Bioinspired Semisynthesis and Structure Revisions of Chlorinated Norsesquiterpenoids Rumphellatins A-C.

The first synthesis of chlorine-containing hemiketals, rumphellatins A-C (-), previously inaccessible by means of total synthesis, was achieved starting from commercially available (-)-β-caryophyllene oxide (). Structures of rumphellatins A () and C () were revised, while structures of rumphellatin B () and intermediate rumphellolide C () were confirmed. The study expands availability of exotic norsesquiterpenoids for profiling their biological activity as well as facilitates the elucidation of biosynthetic pathways of their formation.

Discovery and optimisation of pyrazolo[1,5-]pyrimidines as aryl hydrocarbon receptor antagonists.

The aryl hydrocarbon receptor (AHR) is a versatile ligand-dependent transcription factor involved in diverse biological processes, from metabolic adaptations to immune system regulation. Recognising its pivotal role in cancer immunology, AHR has become a promising target for cancer therapy. Here we report the discovery and structure-activity relationship studies of novel AHR antagonists.

Peptidic Boronic Acid SUB1 Inhibitors with Improved Selectivity over Human Proteasome.

subtilisin-like serine protease 1 (PfSUB1) is essential for egress of invasive merozoite forms of the parasite, rendering PfSUB1 an attractive antimalarial target. Here, we report studies aimed to improve drug-like properties of peptidic boronic acid PfSUB1 inhibitors including increased lipophilicity and selectivity over human proteasome (H20S). Structure-activity relationship investigations revealed that lipophilic P amino acid side chains as well as -capping groups were well tolerated in retaining PfSUB1 inhibitory potency.

Repurposing Hsp90 inhibitors as antimicrobials targeting two-component systems identifies compounds leading to loss of bacterial membrane integrity.

Unlabelled: The discovery of antimicrobials with novel mechanisms of action is crucial to tackle the foreseen global health crisis due to antimicrobial resistance. Bacterial two-component signaling systems (TCSs) are attractive targets for the discovery of novel antibacterial agents. TCS-encoding genes are found in all bacterial genomes and typically consist of a sensor histidine kinase (HK) and a response regulator.

Substrate Analogues Entering the Lipoic Acid Salvage Pathway via Lipoate-Protein Ligase 2 Interfere with Virulence.

Lipoic acid (LA) is an essential cofactor in prokaryotic and eukaryotic organisms, required for the function of several multienzyme complexes such as oxoacid dehydrogenases. Prokaryotes either synthesize LA or salvage it from the environment. The salvage pathway in includes two lipoate-protein ligases, LplA1 and LplA2, as well as the amidotransferase LipL.

Design, quality and validation of the EU-OPENSCREEN fragment library poised to a high-throughput screening collection.

The EU-OPENSCREEN (EU-OS) European Research Infrastructure Consortium (ERIC) is a multinational, not-for-profit initiative that integrates high-capacity screening platforms and chemistry groups across Europe to facilitate research in chemical biology and early drug discovery. Over the years, the EU-OS has assembled a high-throughput screening compound collection, the European Chemical Biology Library (ECBL), that contains approximately 100 000 commercially available small molecules and a growing number of thousands of academic compounds crowdsourced through our network of European and non-European chemists. As an extension of the ECBL, here we describe the computational design, quality control and use case screenings of the European Fragment Screening Library (EFSL) composed of 1056 mini and small chemical fragments selected from a substructure analysis of the ECBL.

Structure-based identification of salicylic acid derivatives as malarial threonyl tRNA-synthetase inhibitors.

Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Threonyl t-RNA synthetase (ThrRS) is one of the enzymes involved in this pathway, and it has been validated as an anti-malarial drug target. Here, we present 9 structurally diverse low micromolar Plasmodium falciparum ThrRS inhibitors that were identified using high-throughput virtual screening (HTVS) and were verified in a FRET enzymatic assay.

Electrochemical Formation of Oxazolines by 1,3-Oxyfluorination of Non-activated Cyclopropanes.

