Vinyl Sulfonamide Research Articles

Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors

SARS-CoV-2 main protease (Mpro) is a validated antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant Mpro mutants against nirmatrelvir have been identified from cell culture viral passage and naturally occurring variants. As such, there is a need for a second generation of Mpro inhibitors. In this study, we explored several reactive warheads in the design of Mpro inhibitors. We identified Jun11119R (vinyl sulfonamide warhead), Jun10221R (propiolamide warhead), Jun1112R (4-chlorobut-2-ynamide warhead), Jun10541R (nitrile warhead), and Jun10963R (dually activated nitrile warhead) as potent Mpro inhibitors. Jun10541R and Jun10963R also had potent antiviral activity against SARS-CoV-2 in Calu-3 cells with EC50 values of 2.92 and 6.47 μM, respectively. X-ray crystal structures of Mpro with Jun10541R and Jun10221 revealed covalent modification of Cys145. These Mpro inhibitors with diverse reactive warheads collectively represent promising candidates for further development.

Discovery of Potent Pyrazoline-Based Covalent SARS-CoV-2 Main Protease Inhibitors.

Among the various genes and proteins encoded by all coronaviruses, one particularly "druggable" or relatively easy-to-drug target is the coronavirus Main Protease (3CLproor Mpro), an enzyme that is involved in cleaving a long peptide translated by the viral genome into its individual protein components that are then assembled into the virus to enable viral replication in the cell. Inhibiting Mpro with a small-molecule antiviral would effectively stop the ability of the virus to replicate, providing therapeutic benefit. In this study, we have utilized activity-based protein profiling (ABPP)-based chemoproteomic approaches to discover and further optimize cysteine-reactive pyrazoline-based covalent inhibitors for the SARS-CoV-2 Mpro. Structure-guided medicinal chemistry and modular synthesis of di- and tri-substituted pyrazolines bearing either chloroacetamide or vinyl sulfonamide cysteine-reactive warheads enabled the expedient exploration of structure-activity relationships (SAR), yielding nanomolar potency inhibitors against Mpro from not only SARS-CoV-2, but across many other coronaviruses. Our studies highlight promising chemical scaffolds that may contribute to future pan-coronavirus inhibitors.

Synthesis of alkyl isothiazolidine-1,1-dioxide 3-carboxylates via the intramolecular carbo-Michael reaction strategy

Herein we present short and cost-effective synthesis of alkyl isothiazolidine-1,1-dioxide 3-carboxylates starting from commercially available α-amino acid ester hydrochlorides. These compounds were designed as sulfonamide-containing bioisosteres of known pharmacological template – pyroglutamic acid (pGlu). Specifically, α-amino acid ester hydrochlorides were sulfonylated with (2-chloroethyl)sulfonyl chloride providing in one-pot manner the corresponding alkyl 2-((vinylsulfonyl)amino)carboxylates. The obtained vinyl sulfonamides possessing SO2NH functionality were alkylated with either MeI or MeOCH2Cl (MOMCl) prior to cyclization step. At the same time, vinyl sulfonamides derived from N-monosubstituted and cyclic amino acid esters were directly involved in NaH-mediated intramolecular carbo-Michael reaction affording the target alkyl isothiazolidine-1,1-dioxide 3-carboxylates. Further acid-promoted cleavage of MOM-protecting group led to NH-unsubstituted target compounds.

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 μM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 μM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.

Synthetic molecules targeting yes associated protein activity as chemotherapeutics against cancer.

The Hippo signaling pathway extorts several signals that concomitantly target the activity of transcriptional cofactor yes associated protein (YAP). YAP is a key regulator that elicits signature gene expression by coupling with transcriptional enhanced associate domain (TEAD) family of transcriptional factors. The YAP-TEAD complex via target gene expression gets associated with the development, proliferation, and progression of cancerous cells. Moreover, YAP adorns cells with several oncogenic traits such as inhibition of apoptosis, enhanced proliferation, drug resistance, and immune response suppression, which later became associated with various diseases, particularly cancer. Therefore, inhibition of the YAP activity is an appealing and viable therapeutic target for cancer treatment. This review highlights the recent advances in existing and novel synthetic therapeutics targeting YAP inhibition and regulation. The synthetically produced YAPD93A belonging to cyclic peptides and DC-TEADin02 and vinyl sulfonamide class of compounds are the most potent compounds to inhibit the YAP-TEAD expression by targeting protein-protein interaction (IC50 =25nM) and palmitate binding central pocket of TEAD (IC50 =197nM), respectively. On the other hand, Chlorpromazine belonging to phenothiazines class has the least potential to suppress YAP via proteasomal degradation (cell viability value of <20% at 40µM).

Ring-closure reactions of functionalized vinyl sulfonamides (microreview)

Ring-closure reactions of functionalized vinyl sulfonamides (microreview)

Sequence-defined oligoampholytes using hydrolytically stable vinyl sulfonamides: design and UCST behaviour

Water soluble sequence-defined oligoampholytes with precisely positioned charges were synthesised via an iterative solid-phase synthesis protocol using vinyl sulfonamide and acrylate building blocks.

