作者: Lee, Sujin ; Park, Yujin ; Heo, Bo Eun ; Hanh, Bui Thi Bich ; Jang, Jichan ; Kim, Tae Ho ; Nguyen, Thanh Quang ; Moon, Cheol ; Choudhary, Arunima ; Jeon, Seunghyeon ; Min, Sun-Joon

Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. Epetraborole, a benzoxaborole, is a clinical candidate developed for Gram-negative infections and has been confirmed to exhibit favorable activity against a well known pulmonary pathogen, Mycobacterium abscessus. However, according to ClinicalTrials.gov, in 2017, a clinical phase II study on the use of epetraborole to treat complicated urinary tract and intra-abdominal infections was terminated due to the rapid emergence of drug resistance during treatment. Nevertheless, epetraborole is in clinical development for nontuberculous mycobacteria (NTM) disease especially for Mycobacterium avium complex-related pulmonary disease (MAC-PD). DS86760016, an epetraborole analog, was further demonstrated to have an improved pharmacokinetic profile, lower plasma clearance, longer plasma half-life, and higher renal excretion than epetraborole in animal models. In this study, DS86760016 was found to be similarly active against M. abscessus in vitro, intracellularly, and in zebrafish infection models with a low mutation frequency. These results expand the diversity of druggable compounds as new benzoxaborole-based candidates for treating M. abscessus diseases.

2022-03-01·Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Benzoindoxazine derivatives containing carbazole for detection of CN− and its application in plant seed extracts and cell imaging

Article

作者: Pan, Wei ; Zhu, Yan ; Zhang, Zhen-You ; Pang, Xian-Hong ; Shen, Shi-Li ; Cao, Xiao-Qun ; Chen, Guo-Guo

Cyanide (CN^-) is a highly toxic compound that exists in many substances and is harmful to the environment and human health. Therefore, it is of great significance to develop excellent CN^- ion probes, especially solvent-induced on-off fluorescent probes. Based on the condensation reaction of indolo[2,1-b][1,3]oxazine molecules with aldehydes, probes (E)-13a-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)-14,14-dimethyl-10-nitro-13a,14-dihydro-8H-benzo[e]benzo[5,6][1,3]oxazino[3,2-a]indole (NCO) and (E)-13a-(2-(9-benzyl-9H-carbazol-3-yl)vinyl)-14,14-dimethyl-10-nitro-13a,14-dihydro-8H-benzo[e]benzo[5,6][1,3]oxazino[3,2-a]indole (NBO) were synthesized to detect CN^-. Compared with other cyanogen ion probes, NCO and NBO have special carbazole ring structures and large conjugate systems. When CN^- is added to the probe-detection solution, color changes that are visible to the naked eye can occur. The UV-vis spectrum test using differential spectroscopy shows that the probe (i) has excellent solvent-induced switching characteristics and stability (CH₃OH-H₂O) and (ii) high selectivity, anti-interference ability, and sensitivity for the detection of CN^-. The fluorescence limit of detections (LODs) are 1.05 µM for NCO and 1.34 µM for NBO. The UV LODs are 0.83 µM for NCO and 0.87 µM for NBO. Fluorescence spectroscopy shows that the probe has remarkable fluorescence properties. Fluorescence titration experiments, liver cancer cell (Hep G2) imaging, and cytotoxicity experiments all show that the probes have high biocompatibility, low toxicity, high cell permeability, and high sensitivity for the detection of CN^- in cells. In addition, NCO and NBO have been successfully used for the detection of cyanogenic glycosides in the seeds of ginkgo, crabapple, apple, and cherry. Test strips were fabricated to detect CN^-. After adding CN^-, the color of the test strip changed significantly-from brown to light yellow; thus, the test strips have a high application value in the fields of drug quality control, drug safety testing, and pharmacological research.

2020-09-01·Bioorganic Chemistry2区 · 化学

Design, synthesis and anti-HIV evaluation of 5-alkyl- 6-(benzo[d][1,3]dioxol-5-alkyl)-2-mercaptopyrimidin-4(3H)-ones as potent HIV-1 NNRTIs

2区 · 化学

Article

作者: Li, Yi-Ming ; Zhang, Rui-Han ; Li, Xiao-Li ; Xiao, Wei-Lie ; Li, Sui-Yuan ; Tang, E ; Ni, Dong-Xuan ; Zhang, Xing-Jie ; Zheng, Yu-Gui ; Cui, Yi-Man ; Zheng, Yong-Tang ; Huang, Si-Ming ; He, Yan-Ping ; Zhang, Hong-Bin ; Luo, Rong-Hua ; Yang, Liu-Meng

In order to discover and develop the new HIV-1 NNRTIs, a series of 5-alkyl-6-(benzo[d][1,3]dioxol-5-ylalkyl)-2-mercaptopyrimidin-4(3H)-ones was synthesized and screened for their in vitro cytotoxicity against HIV-1. Most of the compounds we synthetized showed high activity against wild-type HIV-1 strain (IIIB) while IC₅₀ values are in the range of 0.06-12.95 μM. Among them, the most active HIV-1 inhibitor was compound 6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5b), which exhibited similar HIV-1 inhibitory potency (IC₅₀ = 0.06 μM, CC₅₀ = 96.23 μM) compared with nevirapine (IC₅₀ = 0.04 μM, CC₅₀ >200 μM) and most of compounds exhibited submicromolar IC₅₀ values indicating they were specific RT inhibitors. The compounds 5b, 6-(benzo[d] [1,3]dioxol-5-yl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5c) and 4-(2-((4-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)acetyl)phenylbenzo[d][1,3]dioxole-5-carboxylate (5r) were selected for further study. It was found that all of them had little toxicity to peripheral blood mononuclear cell (PBMC), and had a good inhibitory effect on the replication of HIV-1 protease inhibitor resistant strains, fusion inhibitor resistant strains and nucleosides reverse transcriptase inhibitor resistant strains, as well as on clinical isolates. Besides, compound 5b and 5c showed inhibition of HIV-1 RT RNA-dependent DNA polymerization activity and DNA-dependent DNA polymerization activity, while compound 5r only showed inhibition of HIV DNA-dependent DNA polymerization activity, which was different from classical reverse transcriptase inhibitors. Our study which offered the preliminary structure-activity relationships and modeling studies of these new compounds has provided the valuable avenues for future molecular optimization.

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