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In this work, a fluorescent probe, TPABF-HS, was developed for detecting hydrogen sulfide (H2S) using a human serum albumin (HSA)-binding-based approach for amplifying the fluorescence signal and extending the linear correlation range. Compared to the most recent probes for H2S, the most interesting feature of the detection system developed herein was the especially wide linear range (0–1000 μM (0–100 eq.)), which covered the physiological and pathological levels of H2S. TPABF-HS could be used in applications high sensitivity and selectivity with an LOD value of 0.42 μM. Further, site-competition experiments and molecular docking simulation experiments indicated that signal amplification was realized by the binding of the TPABF fluorophore to the naproxen-binding site of HSA. Moreover, the extension of the measurement span could allow for applications in living cells and Caenorhabditis elegans for imaging both exogenous and endogenous H2S. This work brings new information to the strategy of signal processing by exploiting fluorescent probes. [ABSTRACT FROM AUTHOR]

A series of novel indole‐1,2,4‐triazole derivatives have been designed, synthesized, and evaluated as potential tubulin polymerization inhibitors. The top hit 12, bearing the 3,4,5‐trimethoxyphenyl moiety, exhibited substantial anti‐proliferative activity against HepG2, HeLa, MCF‐7, and A549 cells in vitro with IC50 values of 0.23 ± 0.08 μM, 0.15 ± 0.18 μM, 0.38 ± 0.12 μM, and 0.30 ± 0.13 μM, respectively. It also inhibited tubulin polymerization with the IC50 value of 2.1 ± 0.12 μM, which was comparable with that of the positive controls. Furthermore, compound 12 regulated the expression of cell cycle‐related proteins (Cyclin B1, Cdc25c, and Cdc2) and apoptosis‐related proteins (Bcl‐2, Bcl‐x, and Mcl‐1). Mechanistically, compound 12 could arrest cell cycle at the G2/M phase, thus induce an increase of apoptotic cell death. In addition, molecular docking hinted the possible interaction mode of compound 12 into the colchicine binding site of tubulin heterodimers. According to the applications of microtubule‐targeting agents in both direct and synergistic cancer therapies, we hope this work might be of significance for future researches. [ABSTRACT FROM AUTHOR]

Several novel cycloalkyl‐fused 2,3‐diaryl pyrazole derivatives were designed, synthesized, and evaluated as potential anti‐tubulin agents. Compound A10 exhibited the most potent antiproliferative activity against a panel of cancer lines (IC50 = 0.78–2.42 μM) and low cytotoxicity against 293T & L02 (CC50 values of 131.74 and 174.89 μM, respectively). Moreover, A10 displayed inhibition of tubulin polymerization in vitro, arrested the G2/M phase of the cell cycle, changed morphology of tubulin, increased intracellular reactive oxygen species, and induced apoptosis of HeLa cells. Docking simulation and 3D‐QSAR models were performed to elaborate on the anti‐tubulin mechanism of the derivatives. The inhibition of monoclonal colony formation provided more intuitional data to verify the possibility of A10 as a novel tubulin assembling inhibitor. [ABSTRACT FROM AUTHOR]

A series of new 1-phenylsulphonyl-2-(1-methylindol-3-yl)-benzimidazole derivatives were designed, synthesized and evaluated as potential inhibitors of tubulin polymerization and anthropic cancer cell lines. Among them, compound 33 displayed the most potent tubulin polymerization inhibitory activity in vitro ( IC50 = 1.41 μM) and strong antiproliferative activities against A549, Hela, HepG2 and MCF-7 cell lines in vitro with GI50 value of 1.6, 2.7, 2.9 and 4.3 μM, respectively, comparable with the positive control colchicine ( GI50 value of 4.1, 7.2, 9.5 and 14.5 μM, respectively) and CA-4 ( GI50 value of 2.2, 4.3, 6.4 and 11.4 μM, respectively). Simultaneously, we evaluated that compound 33 could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Immunofluorescence microscopy also clearly indicated compound 33 a potent antimicrotubule agent. Docking simulation showed that compound 33 could bind tightly with the colchicine-binding site and act as a tubulin inhibitor. Three-dimensional- QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin assembling inhibitory activity in the future. [ABSTRACT FROM AUTHOR]

New series of chrysin derivatives ( 4a- 4t) were designed and synthesized by introducing different substituted piperazines at C-7 position. Their inhibitory effects on FabH were evaluated using two Gram-negative bacterial strains, Escherichia coli and Pseudomonas aeruginosa, and two Gram-positive bacterial strains, Bacillus subtilis and Staphylococcus aureus. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with the control positive drugs. Among them, compound 4s exhibited the most potent inhibitory activity with IC50 values of 5.78 ± 0.24 μ m inhibiting E. coli FabH and potent antibacterial activity against S. aureus and E. coli with MIC of 1.25 ± 0.01, 1.15 ± 0.12 μg/mL, respectively, comparing to the control positive drugs penicillin G (7.56 ± 0.30 μ m). Docking simulation was performed to position compound 4s into the FabH active site, and the result showed that compound 4s could bind well with the FabH as potent FabH inhibitor. [ABSTRACT FROM AUTHOR]

[CoIII(L1)2·H2O]NO3(1), [MnII(L1)2·H2O] (2), and [ZnII(L1)2·H2O] (3) with a hydrazone derived from protocatechuic acid (HL1 = C15H13N3O3) were designed, synthesized, and characterized by C, H, N elemental analyses, single-crystal X-ray diffraction, and IR spectra, which revealed that the three complexes are similar structures. Docking study has been done. The urease inhibitory activities of the three complexes were tested. Complexes1and3showed strong inhibitory activity againstjack beanurease with IC50values of 45.9 and 11.64 μM. Complex2had no obvious inhibitory activity to urease; the IC50was > 50 μM. [ABSTRACT FROM AUTHOR]

