Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors.

The success of acrylamide-containing drugs in treating cancers has spurred a passion to search for acrylamide bioisosteres. In our endeavour, we have identified that an allenamide group can be a reactive bioisostere of the acrylamide group. In our development of allenamide-containing compounds, we found that the most potent compound, 14, inhibited the kinase activities of both T790M/L858R double mutant and wild type EGFR in a low nM range. 14 also inhibited the growth of NCI-H1975 lung cancer cells at IC50 = 33 nM, which is comparable to that of acrylamide-containing osimertinib. The western blot analysis showed that the phosphorylation of EGFR, AKT, and ERK1/2 was simultaneously inhibited in a dose-dependent manner when NCI-H1975 cells were treated with 14. By measuring the conjugate addition product formed by 14 and GSH, we obtained a reaction rate constant of 302.5 × 10-3 min-1, which is about 30-fold higher than that of osimertinib. Taken together, our data suggest that the allenamide-containing compounds inhibited EGFR kinases through covalent modifications. Our study indicates that the allenamide group could serve as an alternative electrophilic warhead in the design of targeted covalent inhibitors, and this bioisostere replacement may have broad applications in medicinal chemistry.

Chemical Immobilization Effect on Lithium Polysulfides for Lithium-Sulfur Batteries.

Despite great progress in lithium-sulfur batteries (LSBs), great obstacles still exist to achieve high loading content of sulfur and avoid the loss of active materials due to the dissolution of the intermediate polysulfide products in the electrolyte. Relationships between the intrinsic properties of nanostructured hosts and electrochemical performance of LSBs, especially, the chemical interaction effects on immobilizing polysulfides for LSB cathodes, are discussed in this Review. Moreover, the principle of rational microstructure design for LSB cathode materials with strong chemical interaction adsorbent effects on polysulfides, such as metallic compounds, metal particles, organic polymers, and heteroatom-doped carbon, is mainly described. According to the chemical immobilizing mechanism of polysulfide on LSB cathodes, three kinds of chemical immobilizing effects, including the strong chemical affinity between polar host and polar polysulfides, the chemical bonding effect between sulfur and the special function groups/atoms, and the catalytic effect on electrochemical reaction kinetics, are thoroughly reviewed. To improve the electrochemical performance and long cycling life-cycle stability of LSBs, possible solutions and strategies with respect to the rational design of the microstructure of LSB cathodes are comprehensively analyzed.

Synthesis and in-vitro anti-hepatitis B virus activity of ethyl 6-bromo-8-hydroxyimidazo[1,2-a]pyridine-3-carboxylates.

A series of ethyl 6-bromo-8-hydroxyimidazo[1,2-a]pyridine-3-carboxylate derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in HepG2.2.15 cells. Nearly half of the tested compounds were proved to be highly effective in inhibiting the replication of HBV DNA with IC(50) values ranging from 1.3 to 9.1 µM. Among them, 10o and 10s were identified as the most promising compounds.