Pharmacological validation of dihydrofolate reductase as a drug target in .

The drug development pipeline is poorly populated, with particularly few validated target-lead couples to initiate drug discovery. Trimethoprim, an inhibitor of dihydrofolate reductase (DHFR) used for the treatment of a range of bacterial infections, is not active against . Thus, evidence that DHFR is vulnerable to pharmacological intervention with a small molecule inhibitor is lacking.

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(1)-ones is described. This method enables the construction of valuable 3,3-disubstituted dihydroquinoxalin-2(1)-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.

High-Throughput Photo- and Electrochemical sp-sp 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 sp character. Herein, we apply two alternative approaches via either photo- or electro-catalyzed XEC and showcase their complementarity to access novel tedizolid analogs.

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.

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 . Spontaneous TPP8 resistance mutations mapped to the ATPase domain of M.

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.

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 sp-sp cross-coupling.

Silyl-mediated photoredox-catalyzed Giese reaction: addition of non-activated alkyl bromides.

The emergence of photoredox catalysis has enabled the discovery of mild and efficient conditions for the generation of a variety of radical reaction platforms. Herein is disclosed the development of a conjugate addition reaction of non-activated alkyl bromides to Michael acceptors under visible-light photoredox catalysis. Optimization of the reaction was achieved using high-throughput experimentation (HTE) tools to enable the identification of mild, general and practical reaction conditions.

Development of a sp-sp Stille Cross-Coupling for Rapid Synthesis of HIV NNRTI Doravirine Analogues.

The development of a C(sp)-C(sp) cross-coupling reaction for rapid, parallel synthesis of analogues of two HIV NNRTI clinical candidates is described. This method allowed easy access to the C-ring space using a practical alkylation with commercially available tributyl(iodomethyl)stannane followed by a palladium-catalyzed coupling with a variety of aryl halides (I, Br) in the presence of copper chloride. Optimization and scope of this method are reported.

Synthesis of new unnatural N(α)-Fmoc pyrimidin-4-one amino acids: use of the p-benzyloxybenzyloxy group as a pyrimidinone masking group.

The p-benzyloxybenzyloxy group is used to mask the oxo function of the 4(3H)-pyrimidinone ring in the synthesis of new unnatural amino acids. The synthetic approach is based on an aromatic nucleophilic substitution reaction between 4-[4-(benzyloxy)benzyloxy]-2-(benzylsulfonyl)pyrimidine and the nucleophilic side chain of several N(α)-Boc amino esters, as the key step, followed by a series of standard protecting group transformations. p-Benzyloxybenzyloxy is efficiently removed under mild acid conditions to recover the 4(3H)-pyrimidinone system.