The C-C bond in non-activated cyclopropanes can be intramolecularly cleaved with an electrochemically generated amidyl radical forming oxazolines. In the presence of TBABF, this provides 1,3-oxyfluorination products. C-C bond cleavage of cyclopropane proceeds with inversion of the configuration, suggesting an intramolecular homolytic substitution (Si) mechanism.

Spiropyran-Based Photoisomerizable α-Amino Acid for Membrane-Active Peptide Modification.

Photoisomerizable peptides are promising drug candidates in photopharmacology. While azobenzene- and diarylethene-containing photoisomerizable peptides have already demonstrated their potential in this regard, reports on the use of spiropyrans to photoregulate bioactive peptides are still scarce. This work focuses on the design and synthesis of a spiropyran-derived amino acid, (S)-2-amino-3-(6'-methoxy-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin-6-yl])propanoic acid, which is suitable for the preparation of photoisomerizable peptides.

Discovery of Malarial Threonyl tRNA Synthetase Inhibitors by Screening of a Focused Fragment Library.

While threonyl tRNA synthetase (ThrRS) has clearly been validated as a prospective antimalarial drug target, the number of known inhbitors of this enzyme is still limited. In order to expand the chemotypes acting as inhibitors of ThrRS, a set of fragments were designed which incorporated bioisosteres of the -acylphosphate moiety of the aminoacyladenylate as an intermediate of an enzymatic reaction. -Acyl sulfamate- and -acyl benzenethiazolsulfonamide-based fragments and were identified as inhibitors of the ThrRSby biochemical assay at 100 μM concentration.

Exploring the Binding Pathway of Novel Nonpeptidomimetic Plasmepsin V Inhibitors.

Predicting the interaction modes and binding affinities of virtual compound libraries is of great interest in drug development. It reduces the cost and time of lead compound identification and selection. Here we apply path-based metadynamics simulations to characterize the binding of potential inhibitors to the aspartic protease plasmepsin V (plm V), a validated antimalarial drug target that has a highly mobile binding site.

Semisynthesis of Linariophyllenes A-C and Rumphellolide H, Structure Revisions and Proposed Biosynthesis Pathways.

The first semisynthetic routes toward terrestrial anti-inflammatory natural products linariophyllene A-C and the refined route toward marine natural product rumphellolide H are presented. Among the synthesized target compounds, the correct structure of linariophyllene A was determined to be the diastereomer of the originally proposed structure with an inverted stereocenter at the secondary alcohol. The proposed structures of linariophyllene B and rumphellolide H were confirmed.

Assembling the Methanoindene Cage of Phragmalin-Type Natural Products.

Phragmalin-type limonoids are highly complex natural products based on an unusual octahydro-1-2,4-methanoindene cage. The absence of feasible routes to sufficiently functionalized methanoindene cage building blocks impedes the total synthesis of these natural products. We have developed a short and robust route to methanoindene cage compounds from the Hajos-Parrish ketone (HPK).

Synthesis and evaluation of an agrocin 84 toxic moiety (TM84) analogue as a malarial threonyl tRNA synthetase inhibitor.

An analogue of a toxic moiety (TM84) of natural product agrocin 84 containing threonine amide instead of 2,3-dihydroxy-4-methylpentanamide was prepared and evaluated as a putative threonyl t-RNA synthetase (PfThrRS) inhibitor. This TM84 analogue features submicromolar inhibitory potency (IC = 440 nM) comparable to that of borrelidin (IC = 43 nM) and therefore complements chemotypes known to inhibit malarial PfThrRS, which are currently limited to borrelidin and its analogues. The crystal structure of the inhibitor in complex with the homologue enzyme (EcThrRS) was obtained, revealing crucial ligand-protein interactions that will pave the way for the design of novel ThrRS inhibitors.

3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors.