In this study, we synthesized a series of dihydropyrazole sulfonamide derivatives containing 2-hydroxyphenyl moiety as antitumor agents to target the matrix metalloproteinase-2 (MMP-2). All of the synthesized compounds were examined by bioactivity assays, in which compound 4c turned out as a potential antagonist of MMP-2 along with potent anticancer activity against four tumor cell lines. Structure-activity relationship analysis was also performed to examine how structural changes impacted the bioactivity. Suggested to be caused by the induction of apoptosis, the antitumor mechanism of 4c was further confirmed by PI combining with annexin V-FITC staining assay using flow cytometry analysis. These new findings along with molecular docking observations suggested that compound 4c could be developed as a potential anticancer agent. [ABSTRACT FROM AUTHOR]

VEGFR2 has been proved to play a major role in the regulation of tumor angiogenesis. Twenty-one 4-alkoxyquinazoline-based derivatives have been designed and synthesized as vascular endothelial growth factor receptor 2 ( VEGFR2) inhibitors, and their biological activities were evaluated. Among these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC50 values of 2.89 n m (for VEGFR2) and 0.25 μ m (for MCF-7), which were comparable with the control compound. Docking simulation was performed to position compound 3h into the 4 ASE active site, and the result showed that compound 3h could bind well at the 4 ASE active site. [ABSTRACT FROM AUTHOR]

Interference with dynamic equilibrium of microtubule-tubulin has proven to be a useful tactics in the clinic. Based on investigation into the structure-activity relationship ( SAR) studies of tubulin polymerization inhibitors obtained from several worldwide groups, we attempted to design 691 compounds covering several main heterocyclic scaffolds as novel colchicine-site inhibitors ( CSIs). Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D- QSAR, and pharmacophore model, we can obtain the ultimate 16 target compounds derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A-132 with in silico moderate activity was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay. In additional, the work of synthesis and validation of biological activity for other 15 various structure compounds will be completed in our laboratory. This study not only developed a hierarchical strategy to screen novel tubulin inhibitors effectively, but also widened the spectrum of chemical structures of canonical CSIs. [ABSTRACT FROM AUTHOR]

Four novel complexes, [Cu( L)2(NH3)2(H2O)2] ( 1), {[Cu( L)2(H2O)2] ·2H2O} n ( 2), {[Zn( L)2(H2O)2] ·2H2O} n ( 3), and {[Fe( L)2(H2O)2] ·2H2O} n ( 4) (H L = 2-{[4-amino-3-(pyridin-4-yl)-4,5-dihydro-1 H-1,2,4-triazol-5-yl]thio}acetic acid) were synthesized and characterized by single-crystal X-ray diffraction analysis. Complex 1 exhibited a mononuclear structure. Complexes 2, 3, and 4 featured 2D networks. The crystal structures were stabilized by intermolecular hydrogen bonds to generate 3D supramolecular frameworks. The inhibitory activity was tested in vitro against jack bean urease. Among the four complexes, the two CuII complexes 1 and 2 exhibited better inhibitory activity than the positive reference acetohydroxamic acid, with IC50 values of 4.052 and 6.868 μ M, respectively, whereas the ZnII and FeII complexes showed no activity. To explore the mechanism of inhibition of the enzyme, kinetics studies were carried out; the results indicated that both the activated complexes 1 and 2 operated through a mixed-competitive inhibitory mechanism. Molecular docking was used to insert the most active complex 1 into the crystal structure of jack bean urease at the active site to determine the probable mode of binding. [ABSTRACT FROM AUTHOR]

Two dinuclear Co(II) complexes, [Co2(L)2(EtOH)4]·4ClO4(1) and [Co2(L)2(H2O)2(NO3)2]·2NO3(2) (L = 4-amino-3,5-bis(pyridin-2-yl)-1,2,4-triazole), have been obtained and characterized by IR, elemental analysis, and single-crystal X-ray diffraction analysis. The stabilization of their crystal lattices is maintained by strong H-bonds between counterions and host framework, which lead to various supramolecular architectures. The urease inhibitory properties of1,2, andLwere investigated, where the two complexes revealed strong urease inhibition activities. Docking simulations of2have been performed with H. pylori urease (PDB code: 1E9Z) to rationalize their binding models. [ABSTRACT FROM AUTHOR]

Two mononuclear copper(II) complexes, [Cu(C15H16NO2)2] ( 1) and [Cu(C6H9N2O4)2·3H2O] ( 2·3H2O), were synthesised and structurally characterised by single-crystal X-ray analysis. The copper(II) atom adopts a square-planar environment in complex 1, while the geometry in 2·3H2O could be described as the distorted square pyramidal. Complexes 1 and 2·3H2O were evaluated for their inhibitory activities against Helicobacter pylori ( H. pylori) urease in vitro. They both were found to have strong inhibitory activities against H. pylori urease comparable to that of acetohydroxamic acid (AHA). A docking simulation was performed to position 2 into the H. pylori urease active site to determine the probable binding conformation. [ABSTRACT FROM AUTHOR]

A Schiff-base copper(II) complex, bis(N-n-butylsalicylaldiminato)copper(II), was synthesized and its solid-state structure was determined by X-ray crystallography. Its inhibitory activity against Helicobacter pylori urease was evaluated in vitro and it showed strong inhibitory activity against urease (IC50 = 0.95 µM), compared with acetohydroxamic acid (IC50 = 42.47 µM) as a positive reference. A docking analysis using the AUTODOCK 4.0 program was performed to explain the potent inhibitory activity of the complex against urease. [ABSTRACT FROM AUTHOR]

A Ni(II) Schiff-base complex, Ni(C14H10NOBr2)2, was synthesized and structurally characterized by single-crystal X-ray analysis. Its inhibitory activity against Helicobacter pylori urease was evaluated in vitro and showed strong inhibitory activity against H. pylori urease compared with acetohydroxamic acid (IC50 = 42.12 µmol L-1), which is a positive reference. A docking analysis using the autodock 4.0 program could explain the inhibitory activity of the complex against urease. [ABSTRACT FROM AUTHOR]

