Metal-Free Addition of Alkyl Bromides to Access 3,3-Disubstituted Quinoxalinones Enabled by Visible-Light Photoredox Catalysis.

A metal-free addition of unactivated alkyl bromides to quinoxalin-2(1H)-ones is described. This method enables the construction of valuable 3,3-disubstituted dihydroquinoxalin-2(1H)-ones bearing quaternary carbon centers under mild, visible-light photoredox catalysis. High functional group tolerance is observed in both the quinoxalinone and alkyl bromide partners. The ability to scale up this method was demonstrated under photo-flow conditions to enable gram-scale synthesis.

High-Throughput Photo- and Electrochemical sp2-sp3 Cross-Electrophile Coupling to Access Novel Tedizolid Analogs.

The development of practical synthetic protocols integrating novel technologies may enable rapid and broad exploration of chemical space in medicinal chemistry campaigns. Cross-electrophile coupling (XEC) allows the diversification of an aromatic core with alkyl halides to increase the sp3 character. Herein, we apply two alternative approaches via either photo- or electro-catalyzed XEC and showcase their complementarity to access novel tedizolid analogs. The parallel photochemical and electrochemical reactors with high light intensity and constant voltage respectively were chosen to yield good conversions, which allowed access to a wide range of derivatives in a much shorter time frame.

Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1.

Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1-infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1+ cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4+ T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus.

Tricyclic pyrrolopyrimidines (TPPs) are a new class of antibacterials inhibiting the ATPase of DNA gyrase. TPP8, a representative of this class, is active against Mycobacterium abscessus in vitro. Spontaneous TPP8 resistance mutations mapped to the ATPase domain of M. abscessus DNA gyrase, and the compound inhibited DNA supercoiling activity of recombinant M. abscessus enzyme. Further profiling of TPP8 in macrophage and mouse infection studies demonstrated proof-of-concept activity against M. abscessus ex vivo and in vivo.

Dose Number as a Tool to Guide Lead Optimization for Orally Bioavailable Compounds in Drug Discovery.

Small molecule developability challenges have been well documented over the last two decades. One of these critical developability parameters is aqueous solubility. In general, more soluble compounds have improved oral absorption. While enabling formulation technologies exist to improve bioperformance for low solubility compounds, these are often more complex, expensive, and challenging to scale up. Therefore, to avoid these development issues, medicinal chemists need tools to rapidly profile and improve the physicochemical properties of molecules during discovery. Dose number (Do) is a simple metric to predict whether a compound will be reasonably absorbed based on solubility at an expected clinical dose and represents a valuable parameter to the medicinal chemist defining a clinical candidate. The goal of this mini-Perspective is to present the background of the Do equation and how it can be effectively used to rapidly predict oral absorption potential for molecules in the discovery space.

Synthesis of C6-Substituted Purine Nucleoside Analogues via Late-Stage Photoredox/Nickel Dual Catalytic Cross-Coupling.

Nucleoside analogues have been and continue to be extremely important compounds in drug discovery. Despite the significant effort dedicated to their synthesis, medicinal chemistry campaigns around these structures are often hampered by synthetic challenges. We describe a strategy for the functionalization of purine nucleosides via photoredox and nickel-catalyzed sp2-sp3 cross-coupling. The conditions described herein allow for coupling of unprotected nucleosides with readily available alkyl bromides, providing opportunities for their application to parallel medicinal chemistry.