Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based DHODH inhibitors through a scaffold hop from a pyrrole-based series.

Isosteric 3D Bicyclo[1.1.1]Pentane (BCP) Core-Based Lipids for mRNA Delivery and CRISPR/Cas Gene Editing.

Lipid nanoparticles (LNPs) are an essential component of messenger RNA (mRNA) vaccines and genome editing therapeutics. Ionizable amino lipids, which play the most crucial role in enabling mRNA to overcome delivery barriers, have, to date, been restricted to two-dimensional (2D) architectures. Inspired by improved physicochemical properties resulting from the incorporation of three-dimensionality (3D) into small-molecule drugs, we report the creation of 3D ionizable lipid designs through the introduction of bicyclo[1.

Three-dimensional saturated C(sp)-rich bioisosteres for benzene.

Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor 'drug-like' properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp)-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes.

Direct binding to sterols accelerates endoplasmic reticulum-associated degradation of HMG CoA reductase.

The maintenance of cholesterol homeostasis is crucial for normal function at both the cellular and organismal levels. Two integral membrane proteins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and Scap, are key targets of a complex feedback regulatory system that operates to ensure cholesterol homeostasis. HMGCR catalyzes the rate-limiting step in the transformation of the 2-carbon precursor acetate to 27-carbon cholesterol.

Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates.

Modular functionalization enables versatile exploration of chemical space and has been broadly applied in structure-activity relationship (SAR) studies of aromatic scaffolds during drug discovery. Recently, the bicyclo[1.1.

Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp) bioisosteres.

In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres.

Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in .

A prevalent feature of is a life-long and potentially lethal infection that is due to the nematode parasite's ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasite's nuclear receptor, DAF-12, in governing infection. We identified Δ7-DA as the endogenous DAF-12 ligand and elucidated the hormone's biosynthetic pathway.

An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates.

Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry.

Practical and Modular Construction of C(sp)-Rich Alkyl Boron Compounds.

Alkyl boronic acids and esters play an important role in the synthesis of C(sp)-rich medicines, agrochemicals, and material chemistry. This work describes a new type of transition-metal-free mediated transformation to enable the construction of C(sp)-rich and sterically hindered alkyl boron reagents in a practical and modular manner. The broad generality and functional group tolerance of this method is extensively examined through a variety of substrates, including synthesis and late-stage functionalization of scaffolds relevant to medicinal chemistry.

Sulfur(IV)-Mediated Unsymmetrical Heterocycle Cross-Couplings.

Despite the tremendous utilities of metal-mediated cross-couplings in modern organic chemistry, coupling reactions involving nitrogenous heteroarenes remain a challenging undertaking - coordination of Lewis basic atoms into metal centers often necessitate elevated temperature, high catalyst loading, etc. Herein, we report a sulfur (IV) mediated cross-coupling amendable for the efficient synthesis of heteroaromatic substrates. Addition of heteroaryl nucleophiles to a simple, readily-accessible alkyl sulfinyl (IV) chloride allows formation of a trigonal bipyramidal sulfurane intermediate.

Building C(sp)-rich complexity by combining cycloaddition and C-C cross-coupling reactions.

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres, cycloaddition reactions have featured in numerous total syntheses and are a key component in the education of chemistry students. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp manner.