Graphical abstract Effect of compound 30 on cell cycle progression of A549 cells and G2/M-related proteins; 3D diagram of the interaction between compound 30 and the colchicine binding site. A series of novel benzimidazole grafted benzsulfamide-containing pyrazole ring derivatives were designed, synthesized and evaluated for the inhibitory activity against tubulin polymerization and cancer cells. Also the docking simulation of these compounds was conducted. Highlights • 25 novel benzimidazole grafted benzsulfamide-containing pyrazole ring derivatives have been synthesized. • Their biological activities were evaluated as potential tubulin assembling inhibitors. • Compound 30 showed the most potent inhibitory activity against cancer cell and tubulin. • Crystal structure of compounds 20 and 24 were determined. Abstract Tubulin-targeting drugs have increasingly become the focus of anticancer drugs research. Twenty-five novel benzimidazole grafted benzsulfamide-containing pyrazole ring derivatives were synthesized and evaluated for bioactivity as potential tubulin polymerization inhibitors. Among them, compound 30 showed the most excellent inhibition against tubulin assembly (IC 50 = 1.52 μ M) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC 50 = 0.15, 0.21, 0.33 and 0.17 μ M, respectively for A549, Hela, HepG2 and MCF-7). It could also validly induce A549 cell apoptosis, cause cell cycle arrest in G2/M phase and disrupt the cellular microtubule network. These results, along with molecular docking data, provided an important basis for further optimization of compound 30 as a potential anticancer agent. [ABSTRACT FROM AUTHOR]

• 26 novel thiazole hydrazone derivatives grafted with indole have been synthesized. • Their biological activities were evaluated as potential tubulin assembling inhibitors. • Compound D11 exhibited the most potent inhibitory activity against cancer cell and tubulin. Tubulin-targeting drugs have increasingly become the focus of anticancer drugs research. Twenty-six novel thiazole hydrazone derivatives grafted with indole were synthesized and estimated for bioactivity as potential tubulin polymerization inhibitors. Among them, compound D11 showed the most excellent inhibition against tubulin assembly (IC 50 = 1.68 μ M) and in vitro growth inhibitory activity against three human cancer cell lines (IC 50 = 0.46, 0.21 and 0.32 μ M, respectively for MCF-7, A549 and Hela). Moreover, it can effectively induce apoptosis, block cell cycle in G2/M phase and disrupt the cellular microtubule network. These results, along with molecular docking data, provided an important basis for further optimization of compound D11 as a potential anticancer agent. Effect of compound D11 on antiproliferative activity against three cell lines (MCF-7, A549 and Hela), cell cycle progression of A549 cells, and cell morphology of A549 cells; 3D diagram of the interaction between compound D11 and the colchicine binding site. A series of novel thiazole hydrazone derivatives grafted with indole were designed, synthesized and estimated for the inhibitory activity against tubulin polymerization and cancer cells. Also the docking study of these compounds was conducted. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel triazolone/oxadiazolone was determined as a urease inhibitor. • These inhibitors inhibit urease with a mixed competitive mechanism. • Triadimefon/oxadiazolone as a urea-like fragment specifically binds to urease. • The most active compound showed over 20-fold higher potency than the clinical used drug. • The hit compounds with high safety and favorable solubility are promising inhibitors for further developing. Urease is the main virulence factor of infectious gastritis and gastric ulcers. Urease inhibitors are regarded as the first choice for the treatment of such diseases. Based on the triazolone/oxadiazolone skeleton, a urea-like fragment being able to specifically bind the urease activity pocket and prevent urea from hydrolysis, we designed and synthesized 45 triazolones/oxadiazolones as urease inhibitors. Eight compounds were proved to show excellent inhibitory activity against Helicobacter pylori urease, being more potency than the clinically used urease inhibitor acetohydroxamic acid. The most active inhibitor with IC 50 value of 1.2 μM was over 20-fold higher potent than the positive control. Enzymatic kinetic assays showed that these novel inhibitors reversibly inhibited urease with a mixed competitive mechanism. Molecular dockings provided evidence for the observations in enzyme assays. Furthermore, these novel inhibitors were proved as drug-like compounds with very low cytotoxicity to mammalian cells and favorable water solubility. These results suggested that triazolone and oxadiazolone were promising scaffolds for the design and discovery of novel urease inhibitors, and were expected as good candidates for further drug development. [ABSTRACT FROM AUTHOR]

Mutated adenomatous polyposis coli (APC) selectively combining with Asef has been reported to be implicated in promoting colon cancer proliferation, invasion and metastasis in several cancer biotherapy studies. However, there were universally resistance and harsh terms in disrupting APC-Asef interaction in biotherapy. Under the circumstances small-molecule inhibitors as the new APC interface could resolve the problems. In this research, a series of novel dihydropyrazole derivatives containing morpholine as high potent interaction inhibitors between APC and Asef were first synthesized after selection by means of docking simulation and virtual screening. Afterwards they were evaluated interaction inhibition of APC-Asef and pharmacological efficiency both in vitro and in vivo utilizing orthotopic transplantation model with multi-angle of view. Among them, compound 7g exhibited most excellent anti-proliferation activities against HCT116 cells with IC 50 of 0.10 ± 0.01 μ M than Regorafenib (IC 50 = 0.16 ± 0.04 μ M). The results favored our rational design intention and provides a new class of small-molecule inhibitors available for the development of colon tumor therapeutics targeting APC-Asef interaction inhibitions. Characterization of molecular docking with APC (PDB ID: 3NMX). (A) Molecular docking 3D spatial modeling of Asef with the APC binding site. (B) The histogram about CDOCKER_INTERACTION_ENERGY of compounds 7a-7y. (C) Molecular docking 3D spatial modeling of compound 7g with the APC binding site. (D) Molecular docking 2D interaction modeling of compound 7g with the APC binding site. (E) Molecular docking 3D interaction modeling of compound 7g with the APC binding site. Image 1 • Twenty-five small molecule inhibitors of APC-Asef interaction were designed by CADD and first synthesized. • The most active compound 7 g was selected. • Anti-colon cancer activity of compound 7g were evaluated from the molecular, cellular and animal levels. [ABSTRACT FROM AUTHOR]

