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.

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.

A rapid cell-permeating turn-on probe for sensitive and selective detection of sulfite in living cells.

A rapid cell-permeating probe NJUXJ-1 was introduced for sensitive and selective detection of sulfite in living cells. It generated a turn-on response to sulfite with high sensitivity (detection limit 13.0 nM) and selectivity (at a physiological level) and low toxicity. The fluorescence of the detecting system was steady for a wide pH range (5-8) and a long period of time (over 12 h). The most attractive point, its rapid cell-permeating ability, made it suitable for bioimaging with a 2 min incubation time and shortened the whole detecting period (cell-permeation and reaction), and thus could decrease background interference. It offered a convenient approach for determining exogenous or endogenous sulfite levels in living cells and further 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.

Design and biological evaluation of novel triaryl pyrazoline derivatives with dioxane moiety for selective BRAFV600E inhibition.

A series of novel selective BRAFV600E inhibitory agents (Compound 1-16) 5-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)-N,3-diaryl-4,5-dihydro-1H-pyrazole-1-carbothioamides have been designed and synthesized. Their anti-proliferation and BRAF inhibitory activities were evaluated. Though 15, 4 and 12 all displayed comparable activity with the positive control Vemurafenib, only 12 indicated fine selectivity on BRAFV600E (IC50 = 0.06 µM for BRAFV600E; GI50 = 0.52 µM for A375) over BRAFWT at both kinase and cell levels. This result satisfied the designing concept of improving activity and introducing selectivity. Flow cytometry analysis and western blot convinced the apoptosis induction and kinase inhibitory activity. Docking simulation inferred the differences in binding patterns of BRAFV600E and BRAFWT, pointing out that the future orientation might be seeking for outer space binding of BRAFV600E and avoiding interactions with HIS573 of BRAFWT. These results brought potent BRAF inhibitors one step further to selective agents, enhancing the potential for safe medication.