Search

[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]

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 novel series of sulfonamide-containing aminophosphonate derivatives were developed as selective COX-2 inhibitors and anti-cancer candidates. The top hit compound A23 presented applicative COX-2 inhibitory activity and anti-proliferative capability against HCT116, which were comparable with that of the positive controls respectively. The binding pattern of A23 was inferred by the molecular docking simulation. Moreover, A23 could induce the apoptosis via a mitochondrion-dependent mode and cause the arrest of the cell-cycle in G1 stage. A further investigation in the checkpoints of apoptosis indicated that the node Bcl-2 might connect the selective COX-2 inhibition and the anti-tumor activity. Therefore, this work brought new information for developing COX-2 inhibitors in anti-tumor therapies in future. • Novel sulfonamide-containing aminophosphonate derivatives as selective COX-2 inhibitors. • Top hit A23 presented applicative COX-2 inhibitory activity and anti-proliferative capability. • Top hit A23 induced apoptosis via a mitochondrion-dependent mode and causing blocking in G1 stage. • Indicating that Bcl-2 might connect the selective COX-2 inhibition and anti-tumor activity of A23. As an essential enzyme with a variety of physiological functions, Cyclooxygenase-2 (COX-2) is also closely related to carcinoma due to the observed overexpression. In this work, a novel series of sulfonamide-containing aminophosphonate derivatives (A1-A25) were developed as selective COX-2 inhibitors and anti-cancer candidates. The top hit compound A23 presented applicative COX-2 inhibitory activity (IC 50 = 0.28 µM) and anti-proliferative capability against several cancer cell lines (IC 50 = 2.34–16.43 µM for HeLa, MCF-7, HCT116 and HepG2 cells). Among them, A23 has the most significant inhibitory effect on HCT116 cells, which were comparable with that of the positive controls respectively (eg: IC 50 = 8.73 µM for HCT116). The binding pattern of A23 was inferred by the molecular docking simulation. Moreover, A23 could induce the apoptosis via a mitochondrion-dependent mode and cause the arrest of the cell-cycle in G1 stage. A further investigation in the checkpoints of apoptosis indicated that the node Bcl-2 might connect the selective COX-2 inhibition and the anti-tumor activity. Therefore, this work brought new information for developing COX-2 inhibitors in anti-tumor therapies in future. [ABSTRACT FROM AUTHOR]

A series of novel pyrazoline derivatives containing methyl-1 H -indole moiety were discovered as potential inhibitors for blocking APC-Asef interactions. The top hit Q19 suggested potency of inhibiting APC-Asef interactions and attractive preference for human-sourced colorectal cells. The introduction of methyl-1 H -indole moiety realized the Mitochondrial affection, connecting the impact on the protein-interaction level with the apoptosis events. This work raised referable information for further discovery of inhibitors for blocking APC-Asef interactions. • Providing a novel series of potential inhibitors for blocking APC-Asef interactions. • The series Q1-Q20 were all reported for the first time. • Potency for inhibiting APC-Asef interactions and human-sourced colorectal cells. • The introduction of methyl-1 H -indole moiety realized the Mitochondrial affection. A series of novel pyrazoline derivatives containing methyl-1 H -indole moiety were discovered as potential inhibitors for blocking APC-Asef interactions. The top hit Q19 suggested potency of inhibiting APC-Asef interactions and attractive preference for human-sourced colorectal cells. It was already comparable with the previous representative and the positive control Regorafenib before further pharmacokinetic optimization. The introduction of methyl-1 H -indole moiety realized the Mitochondrial affection thus might connect the impact on the protein-interaction level with the apoptosis events. The molecular docking simulation inferred that bringing trifluoromethyl groups seemed a promising approach for causing more key interactions such as H-bonds. This work raised referable information for further discovery of inhibitors for blocking APC-Asef interactions. [ABSTRACT FROM AUTHOR]

Started from potential Gyrase inhibitory backbone isatin, the oxoindolin derivatives were developed as atypical dual DNA Gyrase and FabH inhibitors via a two-round screening. The top hit I18 suggested comparable Gyrase inhibitory activity (IC 50 = 0.025 μM) and antibacterial effect with the positive control Novobiocin (IC 50 = 0.040 μM). FabH inhibitory activity (IC 50 = 5.20 μM) was also successfully introduced. Docking simulation hinted possible important interacted residues and binding patterns for both target proteins. Adequate Structure-Activity Relation discussions provide the future orientations of modification. • Performing a two-round screening of systematic novel compounds. • Their atypical dual inhibition on DNA Gyrase and FabH evaluated for the first time. • The top hits being comparable to top class drugs in DNA Gyrase inhibition. • Raising new information via SAR discussion and molecular docking. The antibacterial agents and therapies today are facing serious problems such as drug resistance. Introducing dual inhibiting effect is a valid approach to solve this trouble and bring advantages including wide adaptability, favorable safety and superiority of combination. We started from potential DNA Gyrase inhibitory backbone isatin to develop oxoindolin derivatives as atypical dual Gyrase (major) and FabH (assistant) inhibitors via a two-round screening. Aiming at blocking both duplication (Gyrase) and survival (FabH), most of synthesized compounds indicated potency against Gyrase and some of them inferred favorable inhibitory effect on FabH. The top hit I18 suggested comparable Gyrase inhibitory activity (IC 50 = 0.025 μM) and antibacterial effect with the positive control Novobiocin (IC 50 = 0.040 μM). FabH inhibitory activity (IC 50 = 5.20 μM) was also successfully introduced. Docking simulation hinted possible important interacted residues and binding patterns for both target proteins. Adequate Structure-Activity Relation discussions provide the future orientations of modification. With high potency, low initial toxicity and dual inhibiting strategy, advanced compounds with therapeutic methods will be developed for clinical application. [ABSTRACT FROM AUTHOR]

• Novel 1,2-diarylbenzimidazole derivatives were designed and biologically evaluated. • Compound c24 showed the most potency against microtubule and cancer cells. • It showed that compound c24 could arrest cell cycle, leading to apoptosis. • Docking and 3D-QSAR helped to further optimize c24 as potential anticancer drug. Twenty-four 1,2-diarylbenzimidazole derivatives were designed, synthesized and biologically evaluated. It turned out that most of them were potential anticancer drugs. Among them, compound c24 showed the highest anti-tumor activity (GI 50 = 0.71–2.41 μM against HeLa, HepG2, A549 and MCF-7 cells), and low toxicity to normal cells (CC 50 > 100 μM against L02 cells). In the microtubule binding assay, c24 showed the most potent inhibition of microtubule polymerization (IC 50 = 8.47 μM). The binding ability of compound c24 to tubulin crystal was verified by molecular docking simulation experiment. Further studies on HepG2 and HeLa cells showed that compound c24 could cause mitotic arrest of tumor cells to G2/M phase then inducing apoptosis. To sum up, compound c24 is a promising microtubule assembly inhibitor. [ABSTRACT FROM AUTHOR]