Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo.

Rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) poses enormous challenge in the development of broad-spectrum antivirals that are effective against the existing and emerging viral strains. Virus entry through endocytosis represents an attractive target for drug development, as inhibition of this early infection step should block downstream infection processes, and potentially inhibit viruses sharing the same entry route. In this study, we report the identification of 1,3-diphenylurea (DPU) derivatives (DPUDs) as a new class of endocytosis inhibitors, which broadly restricted entry and replication of several SARS-CoV-2 and IAV strains. Importantly, the DPUDs did not induce any significant cytotoxicity at concentrations effective against the viral infections. Examining the uptake of cargoes specific to different endocytic pathways, we found that DPUDs majorly affected clathrin-mediated endocytosis, which both SARS-CoV-2 and IAV utilize for cellular entry. In the DPUD-treated cells, although virus binding on the cell surface was unaffected, internalization of both the viruses was drastically reduced. Since compounds similar to the DPUDs were previously reported to transport anions including chloride (Cl-) across lipid membrane and since intracellular Cl- concentration plays a critical role in regulating vesicular trafficking, we hypothesized that the observed defect in endocytosis by the DPUDs could be due to altered Cl- gradient across the cell membrane. Using in vitro assays we demonstrated that the DPUDs transported Cl- into the cell and led to intracellular Cl- accumulation, which possibly affected the endocytic machinery by perturbing intracellular Cl- homeostasis. Finally, we tested the DPUDs in mice challenged with IAV and mouse-adapted SARS-CoV-2 (MA 10). Treatment of the infected mice with the DPUDs led to remarkable body weight recovery, improved survival and significantly reduced lung viral load, highlighting their potential for development as broad-spectrum antivirals.

Brønsted Acid-Catalyzed Cascade Ring-Opening/Cyclization of 3-Ethoxy Cyclobutanones to Access 2,8-Dioxabicyclo[3.3.1]nonane Derivatives.

A cascade ring opening of 3-ethoxy cyclobutanones followed by a double cyclization strategy has been developed via Brønsted acid catalysis. A range of 2,8-dioxabicyclo[3.3.1]nonanes are obtained from various substituted naphthols in a one-pot and open flux manner. Additionally, a 15-membered macrocycle has been synthesized by ring closing metathesis as a synthetic application.

Electrochemical Oxidative Dearomatization Strategy for Accessing Spiro[4.5]dienones and Derivatives.

Electrochemical dearomatization has been recognized as an attractive tool for the rapid construction of structurally diverse molecules. The designed methodology encompasses an eco-friendly and efficient electrochemical approach to synthesizing spiro[4.5]dienones under mild reaction conditions. Furthermore, detailed mechanistic studies strongly bolster our hypothesis and emphasize the role of HFIP in the mechanism. The protocol is scalable and showcases a broad substrate scope with tolerance toward numerous functional groups. Henceforth, this strategy can be deployed as an alternative and sustainable tool for accessing spiro[4.5]dienones.

Electrochemical Synthesis and Reactivity of Three-Membered Strained Carbo- and Heterocycles.

Three-membered carbocyclic and heterocyclic ring structures are versatile synthetic building blocks in organic synthesis with biological importance. Moreover, the inherent strain of these three-membered rings leads to their ring-opening functionalization through C->C, C->N, and C-O bond cleavage. Traditional synthesis and ring-opening methods for these molecules require the use of acid catalysts or transition metals. Recently, electro-organic synthesis has emerged as a powerful tool for initiating new chemical transformations. In this review, the synthetic and mechanistic aspects of electro-mediated synthesis and ring-opening functionalization of three-membered carbo- and heterocycles are highlighted.

Merging Two Strained Carbocycles: Lewis Acid Catalyzed Remote Site-Selective Friedel-Crafts Alkylation of in Situ Generated ß-Naphthol.

Lewis acid catalyzed tandem activation of the two smallest carbocycles, 3-ethoxy cyclobutanones, and donor-acceptor cyclopropanes has been demonstrated. The diphenyl-substituted 3-ethoxy cyclobutanone rearranges itself by intramolecular cyclization for the in situ generation of 1-phenyl 2-naphthol, which further undergoes remote site-selective Friedel-Crafts alkylation with donor-acceptor cyclopropane to synthesize a series of γ-naphthyl butyric acid derivatives. Further control experiments for mechanistic investigations and synthetic applications have also been carried out.

Accessing Complex Tetrahydrofurobenzo-Pyran/Furan Scaffolds via Lewis-Acid Catalyzed Bicyclization of Cyclopropane Carbaldehydes with Quinone Methides/Esters.

Herein, we report a straightforward one-pot synthesis of tetrahydrofurobenzopyran and tetrahydrofurobenzofuran systems via an in situ ring-expansion of the cyclopropane carbaldehydes followed by a [2 + n] cycloaddition with the quinone derivatives. The transformation not only unveils a new reaction mode of cyclopropane carbaldehydes with quinone methides/esters, but also promotes a step-efficient diastereoselective route to the sophisticatedly fused oxygen tricycles that can be further dehydrogenated to access the valued dihydro-2H-furo[2,3-b]chromene frameworks.