The enzyme FabH catalyzes the initial step of fatty acid biosynthesis that is essential for bacterial survival. Therefore, FabH has been identified as an attractive target for the development of new antibacterial agents. We present here the discovery of a promising new series of Pyrazol-Benzimidazole amides with low toxicity and potent FabH inhibitory. Twenty-seven novel compounds have been synthesized, and all the compounds were characterized by 1H NMR, 13C NMR and MS. Afterwards they were evaluated for in-vitro antibacterial activities against E. coli , P. aeruginosa , B. subtilis and S. aureus , along with E. coli FabH inhibition and cytotoxicity test. Some compounds proved to be of low toxicity and potent, especially compound 31 exhibited the most potential to be a new drug with MIC of 0.49–0.98 μg/mL against the tested bacterial strains and IC 50 of 1.22 μ M against E. coli FabH. Eight analogues 16 , 28 , 30 , 31 , 33 , 34 , 35 and 36 with low range MIC against wild type Xanthomonas Campestris exhibited no inhibition against FabH-deficient mutant strain, which firmly proved the class of compounds arrived at antibacterial activity via interacting with FabH. In silico ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) evaluation also pointed out that these compounds are potential for druggability. Further, effective overall docking scores of all the compounds have been recorded, and docking simulation of compound 31 into E. coli FabH binding pocket has been conducted, where solid binding interactions has been identified. Image 1 • 27 novel Pyrazol-Benzimidazole amide derivatives have been synthesized and evaluated as potential FabH inhibitors. • Cytotoxicity, hemolytic activities and in silico ADMET were also appraised as well as molecular docking. • Compound 31 showed the most potent inhibitory activity against four tested bacterial and FabH. • Crystal structure of compound 17 was determined. [ABSTRACT FROM AUTHOR]

A series of novel chromeno[4,3- c ]pyrazol-4(2 H)-one derivates contained sulfonamido were designed and synthesized, and their anticancer effects in vitro was evaluated to develop some new PI3Kα inhibitors. Most of desired compounds exhibited the better antiproliferative activities against four cancer cell lines than that of LY294002. Out of them, compound 4o displayed the potent antiproliferative activity and high selectivity against the PI3Kα protein and it can induce apoptosis of HCT116 in a dose-dependent manner. Western blot assay indicated that compound 4o obviously down-regulated expression of p-Akt (S473). Molecular docking was performed to clarify the possible binding mode between compound 4o and PI3Kα. All these results indicated that compound 4o could be a potential inhibitor of PI3Kα. [ABSTRACT FROM AUTHOR]

Graphical abstract A series of rhodanine derivatives RB1–RB23 were synthesized through a two-round screening with their Mycobacterial tuberculosis (Mtb) InhA inhibitory activity and Mtb growth blocking capability evaluated. The improved growth-blocking effect on Mtb and low toxicity were attractive for further development. The docking simulation the key interacted residues as Ser20, Phe149, Lys165 and Thr196 in the binding pattern. Highlights • 23 Rhodanine derivatives were synthesized through a two-round screening. • Their anti-bacterial activity was evaluated for the first time. • The top hit showed improved growth-blocking effect on Mtb and low toxicity. • Molecular docking indicated possible binding pattern and key interacted residues. Abstract A series of rhodanine derivatives RB1–RB23 were synthesized through a two-round screening. Their Mycobacterial tuberculosis (Mtb) InhA inhibitory activity and Mtb growth blocking capability were evaluated. The most potent hit compound RB23 indicated comparable InhA inhibiton (IC 50 = 2.55 μM) with the positive control Triclosan (IC 50 = 6.14 μM) and Isoniazid (IC 50 = 8.29 μM). Its improved growth-blocking effect on Mtb and low toxicity were attractive for further development. The docking simulation revealed the possible binding pattern of this series and picked the key interacted residues as Ser20, Phe149, Lys165 and Thr196. The 3D-QSAR model visualized the SAR discussion and hinted new information. Modifying the surroundings near rhodanine moiety might be promising attempts in later investigations. [ABSTRACT FROM AUTHOR]

Abstract Two Cu(II) complexes of the non-steroidal anti-inflammatory drug Naproxen were synthesized, characterized and evaluated for anti-inflammatory, analgesic, ulcerogenic and urease inhibition activities. The complex 1 [Cu(nap) 2 (H 2 O) 3 ]·H 2 O was reported previously, and the crystal structure of complex 2 [Cu(nap) 2 (dap)(H 2 O)] (nap = Naproxen, dap = 1,3-diaminopropane) was confirmed by X-ray diffraction crystallography. The anti-inflammatory and ulcerogenic study showed that the compounds 1 and 2 were the promising anti-inflammatory agents and demonstrated significant gastric tolerance when compared with Naproxen, especially for complex 1 with the edema inhibition of 93.6% after 3 h, and ulcer index of 15 ± 2. Analgesic and urease inhibition assay showed that complex 2 was a potent urease inhibitor with the IC 50 value of 1.69 ± 0.08 μ M and pain inhibition value of 65%. As effective urease inhibitors, molecular docking study was performed to investigate the binding mode of the complexes with urease. Highlights • Two Cu(II) complexes of the non-steroidal anti-inflammatory drug naproxen were synthesized. • Single crystal structure of compound 2 was determined. • Both compounds were the promising anti-inflammatory and analgesic agents with reduced ulcerogenic side effect. • Both compounds had excellent inhibiting effect on urease, which would be the prospective urease inhibitor. • Molecular docking studied the binding mode of the complexes with urease. [ABSTRACT FROM AUTHOR]

Abstract Pre-clinical diagnosis of many diseases required quantitative detection of Human Serum Albumin (HSA). Herein a high-selective HSA sensor RhHSA was picked through a two-round selectivity evolution from the typical "Effector-π-Trigger" style. RhHSA suggested advantages including high selective (∼6 fold for HSA:BSA = 1:10), sensitive (LOD ∼ 5 nM, over 700-fold enhancement), steady (over 24 h) and wide linear range (0–0.5 mg/mL, applicative for conventional HSA measurement). The detecting system was free from media polarity or viscosity. HSA destruction, site competition and molecular docking provided reliable evidence for the fact that RhHSA could be embedded into both ibuprofen and phenylbutazone sites of HSA. These hints also supported the discrimination of HSA from BSA. Stepwisely fluid replacement in living cells and measuring in urine system both inferred the potential of RhHSA in biological applications. Graphical abstract Image 1 Highlights • Selectivity evolution has been conducted for the first time in seeking HSA sensors. • RhHSA showed fine properties, especially the top class discrimination ability of HSA from BSA. • Pioneering stepwisely fluid replacement in living cells to evaluate the depletion of different albumin. • Detection mechanism hinted by HSA destruction, site competition and molecular docking. [ABSTRACT FROM AUTHOR]

