Discovery of pyrido[3,4-b]indol-1-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors.

Bruton's tyrosine kinase (BTK) is an attractive target for the treatment of malignancy and inflammatory/autoimmune diseases. Most of the covalent BTK inhibitors would induce off-target side effects and drug resistance. To improve the drug safety of BTK inhibitors, non-covalent inhibitors have attracted more and more attention. We designed a series of novel pyrido[3,4-b]indol-1-one derivatives (N-A and N-B) via scaffold hopping from CGI-1746. The structure-activity relationship (SAR) of the newly-synthesized compounds was explored. The results showed that compounds 12 and 18 exhibited potent enzymatic potency against BTK with IC50 values of 0.22 µM and 0.19 µM, respectively. In lymphoma cell lines U-937 cells and Ramos cells, compounds 12 and 18 displayed comparative antiproliferative activity with Ibrutinib. Moreover, compound 12 induced G1-phase cell cycle arrest and apoptosis in U-937 cells. And it could effectively inhibit tumor growth in U-937 xenograft mouse model (TGI = 41.90% at 50 mg/kg). In all, the new pyrido[3,4-b]indol-1-one derivatives have the antitumor potency by BTK inhibition and were worthy of further exploration.

Discovery of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors.

Bruton's tyrosine kinase (BTK) is a promising target in the treatment of B cell malignancies and autoimmune disorders. Developing selective non-covalent BTK inhibitors is an important strategy to overcome the side effects and drug resistance induced by covalent BTK inhibitors. In this article, we designed and synthesized pyrrolo[1,2-a]quinoxalin-4(5H)-one and imidazo[1,2-a]quinoxalin-4(5H)-one based selective noncovalent BTK inhibitors via scaffold hopping from BMS-986142 and investigated their biological activities. Among the synthesized compounds, pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives 2 and 4 showed great BTK inhibition potency with IC50 value at 7.41 nM and 11.4 nM, respectively. Besides, they showed equivalent or even better potency in U937 and Ramos cells than BMS-986142. The kinase selectivity profiling study illustrated the excellent selectivity of compound 2 against a panel of 468 kinases. In U937 xenograft models, compound 2 could significantly inhibit tumor growth with TGI = 65.61%. In all, we provided a new scaffold as non-covalent selective BTK inhibitors and the representative compounds exhibited potency both in vitro and in vivo.

Computer-aided design of quadra-ridged waveguide transformers for full-band matching of half-height rectangular waveguides.

A quadra-ridged waveguide transformer (QRWT) is proposed for full-band matching between a standard waveguide and a half-height waveguide, which meets the need for compact waveguide components and the need for multiple sections of irregular transmission lines for better matching in wider operation bands. Unlike conventional matching circuits with monotonically changing impedances, QRWTs form abrupt cross-section changes between transmission line steps. The initial configuration of QRWT is built by CST MICROWAVE STUDIO, a system-level electromagnetic compatibility and general high frequency passive device simulation software, according to the basic electromagnetic (EM) concept and then is optimized by optimization functions from an advanced EM simulator, during the optimization, releasing restrictions as many as possible. To explain the concept, a sample QRWT is designed to match a standard rectangular waveguide WR34 to a half-height waveguide. The reflection coefficient is less than -24 dB in the full operation bandwidth, from 21.7 to 33 GHz. The optimized QRWT has a length of 3.088 mm, 0.218 times the waveguide wavelength at its center operation frequency of 27.35 GHz. For comparison, a two-stage quarter-wave transformer matching circuit is optimized. For similar reflection coefficients in the same bandwidth, the QRWT has a length 57% shorter than the conventional one, and it has an easier manufacturing method using wire-electrode cutting. To verify the design, a back-to-back matching circuit was fabricated using brass material without extra dielectric material. Its measured reflections are less than -16.6 dB, and the insertion loss is less than 0.2 dB.

Analysis of the application effect of continuous care for patients with viral keratitis.