α,ß-Unsaturated Carbonyls for One-Pot Transition-Metal-Free Access to 3,6-Dihydro-2H-pyrans.

An efficient protocol has been developed for accessing mono-, di-, and trisubstituted 3,6-dihydro-2H-pyran derivatives by simply subjecting α,ß-unsaturated carbonyls to the carefully optimized Corey-Chaykovsky reaction conditions. The strategy provides selectively substituted dihydropyran derivatives in good to excellent yields with a broad substrate scope under very mild reaction conditions. Easy transformation of the final 3,6-dihydro-2H-pyran to the valued 5,6-dihydro-2H-pyran-2-one and tetrahydro-2H-pyran derivatives expanded the scope of this methodology to diverse oxacycles. Further, the developed strategy also found application in a two-step route to racemic goniothalamin, which is widely studied for its cytotoxic behavior.

Aza-Oxyallyl Cation Driven 3-Amido Oxetane Rearrangement to 2-Oxazolines: Access to Oxazoline Amide Ethers.

Herein, we report a highly facile and unprecedented activation of 3-amido oxetanes to synthesize 2-oxazoline amide ethers using a transient electrophilic aza-oxyallyl cation as an activating as well as an alkylating agent under mild reaction conditions. The aza-oxyallyl cation driven intramolecular rearrangement of 3-amido oxetanes to 2-oxazolines is the hallmark of this transformation and is a new addition to the reactivity profile of aza-oxyallyl cations.

Electrochemical Generation of a Nonstabilized Azomethine Ylide: Access to Substituted N-Heterocycles.

Azomethine ylides are fascinating 1,3-dipoles for [3 + 2] cycloaddition reactions toward the construction of N-heterocycles. Herein, an efficient and environmentally benign electrochemical approach for the generation of a nonstabilized azomethine ylide has been established under metal-free and external oxidant-free conditions. The resulting 1,3-dipole undergoes a [3 + 2] cycloaddition reaction with olefins. This electrosynthetic methodology indulges a straightforward and facile approach for the construction of substituted pyrrolidines.

Arylcyclopropane yet in its infancy: the challenges and recent advances in its functionalization.

Electronically unbiased arylcyclopropane functionalization has always been a challenge to organic chemists, and the emergence of donor-acceptor cyclopropanes (DACs) has not only vehemently overshadowed them but still dominates the cyclopropane chemistry. Unlike DACs, the absence of pre-installed functional groups makes it harder for them to activate and participate in a reaction. The field has witnessed considerably slow progress since its inception due to the inherent challenges. There are only a few strategies available to open arylcyclopropanes. Therefore, this work is still in its infancy stage in spite of these materials being one of the earliest known type of cyclopropanes. This review manifests the history, endeavors, and achievements alongside the associated challenges, opportunities, and the need for concerted efforts to accomplish the long-awaited golden age of arylcyclopropanes.

Accessing Dihydro-1,2-oxazine via Cloke-Wilson-Type Annulation of Cyclopropyl Carbonyls: Application toward the Diastereoselective Synthesis of Pyrrolo[1,2-b][1,2]oxazine.

A convenient additive-free synthesis of dihydro-4H-1,2-oxazines via a Cloke-Wilson-type ring expansion of the aryl-substituted cyclopropane carbaldehydes with the hydroxylamine salt is introduced. Comparatively less active cyclopropyl ketones also follow a similar protocol if supplemented by catalytic p-toluene sulfonic acid monohydrate. The transformation is performed in an open-to-air flask as it shows negligible sensitivity toward air/moisture. Dihydro-4H-1,2-oxazines when subjected to cycloaddition with the cyclopropane diester afford a trouble-free formulation of the valued hexahydro-2H-pyrrolo[1,2-b][1,2]oxazine derivatives. A cascade one-pot variant of this two-step strategy offers a comparable overall yield of the final product.

Regioselective Brønsted Acid-Catalyzed Annulation of Cyclopropane Aldehydes with N'-Aryl Anthranil Hydrazides: Domino Construction of Tetrahydropyrrolo[1,2-a]quinazolin-5(1H)ones.

A highly regioselective synthesis of tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one derivatives was achieved by reacting cyclopropane aldehydes with N'-aryl anthranil hydrazides in the presence of p-toluene sulfonic acid (PTSA). The transformation involves domino imine formation and intramolecular cyclization to form 2-arylcyclopropyl-2,3-dihydroquinolin-4(1H)-one, followed by nucleophilic ring opening of the cyclopropyl ring to form desired tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one in good to excellent yield with complete regioselectivity. This protocol tolerates a great variety of functional groups and thus provides a simple and step-efficient method for pyrroloquinazolinone synthesis.

Palladium-catalyzed regio- and stereoselective access to allyl ureas/carbamates: facile synthesis of imidazolidinones and oxazepinones.

