Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines.

Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps.

Discovery of -benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV).

Current drugs for treating human cytomegalovirus (HCMV) infections are limited by resistance and treatment-associated toxicities. In developing mechanistically novel HCMV antivirals, we discovered an -benzyl hydroxypyridone carboxamide antiviral hit () inhibiting HCMV in submicromolar range. We describe herein the structure-activity relationship (SAR) for , and the characterization of potent analogs for cytotoxicity/cytostatic property, the preliminary mechanism of action, and the absorption, distribution, metabolism and excretion (ADME) properties.

Potency and metabolic stability: a molecular hybrid case in the design of novel PF74-like small molecules targeting HIV-1 capsid protein.

PF74 (1) is a potent and well-characterized prototypical small molecule targeting human immunodeficiency virus type 1 (HIV-1) capsid protein (CA), but not a viable antiviral lead due to the lack of metabolic stability. We report herein our molecular hybridization-based medicinal chemistry efforts toward potent and metabolically stable PF74-like small molecules. The design of the new sub-chemotype 4 rationally combines binding features of two recently reported PF74-like compounds 2 and 3.

Metal binding 6-arylthio-3-hydroxypyrimidine-2,4-diones inhibited human cytomegalovirus by targeting the pUL89 endonuclease of the terminase complex.

The genome packaging of human cytomegalovirus (HCMV) requires a divalent metal-dependent endonuclease activity localized to the C-terminus of pUL89 (pUL89-C), which is reminiscent of RNase H-like enzymes in active site structure and catalytic mechanism. Our previous work has shown that metal-binding small molecules can effectively inhibit pUL89-C while conferring significant antiviral activities. In this report we generated a collection of 43 metal-binding small molecules by repurposing analogs of the 6-arylthio-3-hydroxypyrimidine-2,4-dione chemotype previously synthesized for targeting HIV-1 RNase H, and by chemically synthesizing new N-1 analogs.

Design, Synthesis and Characterization of HIV-1 CA-Targeting Small Molecules: Conformational Restriction of PF74.

Small molecules targeting the PF74 binding site of the HIV-1 capsid protein (CA) confer potent and mechanistically unique antiviral activities. Structural modifications of PF74 could further the understanding of ligand binding modes, diversify ligand chemical classes, and allow identification of new variants with balanced antiviral activity and metabolic stability. In the current work, we designed and synthesized three series of PF74-like analogs featuring conformational constraints at the aniline terminus or the phenylalanine carboxamide moiety, and characterized them using a biophysical thermal shift assay (TSA), cell-based antiviral and cytotoxicity assays, and in vitro metabolic stability assays in human and mouse liver microsomes.

Novel PF74-like small molecules targeting the HIV-1 capsid protein: Balance of potency and metabolic stability.

Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability to confer antiviral phenotypes in both early and late phases of viral replication. However, the prohibitively low metabolic stability renders PF74 a poor antiviral lead. We report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site.

Novel HIV-1 capsid-targeting small molecules of the PF74 binding site.

The PF74 binding site in HIV-1 capsid protein (CA) is a compelling antiviral drug target. Although PF74 confers mechanistically distinct antiviral phenotypes by competing against host factors for CA binding, it suffers from prohibitively low metabolic stability. Therefore, there has been increasing interest in designing novel sub-chemotypes of PF74 with similar binding mode and improved metabolic stability.

Nitrene Transfer and Carbene Transfer in Gold Catalysis.

Catalytic transformations involving metal carbenes are considered one of the most important aspects of homogeneous transition metal catalysis. Recently, gold-catalyzed generation of gold carbenes from readily available alkynes represents a significant advance in metal carbene chemistry. This Review summarizes the advances in the gold-catalyzed nitrene-transfer reactions of alkynes with nitrogen-transfer reagents, such as azides, nitrogen ylides, isoxazoles, and anthranils, and gold-catalyzed carbene-transfer reactions, involving oxygen atom-transfer reactions of alkynes with nitro compounds, nitrones, sulfoxides, and pyridine -oxides, through the presumable α-imino gold carbene and α-oxo gold carbene intermediates, respectively.

Chemical profiling of HIV-1 capsid-targeting antiviral PF74.

The capsid protein (CA) of HIV-1 plays essential roles in multiple steps of the viral replication cycle by assembling into functional capsid core, controlling the kinetics of uncoating and nuclear entry, and interacting with various host factors. Targeting CA represents an attractive yet underexplored antiviral approach. Of all known CA-targeting small molecule chemotypes, the peptidomimetic PF74 is particularly interesting because it binds to the same pocket used by a few important host factors, resulting in highly desirable antiviral phenotypes.

Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules.