Graphical abstract Compounds of novel cinnamic acyl sulfonamide derivatives as tubulin polymerization inhibitors were designed, synthesized and evaluated for the inhibitory activity against tubulin polymerization and cancer cell inhibitory activity. Docking simulation and 3D-QSAR of these compounds were also conducted. Highlights • 15 novel cinnamic acyl sulfonamide derivatives have been synthesized. • Their biological activities were as potential tubulin polymerization inhibitors. • Compound 5a showed the most inhibitory activity against tubulin and cancer cells. • Crystal structures of compounds 5b and 6c were determined. Abstract A new series of novel cinnamic acyl sulfonamide derivatives were designed and synthesized and evaluated their anti-tubulin polymerization activities and anticancer activities. One of these compounds, compound 5a with a benzdioxan group, was observed to be an excellent tubulin inhibitor (IC 50 = 0.88 µM) and display the best antiproliferative activity against MCF-7 with an IC 50 value of 0.17 μg/mL. Docking simulation was performed to insert compound 5a into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent anti-tubulin polymerization activity. [ABSTRACT FROM AUTHOR]

Graphical abstract By recruiting the important moiety from Shikonin, a series of novel oxoindoline derivatives S1 – S20 were synthesized for inhibiting H. pylori urease. The most potent compound S18 displayed better activity (IC 50 = 0.71 μM; MIC = 0.48 μM) than the positive controls AHA (IC 50 = 17.2 μM) and Metronidazole (MIC = 31.3 μM). It also showed low cytotoxicity. Docking simulation revealed the possible binding pattern. 3D QSAR model was built to discuss SAR and give hints for future researches. Highlights • Twenty oxoindoline derivatives have been synthesized and all are novel. • Their Helicobacter Pylori urease inhibitory activity were evaluated for the first time. • Molecular docking and QSAR discussions indicated larger electron-donating groups for future modification. Abstract By recruiting the important moiety from Shikonin, a series of novel oxoindoline derivatives S1 – S20 have been synthesized for inhibiting H. pylori urease. The most potent compound S18 displayed better activity (IC 50 = 0.71 μM; MIC = 0.48 μM) than the positive controls AHA (IC 50 = 17.2 μM) and Metronidazole (MIC = 31.3 μM). With low cytotoxicity, it showed considerable potential for further development. Docking simulation revealed the possible binding pattern of this series. 3D QSAR model was built to discuss SAR and give useful hints for future modification. [ABSTRACT FROM AUTHOR]

Recent progress in the development of small molecular skeleton-derived polo-like kinase (PLK1) catalytic domain (K D ) inhibitors has led to the synthesis of multiple ligands with high binding affinity. However, few systematic analyses have been conducted to identify key PLK1-PBD domain and characterize their interactions with potent PLK1 inhibitors. Therefore, we designed a series of PLK1-PBD inhibitors with an in silico scaffold modification strategy. A docking simulation combined with a primary screen in vitro were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. The biological profile of 4v suggests that this compound may be developed as a potential anticancer agent. [ABSTRACT FROM AUTHOR]

Tyrosyl-tRNA synthetase (TyrRS) is an aminoacyl-tRNA synthetase family protein that possesses an essential role in bacterial protein synthesis. The synthesis, structure-activity relationship, and evolution of a novel series of adenosine-containing 3-arylfuran-2(5 H )-ones as TyrRS inhibitors are described. Advanced compound d3 from this series exhibited excellent affinity for TyrRS with IC 50 of 0.61 ± 0.04 μM. Bacterial growth inhibition assays demonstrated that d3 showed submicromolar antibacterial potency against Escherichia coli and Pseudomonas aeruginosa , and compared to the marketed antibiotics ciprofloxacin. [ABSTRACT FROM AUTHOR]

Three novel complexes, [Cu( L ) 2 (H 2 O)]( 1 ), [Zn( L ) 2 (H 2 O) 2 ]·CH 3 OH·1.5H 2 O( 2 ), and [Ni( L ) 2 (H 2 O) 1.8 ]·CH 3 OH·1.2H 2 O ( 3 ) (HL = 2-{4-[bis(4-fluorophenyl)methyl]pipera-zin-1-yl} acetic acid), were synthesized and structurally determined by single-crystal X-ray diffraction. Molecular docking study preliminarily revealed that complex 1 had potential Monoamine oxidase B inhibitory activity. All acquired compounds were tested against rat brain MAO-B in vitro. In accordance with the result of calculation, it showed complex 1 (IC 50 = 1.85 ± 0.31 μ M) have good inhibitory activity against MAO-B at the same micromolar concentrations with positive control Iproniazid Phosphate (IP, IC 50 = 7.59 ± 1.17 μ M). These results indicated that complex 1 was a potent MAO-B inhibitor. [ABSTRACT FROM AUTHOR]