Typically, transition metal catalysis enforces the stereodefined outcome of a reaction. Here we disclose the palladium-catalyzed regio- and stereoselective access to allylic ureas/carbamates and their further exploitation to diverse cyclic structures under operationally simple reaction conditions. This protocol features palladium-catalyzed decarboxylative amidation of highly modular VECs with good to excellent yield, minimal waste production, wide substrate scope, and low catalyst loading. In follow-up chemistry, we demonstrated the debenzylation of vinylic imidazolidinones to N-hydroxycyclic ureas and regioselective derivatization towards the facile synthesis of halohydrins and oxiranes under mild reaction conditions in good to excellent yields.

Lewis Acid-Catalyzed [3+3] Annulation of Donor-Acceptor Cyclopropanes and Indonyl Alcohols: One Step Synthesis of Substituted Carbazoles with Promising Photophysical Properties.

A highly efficient protocol to access carbazole from donor-acceptor cyclopropane and indonyl alcohol via [3+3] annulation in the presence of a Lewis acid has been demonstrated. This method facilitates the post functionalization of the substituted carbazole into a fully conjugated π-system exhibiting intense emission bands in the visible range of the spectrum and also offers a convenient route toward the synthesis of pityriazole derivatives.

Exploitation of donor-acceptor cyclopropanes and N-sulfonyl 1-azadienes towards the synthesis of spiro-cyclopentane benzofuran derivatives.

A MgI2 catalyzed formal [3 + 2] cycloaddition reaction between donor-acceptor cyclopropanes and N-sulfonyl 1-azadienes towards the synthesis of highly functionalized spiro-cyclopentane benzofuran derivatives has been developed. This methodology is appreciated in terms of chemoselectivity and mild reaction conditions. In addition, hydrolysis of one of the N-sulfonyl derivatives offered the corresponding spiro dihydrofuran-3-one derivative in the presence of basic alumina.

Lewis Acid Catalyzed Annulation of Cyclopropane Carbaldehydes and Aryl Hydrazines: Construction of Tetrahydropyridazines and Application Toward a One-Pot Synthesis of Hexahydropyrrolo[1,2- b]pyridazines.

In this report, a facile synthesis of tetrahydropyridazines via a Lewis acid catalyzed annulation reaction of cyclopropane carbaldehydes and aryl hydrazines has been demonstrated. Moreover, the generated tetrahydropyridazine further participated in a cycloaddition reaction with donor-acceptor cyclopropanes to furnish hexahydropyrrolo[1,2- b]pyridazines. We also performed these two steps in one pot in a consecutive manner. In addition, a monodecarboxylation reaction of hexahydropyrrolo[1,2- b]pyridazine was achieved with a good yield.

Humanized NOG mice as a model for tuberculosis vaccine-induced immunity: a comparative analysis with the mouse and guinea pig models of tuberculosis.

The humanized mouse model has been developed as a model to identify and characterize human immune responses to human pathogens and has been used to better identify vaccine candidates. In the current studies, the humanized mouse was used to determine the ability of a vaccine to affect the immune response to infection with Mycobacterium tuberculosis. Both human CD4+ and CD8+ T cells responded to infection in humanized mice as a result of infection. In humanized mice vaccinated with either BCG or with CpG-C, a liposome-based formulation containing the M. tuberculosis antigen ESAT-6, both CD4 and CD8 T cells secreted cytokines that are known to be required for induction of protective immunity. In comparison to the C57BL/6 mouse model and Hartley guinea pig model of tuberculosis, data obtained from humanized mice complemented the data observed in the former models and provided further evidence that a vaccine can induce a human T-cell response. Humanized mice provide a crucial pre-clinical platform for evaluating human T-cell immune responses in vaccine development against M. tuberculosis.

Construction of thiazines and oxathianes via [3 + 3] annulation of N-tosylaziridinedicarboxylates and oxiranes with 1,4-dithiane-2,5-diol: application towards the synthesis of bioactive molecules.

Lewis acid catalyzed [3 + 3] annulation of N-tosylaziridinedicarboxylates and oxiranes with in situ generated mercaptoaldehyde for the synthesis of functionalized thiazine and oxathiane derivatives has been developed. Additionally, this method facilitates the derivatization of thiazines by detosylation and Krapcho monodecarboxylation.

Lewis Acid Catalyzed Annulation of Donor-Acceptor Cyclopropane and N-Tosylaziridinedicarboxylate: One-Step Synthesis of Functionalized 2H-Furo[2,3-c]pyrroles.

An efficient MgI2-catalyzed annulation between donor-acceptor cyclopropane and N-tosylaziridinedicarboxylate to access highly substituted 2H-furo[2,3-c]pyrrole bearing two rings and four stereocenters, including one quaternary carbon stereocenter, has been developed. This methodology can be used for the synthesis of biologically active compounds like IKM-159. This work also offers an insight into the mechanism of the annulation process.

Electrochemical oxidative C-C bond cleavage of methylenecyclopropanes with alcohols.

Herein, an electrochemical approach toward the ring opening functionalization of methylenecyclopropanes (MCPs) via C-C bond cleavage in the presence of alcohols is reported. The methodology avoids the usage of external oxidants and shows good functional group tolerance. The mechanistic studies suggest that the reaction proceeds via direct single electron oxidation of the C-C bond of MCPs followed by ring opening to form the desired product.