Roles of inter- and intramolecular tryptophan interactions in membrane-active proteins revealed by racemic protein crystallography.

Tryptophan is frequently found on the surface of membrane-associated proteins that interact with the lipid membrane. However, because of their multifaceted interactions, it is difficult to pinpoint the structure-activity relationship of each tryptophan residue. Here, we describe the use of racemic protein crystallography to probe dedicated tryptophan interactions of a model tryptophan-rich bacteriocin aureocin A53 (AucA) by inclusion and/or exclusion of potential ligands. In the presence of tetrahedral anions that are isosteric to the head group of phospholipids, distinct tryptophan H-bond networks were revealed. H-bond donation by W40 was critical for antibacterial activity, as its substitution by 1-methyltryptophan resulted in substantial loss of activity against bacterial clinical isolates. Meanwhile, exclusion of tetrahedral ions revealed that W3 partakes in formation of a dimeric interface, thus suggesting that AucA is dimeric in solution and dissociated to interact with the phosphate head group in the presence of the lipid membrane. Based on these findings, we could predict the tryptophan residue responsible for activity as well as the oligomeric state of a distant homologue lacticin Q (48%).

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.

Electrochemical sulfinylation of phenols with sulfides: a metal- and oxidant-free cross-coupling for the synthesis of aromatic sulfoxides.

The site-selective C-H functionalization of arenes is of indisputable importance in organic chemistry. Herein, we have demonstrated an electrochemical regioselective oxidative cross-coupling towards the direct C(sp2)-H sulfinylation of phenols with sulfides under mild reaction conditions. The designed methodology furnished aryl sulfoxides in good to moderate yields under exogenous metal and oxidant-free conditions. Moreover, the exploitation of traceless electrons to carry out the tandem site-selective oxidative aryl chalcogenation is the striking feature of this methodology.

Electricity mediated [3+2]-cycloaddition of N-sulfonylcyclopropanes with olefins via N-centered radical intermediates: access to cyclopentane analogs.

An external oxidant free electrochemical strategy is designed towards the ß-scission of strained C-C bonds in cyclopropylamine. Moreover, the mechanistic studies ascertained that the methodology encompasses the N-center radical (NCRs) route and provides access to di- or tri-substituted cyclopentane analogs.

Direct Synthesis of Paracetamol via Site-Selective Electrochemical Ritter-type C-H Amination of Phenol.

The synthesis of paracetamol still relies on multistep protocols involving the utilization of a stoichiometric amount of oxidizing/reducing or other corrosive agents. Herein we report a regioselective electrochemical Ritter-type reaction at the C(sp2)-H of unprotected phenol toward the environmentally benign and direct synthesis of paracetamol. The reaction proceeds under exogenous oxidant- and catalyst-free conditions. The protocol is scalable, can be deployed to a variety of phenols, and offers a sustainable alternative for the synthesis of paracetamol.

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.

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.

Electrochemical rearrangement protocols towards the construction of diverse molecular frameworks.

Rearrangement reactions constitute a critical facet of synthetic organic chemistry and demonstrate an attractive way to take advantage of existing structures to access various important molecular frameworks. Electroorganic chemistry has emerged as an environmentally benign approach to carry out organic transformations by directly employing an electric current and avoids the use of stoichiometric chemical oxidants. The last few years have witnessed a resurgence of electroorganic chemistry that has promoted a renaissance of interest in the development of novel redox electroorganic transformations. This review manifests the evolution of electrosynthesis in the area of rearrangement chemistry and covers the achievements in the field of migration, ring expansion, and rearrangements along with the mechanisms involved.

Electrochemical access to benzimidazolone and quinazolinone derivatives via in situ generation of isocyanates.

Isocyanates are the key intermediates for several organic transformations towards the synthesis of diverse pharmaceutical targets. Herein, we report the development of an oxidant-free protocol for electrochemical in situ generation of isocyanates. This strategy highlights expedient access to benzimidazolones and quinazolinones and eliminates the need for exogenous oxidants. Furthermore, detailed mechanistic studies provide strong support towards our hypothesis of in situ isocyanate generation.

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.

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.