HIV-1 capsid protein (CA) plays an important role in many steps of viral replication and represents an appealing antiviral target. Several CA-targeting small molecules of various chemotypes have been studied, but the peptidomimetic has drawn particular interest due to its potent antiviral activity, well-characterized binding mode, and unique mechanism of action. Importantly, competes against important host factors for binding, conferring highly desirable antiviral phenotypes.

Gold-Catalyzed Oxidative Hydrative Alkenylations of Propargyl Aryl Thioethers with Quinoline N-Oxides Involving a 1,3-Sulfur Migration.

This work reports gold-catalyzed oxidative alkenylations of quinoline N-oxides with propargyl aryl thioethers to afford 3-hydroxy-1-alkylidenephenylthiopropan-2-one via a 1,3-sulfur group migration. The mechanism of this reaction is postulated to involve an α-oxo gold carbene intermediate followed by formation of a four-membered sulfonium ring that is ring-opened by one HO to form a gold enolate. A final condensation of this enolate with a second quinoline N-oxide delivers an alkenylation product accompanied by a 1,3-sulfur shift.

Gold-Catalyzed Michael-Type Reactions and [4 + 2]-Annulations between Propiolates and 1,2-Benzisoxazoles with Ester-Directed Chemoselectivity.

This work reports gold-catalyzed reactions between 1,2-benzisoxazoles and propiolate derivatives with ester-controlled chemoselectivity. For ethyl propiolates 1', their gold-catalyzed reactions afforded Michael-type products 4, whereas tert-butyl propiolates 1 preferably underwent [4 + 2]-annulations, further yielding 6 H-1,3-oxazin-6-one derivatives 3.

Catalytic Transformations of Alkynes into either α-Alkoxy or α-Aryl Enolates: Mannich Reactions by Cooperative Catalysis and Evidence for Nucleophile-Directed Chemoselectivity.

The catalytic formation of gold enolates from alkynes, nitrones, and nucleophiles is described, and their Mannich reactions result in nucleophile-directed chemoselectivity through cooperative catalysis. For 1-alkyn-4-ols and 2-ethynylphenols, their gold-catalyzed nitrone oxidations afforded N-containing dihydrofuran-3(2H)-ones with syn selectivity. The mechanism involves the Mannich reactions of gold enolates with imines through an O-H-N hydrogen-bonding motif.

Gold-Catalyzed [4+2] Annulation/Cyclization Cascades of Benzisoxazoles with Propiolate Derivatives to Access Highly Oxygenated Tetrahydroquinolines.

This work describes gold-catalyzed annulations of electron-deficient alkynes with benzisoxazoles to yield quinoline oxides chemoselectively. Chemical functionalizations of these resulting azacyclic compounds afforded various oxygenated tetrahydroquinolines which are present as the cores of many bioactive molecules. With the same reactants, a new relay catalysis using gold and zinc(II) catalysts affords highly oxygenated tetrahydroquinoline derivatives stereoselectively.

Development of Gold-catalyzed [4+1] and [2+2+1]/[4+2] Annulations between Propiolate Derivatives and Isoxazoles.

Two new gold-catalyzed annulations of isoxazoles with propiolates have been developed. Most isoxazoles follow an initial O attack on the alkyne to afford a [4+1] annulation product. This process results in a remarkable alkyne cleavage of initial propiolates.

Gold-catalyzed [4+3] and [4+4]-annulation reactions of t-butyl propiolate derivatives with epoxides and oxetanes for the construction of 1,4-dioxepane and 1,5-dioxocane cores.

Gold-catalyzed [4+n]-annulations (n = 3, 4) of tert-butyl propiolate derivatives with epoxides or oxetanes proceed smoothly to yield seven- or eight-membered oxacyclic products efficiently. In the context of the [4+3]-annulations, product analysis reveals a retention of stereochemistry upon the intramolecular SN2 attack of an epoxide. We also report the [4+5]-annulation between one tert-butyl propiolate and γ-lactol, to manifest the utility toward medium-sized rings.

Diversity in Gold-Catalyzed Formal Cycloadditions of Ynamides with Azidoalkenes or 2H-Azirines: [3+2] versus [4+3] Cycloadditions.

Gold-catalyzed cycloadditions of ynamides with azidoalkenes or 2H-azirines give [3+2] or [4+3] formal cycloadducts of three classes. Cycloadditions of ynamides with 2H-azirine species afford pyrrole products with two regioselectivities when the Cβ -substituted 2H-azirine is replaced from an alkyl (or hydrogen) with an ester group. For ynamides substituted with an electron-rich phenyl group, their reactions with azidoalkenes proceed through novel [4+3] cycloadditions to deliver 1H-benzo[d]azepine products instead.