• New 1,3-diaryl pyrazolyl ester derivatives developed as COX-2 inhibitors with anti-tumor effect. • Top hit Y1–6 exhibiting selective COX-2 inhibitory and anti-proliferation activities. • Inducing both the apoptosis and cell cycle arrest at G2/M phase of MB-MDA-231 cells with Y1–6. • Key residues indicated by docking simulation for improving the binding patterns. Herein, a novel series of 1,3-diaryl pyrazolyl ester derivatives were synthesized and evaluated as potential COX-2 inhibitory candidates with anti-tumor effect. Among the four sub-series, Sub-series 1 with β -naphthalene indicated the highest percentage of generating potential candidates. Preliminary analysis of Structure-Activity Relationship indicated that single electron-withdrawing substitute on the para -position of the aryl introduced by the generation of ester seemed the most effective selection. The top hit, Y1–6 , indicated potent inhibitory activity on COX-2, sound anti-tumor effect, low cyto-toxicity, and high selectivity towards COX-2 from COX-1. In dose-dependent and time-dependent manners, Y1–6 could induce both the apoptosis and cell cycle arrest at G2/M phase of MB-MDA-231 cells. It could induce the generation of ROS and reduce the generation of PGE 2 to realize the inflammation-cancer interaction. Besides, molecular docking simulation suggested the key residues to ensure the firmly binding as ARG106, SER339, HIS75, LEU338 and TRP373. This work was informatic for developing better candidates as well as revealing the mechanism between inflammation and cancer. [Display omitted] A novel series of 1,3-diaryl pyrazolyl ester derivatives were synthesized and evaluated as potential COX-2 inhibitory candidates with anti-tumor effect. The top hit, Y1–6 , indicated potent inhibitory activity on COX-2, sound anti-tumor effect, low cyto-toxicity, and high selectivity towards COX-2 from COX-1. In dose-dependent and time-dependent manners, Y1–6 could induce both the apoptosis and cell cycle arrest at G2/M phase of MB-MDA-231 cells. It could induce the generation of ROS and reduce the generation of PGE 2 to realize the inflammation-cancer interaction. Besides, molecular docking simulation suggested the key residues to ensure the firmly binding. [ABSTRACT FROM AUTHOR]

1-((2,3-Dihydrobenzo[ b ][1,4]dioxin-6-yl)methyl)-4-substituted-phenylpiperazine moiety was prepared and has been found to be a new and selective ligand for the enzyme cyclooxygenase-2 (COX-2). The biological activity of compound 3k as anti-inflammatory agent was further investigated both in vitro and in vivo. Notably, compound 3k exhibited the best anti-inflammatory activity among the eleven designed compounds with no toxicity, as determined by the ulcerogenic activity. Computational docking studies also showed that compound 3k has interaction with COX-2 key residues in the active site. Compound 3k maybe a new anti-inflammatory lead-candidate as powerful and novel non-ulcerogenic. [ABSTRACT FROM AUTHOR]

[Display omitted] • (N -Aryl- N -arylsulfonyl)aminoacetohydroxamic acids were identified as novel urease inhibitors. • The novel inhibitors inhibit urease with a mixed mechanism and show no perceptible cytotoxicity. • The most active compound showed over 690-fold higher potency than the clinical used urease inhibitor. • The novel inhibitors bound urease active site with a "Y"-like shape. Thirty-three (N -aryl- N -arylsulfonyl)aminoacetohydroxamic acids were synthesized in an effort to develop novel urease inhibitors. Among these compounds, 2-(N -(3-nitrophenyl)- N -(4- tert -butylphenylsulfonyl))aminoacetohydroxamic acid (e2) exhibited excellent inhibitory activity against Helicobacter pylori urease with no perceptible cytotoxicity to mammalian cells. Compound e2 showed over 690-fold higher potency than the clinical used urease inhibitor acetohydroxamic acid, reversibly inhibiting urease with a mixed mechanism. Molecular modeling revealed that (N -aryl- N -arylsulfonyl)aminoacetohydroxamic acids may possibly bind Ni ions and two hydrophobic regions with a 'Y'-like shape. [ABSTRACT FROM AUTHOR]

Three mononuclear Cu(II) complexes Cu(HL 1 )Cl 2 ( 1 ), Cu(HL 2 )Cl 2 ( 2 ), and Cu(L 3 )SCN ( 3 ) have been synthesized based on chelating hydrazone ligands HL 1 , HL 2 , and HL 3 , respectively. These new compounds gave satisfactory IR-spectroscopic data and were further characterized by elemental and X-ray diffraction analyses. Their urease inhibitory evaluation was tested in vitro against jack bean urease. The results showed that the inhibitory activities of the copper complexes are all superior to the positive reference. Enzyme kinetics studies were undertaken to estimate the inhibition mechanism of the copper complexes. Molecular docking simulations have been performed to rationalize their binding models. In addition, their interactions with serum albumin were also studied. [ABSTRACT FROM AUTHOR]

The increasingly acquired resistance to vemurafenib and side effects of known inhibitors motivate the search for new and more effective anti-melanoma drugs. In this Letter, virtual screening and scaffold growth were combined together to achieve new molecules as BRAF V600E inhibitors. Along with docking simulation, a primary screen in vitro was performed to filter the modifications for the lead compound, which was then substituted, synthesized and evaluated for their inhibitory activity against BRAF V600E and several melanoma cell lines. Out of the obtained compounds, derivative 3l was identified as a potent BRAF V600E inhibitor and exerted an anticancer effect through BRAF V600E inhibition. The following biological evaluation assays confirmed that 3l could induce cell apoptosis and marked DNA fragmentation. Furthermore, 3l could arrest the cell cycle at the G0/G1 phase in melanoma cells. The docking simulation displayed that 3l could tightly bind with the crystal structure of BRAF V600E at the active site. Overall, the biological profile of 3l suggests that this compound may be developed as a potential anticancer agent. [ABSTRACT FROM AUTHOR]

Helicobacter pylori urease is involved in several physiologic responses such as stomach and duodenal ulcers, adenocarcinomas and stomach lymphomas. Thus, inhibition of urease is taken for a good chance to treat H. pylori -caused infections, we have therefore focused our efforts on seeking novel urease inhibitors. Here, a series of arylpropionylhydroxamic acids were synthesized and evaluated for urease inhibition. Out of these compounds, 3-(2-benzyloxy-5-chlorophenyl)-3-hydroxypropionylhydroxamic acid ( d24 ) was the most active inhibitor with IC 50 of 0.15 ± 0.05 μM, showing a mixed inhibition with both competitive and uncompetitive aspects. Non-linear fitting of kinetic data gives kinetics parameters of 0.13 and 0.12 μg·mL −1 for K i and K i ′, respectively. The plasma protein binding assays suggested that d24 exhibited moderate binding to human and rabbit plasma proteins. [ABSTRACT FROM AUTHOR]

