resonance and yielded K d values of 2.46 μM. The LD 50 was 869.0 mgkg −1 . These data suggest that HSP70-36 may be a potential candidate compound for tumour treatment. [ABSTRACT FROM AUTHOR]

The grafting of galactose units onto poly(ε-caprolactone) (PCL) substrates by a wet chemistry two-step procedure is proposed. Even though a reduction of hardness from 0.58–0.31 GPa to 0.12–0.05 GPa is achieved, the chemical functionalization does not negatively affect the tensile modulus (332.2 ± 31.3 MPa and 328.5 ± 34.7 MPa for unmodified and surface-modified PCL, respectively) and strength (15.1 ± 1.3 MPa and 14.8 ± 1.5 MPa as assessed before and after the surface modification, respectively), as well as the mechanical behaviour evaluated through small punch test. XPS and enzyme-linked lectin assay (ELLA) demonstrate the presence, and also the correct exposition of the saccharidic epitope on PCL substrates. The introduction of carbohydrate moieties on the PCL surfaces clearly enhances the hydrophilicity of the substrate, as the water contact angle decreases from 82.1 ± 5.8° to 62.1 ± 4.2°. Furthermore, preliminary biological analysis shows human mesenchymal stem cell viability over time and an improvement of cell adhesion and spreading. [ABSTRACT FROM AUTHOR]

A new ferrocene containing poly(azomethine)ester (PFe) was synthesized by polycondensation of a preformed 4-((2-(4hydroxybenzylideneamino)ethylimino)methyl)phenol, (SB) and 1,1′-ferrocenyl dicarbonyl chloride. Various aliphatic and aromatic sequences (1,3-propan-diol, 1,6-hexan-diol, poly(dimethylsiloxane), hydroxyl-terminated (n = 550)), (1,1,1,3,3,3-hexaflouro)bisphenol propane and bisphenol A) were incorporated in the parent chain to synthesize respective terpolymers. Spectroscopic and elemental data were used to study structure of the prepared material which was then screened for antibacterial, brine shrimp cytotoxic, free radical induced oxidative DNA damage and DPPH free radical scavenging activity. Among all, PFeF showed growth inhibition of Staphylococcus aureus , Micrococcus luteus , Bordetella bronchiseptica and Salmonella typhimurium . In brine shrimp cytotoxicity assay PFeF and PFePr exhibited LD 50 < 1 ppm showing highly cytotoxic behavior. Schiff base monomer (SB) significantly inhibited the tumor (36.02%) and revealed higher radical scavenging activity (IC 50 13.65 ppm) than polymers. In general, all polymers (PAMEs) had good antioxidant and DNA protecting behavior. Molecular docking and QSAR studies carried to investigate the interactions between polymers and double stranded DNA showed good correlation of binding strength and activity of the material. The binding constant (K b ) is indicative of the binding strength of the material with DNA. The high value of K b implied that respective drugs bind to DNA most strongly. [ABSTRACT FROM AUTHOR]

Novel Schiff’s base ligand, benzil bis(5-amino-1,3,4-thiadiazole-2-thiol) was synthesized by the condensation of benzil and 5-amino-1,3,4-thiadiazole-2-thiol in 1:2 ratio. The structure of ligand was determined on the basis of elemental analyses, IR, 1 H NMR, mass, and molecular modeling studies. Synthesized ligand behaved as tetradentate and coordinated to metal ion through sulfur atoms of thiol ring and nitrogen atoms of imine group. Ni(II), and Cu(II) complexes were synthesized with this nitrogen–sulfur donor (N 2 S 2 ) ligand. Metal complexes were characterized by elemental analyses, molar conductance, magnetic susceptibility measurements, IR, electronic spectra, EPR, thermal, and molecular modeling studies. All the complexes showed molar conductance corresponding to non-electrolytic nature, expect [Ni(L)](NO 3 ) 2 complex, which was 1:2 electrolyte in nature. [Cu(L)(SO 4 )] complex may possessed square pyramidal geometry, [Ni(L)](NO 3 ) 2 complex tetrahedral and rest of the complexes six coordinated octahedral/tetragonal geometry. Newly synthesized ligand and its metal complexes were examined against the opportunistic pathogens. Results suggested that metal complexes were more biological sensitive than free ligand. [ABSTRACT FROM AUTHOR]

A series of several new isoniazid derivatives, isonicotinic acid 2-(2-hydroxy-8-substituted-tricyclo[7.3.1.0 2.7 ]tridec-13-ylidene)-hydrazides, were synthesized and fully characterized. These new isoniazid derivatives were studied regarding their antibacterial activity and cytotoxicity, as well as their influences on some metabolizing enzymes. The best anti-mycobacterial activity was observed in the case of compounds containing alkyl side chains in the 8 position of tricyclo[7.3.1.0 2.7 ]tridec-13-ylidene group. On contrary, the antimicrobial activity of these new compounds against various non-tuberculosis strains showed the best activity to be with the phenyl side chain of compound 6 . It proved also to be the most toxic, inducing apoptosis and blocking the cell cycle in G0/G1 phase. The cell cycle was blocked in G0/G1 phase also by compound 3 , but this compound did not show any toxicity. All compounds induced the expression of NAT1 and NAT2 genes in HT-29 cell line, and the expression of CYP1A1 in HT-29 and HCT-8 cell lines. The expression level of CYP3A4 was increased by compounds 1 , 6 and 7 in HCT-8 cells. These results indicated that the activation of other metabolizing pathways, apart from those of isoniazid, take place. It might also point out the possibility of an increased isoniazid acetylation ratio by co-administration with new compounds in slow acetylators. [ABSTRACT FROM AUTHOR]