Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety

We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way

Design, synthesis and antimycobacterial activity of novel nitrobenzamide derivatives

We report herein the design and synthesis of a series of novel nitrobenzamide derivatives. Results reveal that many of them display considerable in vitro antitubercular activity. Four N-benzyl or N-(pyridine-2-yl)methyl 3,5-dinitrobenzamides A6, A11, C1 and C4 have not only the same excellent MIC values of 1500), opening a new direction for further development

Tunable Electroosmosis-Based Femto-Liter Pipette: A Promising Tool toward Living-Cell Surgery

Single-cell analysis has attracted increasing attention because of cell heterogeneities. Various strategies have been developed for analyzing single cells, but most of these analytical processes kill the cells. Tools that can qualitatively and quantitatively measure the cellular contents without killing the cell are highly demanding because they enable us to conduct single-cell time-course studies (e.g., to examine how a cell responds to a therapy before, during, and after a treatment). Here we develop a femto-liter (fL) pipet to serve this purpose. To ensure that we can accurately and precisely pipet fL solutions, we fill all conduits with liquid and use an electroosmotic pump (EOP) as the driving force to facilitate withdrawal of cellular contents from single cells. We tentatively term this device an <u>E</u>OP-<u>d</u>riven <u>p</u>ipette or EDP. We characterize the EDP for accurately and precisely withdrawing solution from ∼250 fL to 80 nL; a volume range that covers the applications for most types of cells. To demonstrate the feasibility of utilizing the EDP for a single-cell time-course study, we utilize the EDP to take the cellular contents out at different times during the course of a zebrafish embryo development for cholesterol measurements. More than 50% of the embryos survive after each pipetting and analysis step, and this number will increase considerably as we improve our cell manipulation skills and reduce the pipet-tip diameter. We expect this EDP to become an effective tool for single-cell time-course studies

Identification of Better Pharmacokinetic Benzothiazinone Derivatives as New Antitubercular Agents

A series of new 8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one­(BTZ) derivatives containing a C-2 nitrogen spiro-heterocycle moiety based on the structures of BTZ candidates BTZ043 and PBTZ169 were designed and synthesized as new antitubercular agents. Many of them were found to have excellent <i>in vitro</i> activity (MIC < 0.15 μM) against the drug susceptive <i>Mycobacterium tuberculosis</i> H37Rv strain and two clinically isolated multidrug-resistant strains. Compounds <b>11l</b> and <b>11m</b> display acceptable safety, greater aqueous solubility, and better pharmacokinetic profiles than PBTZ169, suggesting their promising potential to be lead compounds for future antitubercular drug discovery

Identification of <i>N</i>‑Benzyl 3,5-Dinitrobenzamides Derived from PBTZ169 as Antitubercular Agents

A series of benzamide scaffolds were designed and synthesized by the thiazinone ring opening of PBTZ169, and <i>N</i>-benzyl 3,5-dinitrobenzamides were finally identified as anti-TB agents in this work. 3,5-Dinitrobenzamides <b>D5</b>, <b>6</b>, <b>7</b>, and <b>12</b> exhibit excellent <i>in vitro</i> activity against the drug susceptive <i>Mycobacterium tuberculosis</i> H37Rv strain (MIC: 0.0625 μg/mL) and two clinically isolated multidrug-resistant strains (MIC < 0.016–0.125 μg/mL). Compound <b>D6</b> displays acceptable safety and better pharmacokinetic profiles than PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery

Weak influence of the secondary surface processes on the regolith of Chang’E-5 landing site

Soils at the Chang’E-5 landing site on the Moon were weakly influenced by secondary surface processes, according to analyses of light noble gas characteristics which are relatively less fractionated than those in other lunar soil