ABSTRACT
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. This class of small molecules, referred to as pyridopyrimidinones (PDPMs), showed a wide range of biological activities. Through the synthesis and testing of several exploratory chemical libraries based on this molecule, we identified several compounds that had increased potency from the micromolar into the nanomolar range. Two compounds, designated (12) and (16), showed inhibitory concentrations of 326 nM and 101 nM, respectively, which was more than a 10-fold increase in potency to CMLDBU6128 with an inhibitory concentration of around 6 µM. We also expanded our investigation of the breadth of action of these molecules and showed that they can inhibit the replication of variola virus, a related orthopoxvirus. Together, these findings highlighted the promise of this new class of antipoxviral agents as broad-spectrum small molecules with significant potential to be developed as antiviral therapy. This would add a small molecule option for therapy of spreading diseases, including monkeypox and cowpox viruses, that would also be expected to have efficacy against smallpox.
Subject(s)
Mpox (monkeypox) , Orthopoxvirus , Smallpox , Vaccinia , Variola virus , Humans , Smallpox/drug therapy , Vaccinia/drug therapy , Vaccinia virusABSTRACT
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 (Cryptococcus neoformans, Candida albicans) and human isoforms of Hsp90 in biochemical assays. Here, we report an iterative structure-property optimization toward RAPs capable of inhibiting C. neoformans growth in culture. In addition, we report the first X-ray crystal structures of C. neoformans Hsp90 nucleotide binding domain (NBD), as the apoprotein and in complexes with the non-species-selective Hsp90 inhibitor NVP-AUY922 and three RAPs revealing unique ligand-induced conformational rearrangements, which reaffirm the hypothesis that intrinsic differences in protein flexibility can confer selective inhibition of fungal versus human Hsp90 isoforms.
Subject(s)
Antifungal Agents/pharmacology , Cryptococcus neoformans/drug effects , Fungi/drug effects , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyrazoles/pharmacology , Animals , Antifungal Agents/chemistry , Cell Line , Cell Survival/drug effects , Crystallography, X-Ray , Humans , Mice , Microbial Sensitivity Tests , Microsomes, Liver/metabolism , Protein Binding , Pyrazoles/chemistry , Species Specificity , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Alcohols/chemistry , Iron/chemistry , Tetrahydroisoquinolines/chemical synthesis , Amination , Catalysis , Molecular Structure , Stereoisomerism , Tetrahydroisoquinolines/chemistryABSTRACT
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. This Letter describes a general iron-based system that catalyzes the hydroamination and hydroetherification of simple unactivated olefins.
Subject(s)
Alkenes/chemistry , Iron/chemistry , Catalysis , Ligands , Molecular StructureABSTRACT
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. Starting from enantioenriched alcohols, the intramolecular variant proceeds with stereoinversion to produce enantioenriched 2- and 2,2-subsituted pyrrolidines and indolines, without prior derivatization of the alcohol or solvolytic conditions.