BACKGROUND: In recent years, the incidence of viral keratitis has been on the rise. OBJECTIVE: This study explored the application effect of continuous care for patients with viral keratitis. METHODS: A total of 148 patients with viral keratitis admitted to the ophthalmology department of the authors' hospital from January 2019 to December 2020 were selected and divided into the observation group and the control group via the random number table method, with 74 cases in each group. Continuous care was conducted following routine discharge guidance for patients in the observation group, while routine discharge guidance only was provided for the control group. The patients in both groups were continuously observed for one year. The medication compliance, return visit rate, recurrence rate, nursing satisfaction, and quality of life between the two groups were compared and analyzed after one year. RESULTS: The medication compliance was higher in the observation than in the control group and the difference was statistically significant (P< 0.05). The rate of return visits at 1 week, 1 month, 3 months, 6 months, and 1 year in the observation group were higher than those in the control group and the differences were statistically significant (P< 0.05). The difference in the recurrence rate between the two groups at 1 week was not statistically significant (P> 0.05), while the recurrence rate at 1, 3, and 6 months, and 1 year in the observation group were higher than those in the control group, and the difference was statistically significant (P< 0.05). The total score of the quality of life in the observation group was higher than in the control group and the difference was statistically significant (P< 0.05). CONCLUSION: Continuous care had a good application effect on patients with viral keratitis, which could potentially effectively improve medication compliance and the rate of return visits, reduce recurrence rate, and improve patient satisfaction and their quality of life. Accordingly, the results of this study present high clinical value.

Discovery of Pteridine-7(8H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK).

Bruton's tyrosine kinase (BTK) is an attractive therapeutic target in the treatment of cancer, inflammation, and autoimmune diseases. Covalent and noncovalent BTK inhibitors have been developed, among which covalent BTK inhibitors have shown great clinical efficacy. However, some of them could produce adverse effects, such as diarrhea, rash, and platelet dysfunction, which are associated with the off-target inhibition of ITK and EGFR. In this study, we disclosed a series of pteridine-7(8H)-one derivatives as potent and selective covalent BTK inhibitors, which were optimized from 3z, an EGFR inhibitor previously reported by our group. Among them, compound 24a exhibited great BTK inhibition activity (IC50 = 4.0 nM) and high selectivity in both enzymatic (ITK >250-fold, EGFR >2500-fold) and cellular levels (ITK >227-fold, EGFR 27-fold). In U-937 xenograft models, 24a significantly inhibited tumor growth (TGI = 57.85%) at a 50 mg/kg dosage. Accordingly, 24a is a new BTK inhibitor worthy of further development.

Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors.

Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site. The newly-synthesized compounds displayed high potency against EGFR-C797S resistance mutation. Among them, compound 14d presented high anti-proliferative effect against BaF3-EGFRL858R/T790M/C797S (IC50 = 0.75 µM) and BaF3-EGFR19del/T790M/C797S (IC50 = 0.09 µM) cells. Moreover, 14d resulted in obvious inhibition activities against EGFR and its downstream signaling pathways in a dose-dependent manner in BaF3-EGFR19del/T790M/C797S cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR19del/T790M/C797S xenograft model (30 mg/kg, TGI = 67.95%). These results demonstrated that 14d is a novel and effective EGFR-C797S inhibitor which spanning the ATP binding pocket and the allosteric site and effective both in vitro and in vivo.

Controlled Release Mechanism and Antibacterial Effect of Layer-By-Layer Self-Assembly Thyme Oil Microcapsule.

Thyme essential oil-loaded microcapsules (TMS) were fabricated using natural polysaccharide chitosan (CS) and sodium alginate (SA) as the shell material via the method of layer-by-layer (LBL) assembly. The accumulated release rates of thyme oil and microcapsules at 4 °C were 42.50% and 10.16%, respectively. After heating at 100 °C for 5 hr, the release rate of the 0, 2, 4, 6 layers assembled microcapsules were 100%, 48.84%, 28.38%, 19.3%, severally. Microcapsules also had good pH sensitivity in the range of 4 to 10. Antimicrobial function studies showed that the microcapsules are more effective than thyme oil for three tested microorganisms. When the temperature rose from 37 °C to 121 °C, the antibacterial zone of thyme oil gradually decreased from 18.5 ± 0.6 mm to 12.3 ± 0.6 mm, although inhibition rate of microcapsules increased from 87.97% to 99.75%. The antibacterial effect of thyme oil declined with the increase of pH, in terms of microcapsules, the efficiency was better under acidic or alkaline conditions. The thyme oil microcapsules can suppress the growth of Staphylococcus aureus in milk and prolong its shelf life. It was determined that this microcapsule could be a potential alternative as a natural antimicrobial agent in food and pharmaceutical industries. PRACTICAL APPLICATION: This work provided release performance and mechanism of layer-by-layer (LBL) thyme oil microcapsule under different conditions, and further studies showed its antibacterial ability to explore how herb essential oils can be potentially applied in food packaging and antibacterial areas.