Preparation of Functionalized α,β-Unsaturated Sulfonamides via Olefin Cross-Metathesis.

The synthesis of functionalized α,β-unsaturated sulfonamides by means of cross-metathesis of vinyl sulfonamides and olefins has been developed. The reaction proceeds smoothly in the presence of Hoveyda–Grubbs catalyst and its nitro analogue, providing a wide range of substituted products. The usefulness of this methodology has been proven in the preparation of new derivatives of biologically active ingredients, moxifloxacin and naratriptan.

Organocatalytic enantioselective synthesis of 2,5,5-trisubstituted piperidines bearing a quaternary stereocenter. Vinyl sulfonamide as a new amine protecting group.

An organocatalytic desymmetrizing intramolecular aza-Michael reaction with vinyl sulfonamides as nucleophilic nitrogen source has been devised for the synthesis of a new family of 2,5,5-trisubstituted piperidines bearing a quaternary sterocenter. The process takes place with excellent levels of enantioselectivity and moderate to good diastereoselectivity. The vinyl sulfonamide moiety can be removed by means of an ozonolysis reaction.

Sequence-defined vinyl sulfonamide click nucleic acids (VS-CNAs) and their assembly into dynamically responsive materials.

Synthetic DNA analogues are of great interest for their application in information storage, therapeutics, and nanostructured materials, yet are often limited in scalability. Vinyl sulfonamide click nucleic acids (VS-CNAs) have been developed to overcome this limitation using the highly efficient thiol-Michael 'click' reaction. Utilizing all four nucleobases, sequence-defined click nucleic acids (CNAs) were synthesized using a simple and scalabale solution-phase approach. Employing a polyethylene glycol (PEG) support, synthesis of the CNA sequence, GATTACA, was achieved in high yields. CNA crosslinked hydrogels were assembled using multiarm PEG-CNAs resulting in materials that dynamically respond to temperature, strain, and competitive sequences.

Vinyl sulfonamide based thermosetting composites via thiol-Michael polymerization

ObjectiveTo assess the performance of thiol Michael photocurable composites based on ester-free thiols and vinyl sulfonamides of varying monomer structures and varied filler loadings and to contrast the properties of the prototype composites with conventional BisGMA-TEGDMA methacrylate composite. MethodsSynthetic divinyl sulfonamides and ester-free tetrafunctional thiol monomers were utilized for thiol-Michael composite development with the incorporation of thiolated microfiller. Polymerization kinetics was investigated using FTIR spectroscopy. Resin viscosities were assessed with rheometry. Water uptake properties were assessed according to standardized methods. Thermomechanical properties were analyzed by dynamic mechanical analysis. Flexural modulus/strength and flexural toughness were measured on a universal testing machine in three-point bending testing mode. ResultsThe vinyl sulfonamide-based thiol-Michael resin formulation demonstrated a wide range of viscosities with a significant increase in the functional group conversion when compared to the BisGMA-TEGDMA system. The two different types of vinyl sulfonamide under investigation demonstrated significant differences towards the water sorption. Tertiary vinyl sulfonamide did not undergo visible swelling whereas the secondary vinyl sulfonamide composite swelled extensively in water. With the introduction of rigid monomer into the polymer matrix the glass transition temperature increased and so increased the toughness. Glassy thiol-Michael composites were obtained by ambient curing. SignificanceEmploying the newly developed step-growth thiol-Michael resins in dental composites will provide structural uniformity, improved stability and lower water sorption.

Diastereoselective Monofluorocyclopropanation Using Fluoromethylsulfonium Salts.

Diarylfluoromethylsulfonium salts, alternatives to freons or advanced fluorinated building blocks, are bench stable and easy-to-use sources of direct fluoromethylene (:CHF) transfer to alkenes. These salts enabled development of a trans-selective monofluorinated Johnson-Corey-Chaykovsky reaction with vinyl sulfones or vinyl sulfonamides to access synthetically challenging monofluorocyclopropane scaffolds. The described method offers rapid access to monofluorinated cyclopropane building blocks with further functionalization opportunities to deliver more complex synthetic targets diastereoselectively.

Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator.

The main pathway responsible for cellular regulation against oxidative stress is nuclear factor E2-related factor-2 (Nrf2) signaling. We previously synthesized and reported a novel vinyl sulfone (1) as an Nrf2 activator with therapeutic potential for Parkinson's disease (PD). In this study, we changed the vinyl sulfone to vinyl sulfonamide or vinyl sulfonate to improve Nrf2 activating efficacy. We observed that the introduction of vinyl sulfonamide led to a reduction of the effects on Nrf2 activation, whereas vinyl sulfonate compounds exhibited superior activity compared to the vinyl sulfone compounds. Among the vinyl sulfonates, 3c exhibited 6.9- and 83.5-fold higher effects on Nrf2 activation than the corresponding vinyl sulfone (1) and vinyl sulfonamide (2c), respectively. Compound 3c was confirmed to induce expression of the Nrf2-dependent antioxidant enzymes at the protein level in cells. In addition, 3c mitigated PD-associated behavioral deficits by protecting DAergic neurons in the MPTP-induced mouse model of PD.

Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy.

Vinyl sulfonamides are valuable electrophiles for targeted protein modification and inhibition. We describe a novel approach to the synthesis of terminal vinyl sulfonamides which uses mild oxidative conditions to induce elimination of an α-selenoether masking group. The method complements traditional synthetic approaches and typically yields vinyl sulfonamides in high purity after aqueous work-up without requiring column chromatography of the final electrophilic product. The methodology is applied to the synthesis of covalent fragments for use in irreversible protein tethering and crucially enables the attachment of diverse fragments to the vinyl sulfonamide warhead via a chemical linker. Using thymidylate synthase as a model system, ethylene glycol is identified as an effective linker for irreversible protein tethering.

On-Resin Macrocyclization of Peptides Using Vinyl Sulfonamides as a Thiol-Michael "Click" Acceptor.

Macrocyclization of linear peptides imparts improved stability to enzymatic degradation and increases potency of function. Many successful macrocyclization of peptides both in solution and on-resin have been achieved but are limited in scope as they lack selectivity, require long reaction times, or necessitate heat. To overcome these drawbacks a robust and facile strategy was developed employing thiol-Michael click chemistry via an N-methyl vinyl sulfonamide. We demonstrate its balance of reactivity and high stability through FTIR model kinetic studies, reaching 88% conversion over 30 min, and NMR stability studies, revealing no apparent degradation over an 8 day period in basic conditions. Using a commercially available reagent, 2-chloroethane sulfonyl chloride, the cell adhesion peptide, RGDS, was functionalized and macrocyclized on-resin with a relative efficiency of over 95%. The simplistic nature of this process demonstrates the effectiveness of vinyl sulfonamides as a thiol-Michael click acceptor and its applicability to many other bioconjugation applications.

Dual Role of Vinyl Sulfonamides as N‐Nucleophiles and Michael Acceptors in the Enantioselective Synthesis of Bicyclic δ‐Sultams

AbstractA new methodology for the synthesis of enantiomerically enriched bicyclic δ‐sultams is described, involving an initial organocatalytic intramolecular aza‐Michael reaction of vinyl sulfonamides bearing a conjugated ketone at a remote position. The resulting Michael adducts were then subjected to an intramolecular conjugate addition over the vinyl sulfone moiety, thus rendering the final bicyclic sultams containing two stereocenters. The key point of this strategy relies on the use of vinyl sulfonamides as both, nitrogen nucleophiles and Michael acceptors. The use of phosphazene‐derived bases avoided the racemization of the intermediate derivatives, rendering 6‐membered ring bicyclic δ‐sultams in enantiomerically enriched manner with a small erosion of enantiopurity. Anyway, after recrystallization, final sultams were obtained in almost enantiomerically pure form. Nevertheless, the enantioselective synthesis of either 5‐membered ring products or benzofused derivatives was found to be out of the scope of our strategy.magnified image

Multifunctional monomers based on vinyl sulfonates and vinyl sulfonamides for crosslinking thiol-Michael polymerizations: monomer reactivity and mechanical behavior.

Multifunctional vinyl sulfonates and vinyl sulfonamides were conveniently synthesized and assessed in thiol-Michael crosslinking polymerizations. The monomer reactivities, mechanical behavior and hydrolytic properties were analyzed and compared with those of analogous thiol-acrylate polymerizations. Materials with a broad range of mechanical properties and diverse hydrolytic stabilities were obtained.

A summary of seven- and eight-membered ring sultam syntheses via three Michael addition reactions.

A series of seven- and eight-membered ring -N,O-, -N,N-, and -N,S-sultams were effectively synthesized via tandem reactions involving oxa-, aza-, and thia-Michael addition to vinyl sulfonamides. These reactions are summarized here since they enrich current synthetic methodologies for sultams and provide a good example of sultam diversity-oriented synthesis. All reactions proceeded under relatively mild and environmentally friendly conditions, and all these reactions are quite suitable for the rapid preparation of sultam compound libraries, which are valuable for biological activity explorations.

Diversity-oriented syntheses: coupling reactions between electron-deficient olefins and aryl aldehydes via C(sp2)-H functionalization.

A diversity-oriented syntheses by coupling three electron-deficient olefins (vinyl sulfonamides, methacrylamides, and methyl acrylates, respectively) with aryl aldehydes via C(sp(2))-H functionalization were reported. These reactions gave four different skeletal products respectively under environment-friendly and mild conditions. All these reactions are highly regioselective and effective, very suitable for the preparation of synthetic building blocks and compound library, the results will enrich current coupling chemistry of olefins with aldehydes and can be applied to other chemistry areas as well.