SARS-CoV-2 nsp14 guanine-7-methyltransferase plays an important role in the viral RNA translation process by catalyzing the transfer of a methyl group from -adenosyl-methionine (SAM) to viral mRNA cap. We report a structure-guided design and synthesis of 3-(adenosylthio)benzoic acid derivatives as nsp14 methyltransferase inhibitors resulting in compound with subnanomolar inhibitory activity and improved cell membrane permeability in comparison with the parent inhibitor. Compound acts as a bisubstrate inhibitor targeting both SAM and mRNA-binding pockets of nsp14.

Subtilisin-like Serine Protease 1 (SUB1) as an Emerging Antimalarial Drug Target: Current Achievements in Inhibitor Discovery.

Widespread resistance to many antimalarial therapies currently in use stresses the need for the discovery of new classes of drugs with new modes of action. The subtilisin-like serine protease SUB1 controls egress of malaria parasites (merozoites) from the parasite-infected red blood cell. As such, SUB1 is considered a prospective target for drugs designed to interrupt the asexual blood stage life cycle of the malaria parasite.

Exploring Aspartic Protease Inhibitor Binding to Design Selective Antimalarials.

Selectivity is a major issue in the development of drugs targeting pathogen aspartic proteases. Here, we explore the selectivity-determining factors by studying specifically designed malaria aspartic protease (plasmepsin) open-flap inhibitors. Metadynamics simulations are used to uncover the complex binding/unbinding pathways of these inhibitors and describe the critical transition states in atomistic resolution.

Functionalization of Tetrazoles Bearing the Electrochemically Cleavable 1-(6-Methylpyridyl-2-methyl) Protecting Group.

6-Methylpyridyl-2-methyl protected tetrazoles can be C-H deprotonated using the turbo-Grignard reagent and involved in the reactions with aldehydes and ketones. The protecting group can be cleaved under reductive electrochemical conditions using Pb bronze as a cathode and Zn as a sacrificial anode.

Synthesis of indazoles from 2-formylphenylboronic acids.

A method for the synthesis of indazoles was developed which involves a copper(ii) acetate catalysed reaction of 2-formylboronic acids with diazadicaboxylates followed by acid or base induced ring closure. Hydrazine dicarboxylates were also shown as competent reaction partners for the synthesis of indazoles, however, they required a stoichiometric amount of copper(ii) acetate for the C-N bond formation step. The transformation can be efficiently performed as a two step-one pot procedure to give a range of 1-alkoxycarbonyl indazoles.

Convergent biomimetic semisynthesis of disesquiterpenoid rumphellolide J.

The convergent biomimetic gram-scale synthesis of disesquiterpenoid ester rumphellolide J is described. 4β,8β-Epoxycaryophyllan-5-ol was prepared in 67% yield (1.4 g) from naturally ambudant (-)-β-caryophyllene.

Functionalization of 1-Protected Tetrazoles by Deprotonation with the Turbo Grignard Reagent.

1-PMB-protected tetrazole undergoes C-H deprotonation with the turbo Grignard reagent, providing a metalated intermediate with increased stability. This can be used for the reaction with electrophiles such as aldehydes, ketones, Weinreb amides, and iodine. C-H deprotonation with the turbo Grignard reagent is compatible with the PMB-protecting group at the tetrazole, which can be cleaved using oxidative hydrogenolysis and acidic conditions.

Discovery of SARS-CoV-2 Nsp14 and Nsp16 Methyltransferase Inhibitors by High-Throughput Virtual Screening.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes.

Potent SARS-CoV-2 mRNA Cap Methyltransferase Inhibitors by Bioisosteric Replacement of Methionine in SAM Cosubstrate.

Viral mRNA cap methyltransferases (MTases) are emerging targets for the development of broad-spectrum antiviral agents. In this work, we designed potential SARS-CoV-2 MTase Nsp14 and Nsp16 inhibitors by using bioisosteric substitution of the sulfonium and amino acid substructures of the cosubstrate S-adenosylmethionine (SAM), which serves as the methyl donor in the enzymatic reaction. The synthetically accessible target structures were prioritized using molecular docking.