Discovery of novel oxoindolin derivatives as atypical dual inhibitors for DNA Gyrase and FabH.

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 (IC50 = 0.025 µM) and antibacterial effect with the positive control Novobiocin (IC50 = 0.040 µM). FabH inhibitory activity (IC50 = 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.

An umbelliferone-derivated fluorescent sensor for selective detection of palladium(II) from palladium(0) in living cells.

Palladium (Pd) has drawn worldwide attentions because its connections to industry, chemistry, biological material and public health. Quantitative and selective detection tools for Pd and its ion forms are in urgent necessity. Here an umbelliferone derivative Umb-Pd2 was provided as a small, steady, safe and selective sensor for detecting Pd(II). It indicated advantages including sensitive (LOD 1.1 nM), wide pH tolerance (5.0-10.0), applicable linear range (0-1.8 equivalent) and low toxicity. The most attractive point was its explicit selectivity towards Pd(II) from Pd(0) in both independent and coexistence systems. This distinguishing ability was further utilized in imaging in living cells, raising this work as a rare and important example among all the published papers on palladium sensing. Thus, Umb-Pd2 supplied a potential approach for further improvement and applications in both daily chemistry and public health.

Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents.

In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC50 = 6.43-10.97 µM for F10, HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50 = 194.01 µM vs.celecoxib: IC50 = 97.87 µM for 293T cells), and excellent inhibitory activities on COX-2 (IC50 = 0.17 µM) and 5-LOX (IC50 = 0.68 µM). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10 cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy.

Introducing Broadened Antibacterial Activity to Rhodanine Derivatives Targeting Enoyl-Acyl Carrier Protein Reductase.

Broadened antibacterial activity was introduced to rhodanine derivatives targeting Mycobacterial tuberculosis enoyl-acyl carrier protein reductase (Mtb InhA) by recruiting feature of xacins to bring DNA Gyrase B inhibitory capability. This is significant for preventing further bacterial injections in the tuberculosis treatment. The most potent compound Cy14 suggested comparable bioactivity (IC50 = 3.18 µM for Mtb InhA; IC50 = 10 nM for DNA Gyrase B) with positive controls. Structure-activity relationship discussion and molecular docking model revealed the significance of rhodanine moiety and derived methoxyl on meta-position, pointing out orientations for future modification.

A fluorescent sensor for discrimination of HSA from BSA through selectivity evolution.

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.

Developing potential Helicobacter pylori urease inhibitors from novel oxoindoline derivatives: Synthesis, biological evaluation and in silico study.

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 (IC50 = 0.71 µM; MIC = 0.48 µM) than the positive controls AHA (IC50 = 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.

2-Bromo-4,4-dimethyl-1-(2,4,5-trimethoxy-phen-yl)pentan-3-one.

The three meth-oxy groups of the title compound, C(16)H(23)BrO(4), are almost coplanar with the attached aromatic ring, forming dihedral angles of 7.19 (13), 2.48 (13) and 7.24 (12)°. The crystal structure shows an intra-molecular and an inter-molecular C-H⋯O inter-action.