pH/GSH dual responsive nanosystem for nitric oxide generation enhanced type I photodynamic therapy.

Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy (PDT) due to oxygen consumption. Type I PDT, which can operate independently of oxygen, is a viable option for treating hypoxic tumors. In this study, we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment (TME) to enhance type I PDT through glutathione (GSH) depletion.

Design, synthesis, and mechanistic study of 2-piperazineone-bearing peptidomimetics as novel HIV capsid modulators.

HIV-1 capsid (CA) is an attractive target for its indispensable roles in the viral life cycle. We report the design, synthesis, and mechanistic study of a novel series of 2-piperazineone peptidomimetics as HIV capsid modulators by mimicking the structure of host factors binding to CA. F-Id-3o was the most potent compound from the synthesized series, with an anti-HIV-1 EC value of 6.

The Quinone-Derived Small Molecule M5N32 Is an Effective Anti-Helicobacter pylori Agent Both In Vivo and In Vitro.

Background: Helicobacter pylori has become increasingly resistant to all commonly used clinical antibiotics. Therefore, new anti-H. pylori drugs need to be identified.

Discovery of Novel Bicyclic Imidazolopyridine-Containing Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Improved Efficacy and Favorable Druggability.

Lesinurad is a uricosuric agent for the treatment of hyperuricemia associated with gout, which was found lacking in efficacy and safety. Here, scaffold hopping and molecular hybridization were exploited to modify all the structural components of lesinurad, and 36 novel compounds bearing bicyclic imidazolopyridine core were obtained. In a mouse model of acute hyperuricemia, 29 compounds demonstrated increased serum uric acid (SUA)-reducing activity; SUA was treated with , , and about fourfold lower compared with that of lesinurad.

Design, synthesis, and mechanistic investigations of phenylalanine derivatives containing a benzothiazole moiety as HIV-1 capsid inhibitors with improved metabolic stability.

Further clinical development of PF74, a lead compound targeting HIV-1 capsid, is impeded by low antiviral activity and inferior metabolic stability. By modifying the benzene (region I) and indole of PF74, we identified two potent compounds (7m and 7u) with significantly improved metabolic stability. Compared to PF74, 7u displayed greater metabolic stability in human liver microsomes (HLMs) with half-life (t) 109-fold that of PF74.

Design, synthesis, and mechanism study of dimerized phenylalanine derivatives as novel HIV-1 capsid inhibitors.

HIV-1 capsid (CA) plays indispensable and multiple roles in the life cycle of HIV-1, become an attractive target in antiviral therapy. Herein, we report the design, synthesis, and mechanism study of a novel series of dimerized phenylalanine derivatives as HIV-1 capsid inhibitors using 2-piperazineone or 2,5-piperazinedione as a linker. The structure-activity relationship (SAR) indicated that dimerized phenylalanines were more potent than monomers of the same chemotype.

Discovery of potent and selective Cdc25 phosphatase inhibitors via rapid assembly and in situ screening of Quinonoid-focused libraries.

Cell division cycle 25 (Cdc25) phosphatase is an attractive target for drug discovery. The rapid assembly and in situ screening of focused combinatorial fragment libraries using efficient modular reactions is a highly robust strategy for discovering bioactive molecules. In this study, we have utilized miniaturized synthesis to generate several quinonoid-focused libraries, by standard CuAAC reaction and HBTU-based amide coupling chemistry.

Discovery, optimization, and target identification of novel coumarin derivatives as HIV-1 reverse transcriptase-associated ribonuclease H inhibitors.

Despite significant advances in antiretroviral therapy, acquired immunodeficiency syndrome remains as one of the leading causes of death worldwide. New antiretroviral drugs combined with updated treatment strategies are needed to improve convenience, tolerability, safety, and antiviral efficacy of available therapies. In this work, a focused library of coumarin derivatives was exploited by cell phenotypic screening to discover novel inhibitors of HIV-1 replication.

Medicinal chemistry insights into novel CDC25 inhibitors.

Cell division cycle 25 (CDC25) phosphatases, a kind of cell cycle regulators, have become an attractive target for drug discovery, as they have been found to be over-expressed in various human cancer cells. Several CDC25 inhibitors have achieved significant attention in clinical trials with possible mechanistic actions. Prompted by the significance of CDC25 inhibitors with medicinal chemistry prospect, it is an apt time to review the various drug discovery methods involved in CDC25 drug discovery including high throughput screening (HTS), virtual screening (VS), fragment-based drug design, substitution decorating approach, structural simplification approach and scaffold hopping method to seek trends and identify promising new avenues of CDC25 drug discovery.