Three novel mononuclear complexes, [M Ⅱ ( L ) 2 ·2H 2 O], (M = Cu, Ni or Cd; HL = 4-(3,4-dichlorophenyl)piperazine-1-carboxylic acid)were synthesized and structurally determined by single-crystal X-ray diffraction. Molecular docking study preliminarily revealed that complex 1 had potential urease inhibitory activity. In accordance with the result of calculation, in vitro tests of the inhibitory activities of complexes 1–3 against jack bean urease showed complex 1 (IC 50 = 8.17 ± 0.91 μ M) had better inhibitory activities than the positive reference acetohydroxamic acid (AHA) (IC 50 = 26.99 ± 1.43 μ M), while complexes 2 and 3 showed no inhibitory activities., kinetics study was carried out to explore the mechanism of the inhibiting of the enzyme, and the result indicated that complex 1 was a competitive inhibitor of urease. Albumin binding experiment and in vitro toxicity evaluation of complex 1 were implemented to explore its Pharmacological properties. [ABSTRACT FROM AUTHOR]

Four novel mononuclear complexes, [Cd( L ) 2 ·2H 2 O] ( 1 ), [Ni( L ) 2 ·2H 2 O] ( 2 ) [Cu( L ) 2 ·H 2 O] ( 3 ), and [Zn( L ) 2 ·2H 2 O] ( 4 ) (CCDC numbers: 1444630–1444633 for complexes 1 – 4 ) (HL = 4-(2,3-dichlorophenyl)piperazine-1-carboxylic acid) were synthesized, and have been characterized by IR spectroscopy, elemental analysis, and X-ray crystallography. Molecular docking study preliminarily revealed that complex 1 had potential telomerase inhibitory activity. In accordance with the result of calculation, in vitro tests of the inhibitory activities of complex 1 against telomerase showed complex 1 (IC 50 = 8.17 ± 0.91 μM) had better inhibitory activities, while complexes 2 , 3 and 4 showed no inhibitory activities. Antiproliferative activity in human cancer cell line HepG2 was further determined by MTT assays. The IC 50 value (6.5 ± 0.2 μM) for the complex 1 having good inhibitory activity against HepG2 was at the same micromolar concentrations with cis -platinum (2.2 ± 1.2 μM). While the IC 50 value for the metal-free ligand, complex 2 , 3 and 4 was more than 100 μM. These results indicated that telomerase was potentially an anticancer drug target and showed that complex 1 was a potent inhibitor of human telomerase as well as an antiproliferative compound. [ABSTRACT FROM AUTHOR]

A series of novel dioxin-containing triaryl pyrazoline derivatives C1 – C20 have been synthesized. Their B-Raf inhibitory and anti-proliferation activities were evaluated. Compound C6 displayed the most potent biological activity against B-Raf V600E and WM266.4 human melanoma cell line with corresponding IC 50 value of 0.04 μM and GI 50 value of 0.87 μM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-Raf V600E from B-Raf WT , C-Raf and EGFR and low toxic. The docking simulation suggested the potent bioactivity might be caused by breaking the limit of previous binding pattern. A new 3D QSAR model was built with the activity data and binding conformations to conduct visualized SAR discussion as well as to introduce new directions. Stretching the backbone to outer space or totally reversing the backbone are both potential orientations for future researches. [ABSTRACT FROM AUTHOR]

COX-2 has long been exploited in the treatment of inflammation and relief of pain; however, research increasingly suggests COX-2 inhibitors might possess potential benefits to thwart tumour processes. In the present study, we designed a series of novel COX-2 inhibitors based on analysis of known inhibitors combined with an in silico scaffold modification strategy. A docking simulation combined with a primary screen in vitro were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Derivative 4d was identified as a potent COX-2 enzyme inhibitor and exerted an anticancer effect through COX-2 inhibition. Further investigation confirmed that 4d could induce A549 cell apoptosis and arrest the cell cycle at the G2/M phase. Moreover, treatment with 4d reduced A549 cell adhesive ability and COX-2 expression. The morphological variation of treated cells was also visualized by confocal microscopy. Overall, the biological profile of 4d suggests that this compound may be developed as a potential anticancer agent. [ABSTRACT FROM AUTHOR]

A series of novel ( E )-1,3-diphenyl-1 H -pyrazole derivatives containing O-benzyl oxime moiety were firstly synthesized and their immunosuppressive activities were evaluated. Among all the compounds, 4n exhibited the most potent inhibitory activity (IC 50 = 1.18 μ M for lymph node cells and IC 50 = 0.28 μ M for PI3Kγ), which was comparable to that of positive control. Moreover, selected compounds were tested for their inhibitory activities against IL-6 released in ConA-simulated mouse lymph node cells, 4n exhibited the most potent inhibitory ability. Furthermore, in order to study the preliminary mechanism of the compounds with potent inhibitory activity, the RT-PCR experiment was performed to assay the effect of selected compounds on mRNA expression of IL-6. Among them, compound 4n strongly inhibited the expression of IL-6 mRNA. [ABSTRACT FROM AUTHOR]

Herein we describe the synthesis and evaluation of a series of adenosine analogs for in vitro antibacterial activity against Staphylococcus aureus , Escherichia coli and Pseudomonas aeruginosa . Out of these compounds, compound c6 has much stronger antibacterial potency against Pseudomonas aeruginosa than ciprofloxacin, and was determined to target tyrosyl-tRNA synthetase with IC 50 of 0.8 ± 0.07 μM. Structure–activity relationship analysis suggested that introduction of a fluorine atom at the 3′-position of benzene ring of the phenylacetyl moiety significantly increased affinities to the enzyme. In comparison with isopropylidene analogs, 2′,3′-deprotected compounds displayed higher inhibitory activity. Molecular dockings provided an explanation for observations in biological assays. [ABSTRACT FROM AUTHOR]

Tyrosyl-tRNA synthetase (TyrRS), an essential enzyme in bacterial protein biosynthesis, is an attractive therapeutic target for finding novel antibacterial agents, and a series of N 2-(arylacetyl)glycinanilides has been herein synthesized and identified as TyrRS inhibitors. These efforts yielded several compounds, with IC 50 in the low micromolar range against TyrRS from Staphylococcus aureus . Out of the obtained compounds, 3ap is the most active and exhibits excellent activity against both Gram-positive ( S. aureus ) and Gram-negative ( Escherichia coli and Pseudomonas aeruginosa ) bacterial strains. In comparison with the parent scaffold 3-arylfuran-2(5 H )-one, N 2-(arylacetyl)glycinanilide significantly improved the potency against Gram-negative bacterial strains, indicating that this scaffold offers a significant potential for developing new antibacterial drugs. [ABSTRACT FROM AUTHOR]

