Identification of Small Molecules with Improved Potency against Orthopoxviruses from Vaccinia to Smallpox.

The genus Orthopoxvirus contains several human pathogens, including vaccinia, monkeypox, cowpox, and variola virus, the causative agent of smallpox. Although there are a few effective vaccines, widespread prophylactic vaccination has ceased and is unlikely to resume, making therapeutics increasingly important to treat poxvirus disease. Here, we described efforts to improve the potency of the anti-poxvirus small molecule CMLDBU6128.

Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity.

The essential eukaryotic chaperone Hsp90 regulates the form and function of diverse client proteins, many of which govern thermotolerance, virulence, and drug resistance in fungal species. However, use of Hsp90 inhibitors as antifungal therapeutics has been precluded by human host toxicities and suppression of immune responses. We recently described resorcylate aminopyrazoles (RAPs) as the first class of Hsp90 inhibitors capable of discriminating between fungal (, ) and human isoforms of Hsp90 in biochemical assays.

Synthesis of Tetrahydroisoquinolines Through an Iron-Catalyzed Cascade: Tandem Alcohol Substitution and Hydroamination.

Rapid assembly of saturated nitrogen heterocycles-the synthetically more challenging variants of their aromatic relatives-can expedite the synthesis of biologically relevant molecules. Starting from a benzylic alcohol tethered to an unactivated alkene, an iron-catalyzed tandem alcohol substitution and hydroamination provides access to tetrahydroisoquinolines in a single synthetic step. Using a mild iron-based catalyst, the combination of these operations forms two carbon-nitrogen bonds and provides a unique annulation strategy to access this valuable core.

Iron-Catalyzed Hydroamination and Hydroetherification of Unactivated Alkenes.

The hydrofunctionalization of alkenes, explored for over 100 years, offers the potential for a direct, atom-economical approach to value-added products. While thermodynamically favored, the kinetic barrier to such processes necessitates the use of catalysts to control selectivity and reactivity. Modern variants typically rely on noble metals that require different ligands for each class of hydrofunctionalization, thereby limiting generality.

Stereoinversion of Unactivated Alcohols by Tethered Sulfonamides.

The direct, catalytic substitution of unactivated alcohols remains an undeveloped area of organic synthesis. Moreover, catalytic activation of this difficult electrophile with predictable stereo-outcomes presents an even more formidable challenge. Described herein is a simple iron-based catalyst system which provides the mild, direct conversion of secondary and tertiary alcohols to sulfonamides.