A series of novel salicylic acid derivatives containing metronidazole as Staphylococcus aureus Tyrosyl-tRNA synthetase (TyrRS) inhibitors have been synthesized and evaluated their biology activities as potential antibacterial agents. Among these compounds, compound 5r exhibited the most potent antibacterial activity against Gram-positive ( S. aureus ATCC 6538 and Bacillus subtilis ATCC 6633) and Gram-negative ( Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 13525) with MICs of 0.39–1.57 μg/mL and showed the most potent S. aureus Tyrosyl-tRNA synthetase inhibitory with 2.3 μM. Docking simulation was performed to insert compound 5r into the crystal structure of S. aureus Tyrosyl-tRNA synthetase active site to determine the probable binding model. These results suggested that compound 5r may be a promising antibacterial agent. [ABSTRACT FROM AUTHOR]

3-Arylfuran-2(5 H )-one derivatives show good antibacterial activity and were determined as tyrosyl-tRNA synthetase (TyrRS) inhibitors. In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to treat infections caused by Helicobacter pylori . Twenty 3-arylfuran-2(5 H )-ones were synthesized and evaluated for anti- H. pylori , antioxidant and anti-urease activities which are closely interconnected with H. pylori infection. The results displayed that some of the compounds show excellent antioxidant activity, and good anti- H. pylori and urease inhibitory activities. Out of these compounds, 3-(3-methylphenyl)furan-2(5 H )-one ( b9 ) showed the most potent antioxidant activity (IC 50 = 8.2 μM) and good anti- H. pylori activity (MIC 50 = 2.6 μg/mL), and it can be used as a good candidate for discovering novel anti-gastric ulcer agent. [ABSTRACT FROM AUTHOR]

Therapies based on urease inhibition are now seriously considered as the first line of treatment for infections caused by Helicobacter pylori . However, the present inhibitors are ineffective or unstable in highly acidic gastric juice. Here, we report a series of benzylanilines as effective inhibitors of H. pylori urease. Out of the obtained twenty-one compounds, N -(3,4-dihydroxybenzyl)-4-nitroaniline ( 4 ) was evaluated in detail and shows promising features for development as anti- H. pylori agent. Excellent potency against urease in both cell-free extract and intact cell was observed at low concentrations of 4 (IC 50 = 0.62 ± 0.04 and 1.92 ± 0.09 μM), which showed over 29- and 54-fold increase in potency with respect to the positive control AHA. The SAR analysis revealed that protection of 3,4-dihydroxy group of 4 as methoxy or changes of 4-NO 2 will result in a moderate to dramatic decrease in potency. [ABSTRACT FROM AUTHOR]

A series of 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives were designed, synthesized and evaluated as potential tubulin polymerization inhibitors and for the cytotoxicity against anthropic cancer cell lines. Among the novel compounds, compound 11f was demonstrated the most potent tubulin polymerization inhibitory activity (IC 50 = 1.5 μM) and antiproliferative activity against A549, HepG2 and MCF-7 (GI 50 = 2.4, 3.8 and 5.1 μM, respectively), which was compared with the positive control colchicine and CA-4. We also evaluated that compound 11f could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Docking simulation and 3D-QSAR model in these studies provided more information that could be applied to design new molecules with more potent tubulin inhibitory activity. [ABSTRACT FROM AUTHOR]

A series of novel pyrazoline-containing derivatives ( 15 – 47 ) has been designed, synthesized and evaluated for their biological activities. Among them, compound 18 displayed the most potent antiproliferative activity against A549, MCF-7 and HepG-2 cells line (IC 50 = 0.07 μM, 0.05 μM, 0.03 μM, respectively) and the tubulin polymerization inhibitory activity (IC 50 = 1.88 μM), being comparable to CA-4. Furthermore, we also tested that compound 18 was a potent inducer of apoptosis in HepG-2 cells and it had cellular effects typical for microtubule interacting agents, causing accumulation of cells in the G2/M phase of the cell cycle. These studies, along with molecular docking, provided a new molecular scaffold for the further development of antitumor agents that target tubulin. [ABSTRACT FROM AUTHOR]

A series of novel 5-phenyl-1 H -pyrazol derivatives ( 5a – 5x ) containing cinnamamide moiety were synthesized and their biological activities as potential tubulin polymerization inhibitors were evaluated. Among them, compound 5j exhibited the most potent inhibitory activity with an IC 50 value of 1.02 μM for tubulin, which was superior to that of Colchicine (IC50 = 1.34 μM). Docking simulation was performed to insert compound 5j into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin inhibitory activity. [ABSTRACT FROM AUTHOR]

Many reports implied that the BRAF serine/threonine kinase was mutated in various types of human tumors, which were related with cell growth, survival and differentiation. To provide new therapeutic opportunities, a series of novel 4,5-dihydro-1 H -pyrazole derivatives ( 6a – 10d ) containing thiazole moiety as potential V600E mutant BRAF kinase (BRAF V600E ) inhibitors were designed and synthesized. All compounds were evaluated in vitro for anticancer activities against WM266.4 human melanoma cell line and breast cancer MCF-7 cell line. Compound 10d displayed the most potential antiproliferative activity with an IC 50 value of 0.12 μM against cell line WM266.4 and 0.16 μM against MCF-7 with positive control Sorafenib. Results of the inhibitory activity against BRAF V600E revealed that compound 10d was bearing the best bioactivity with IC 50 of 0.05 μM as well. On the basis of the result of flow cytometry, with the dose of compound 10d increasing, more and more cancer cell gradually encountered apoptosis or died, which indicated the compound 10d could induce remarkable apoptosis of MCF-7 and WM266.4 cells in a dose dependent manner. Furthermore, docking simulation of inhibitor analogues and 3D-QSAR modeling provided potential binding model and further knowledge of pharmacophore. [ABSTRACT FROM AUTHOR]