2-(3-Chloro-4-hydroxy­phen­yl)-N-(3,4-dimethoxy­pheneth­yl)acetamide

The title compound, C18H20ClNO4, was synthesized during the generation of a combinatorial library based on the fungal natural product 3-chloro-4-hydroxy­phenyl­acetamide. It crystallizes as discrete mol­ecules linked by inter­molecular C(9) chains of N—H⋯O and O—H⋯O hydrogen bonds which in turn combine to form chains of R 2 2(20) rings

N-Benzyl-2-(3-chloro-4-hy­droxy­phen­yl)acetamide

The title compound, C15H14ClNO2, was synthesized as part of a project to generate a combinatorial library based on the fungal natural product 2-(3-chloro-4-hy­droxy­phen­yl)acetamide. It crystallizes as non-planar discrete mol­ecules [the peripheral 3-chloro-4-hy­droxy­phenyl and benzyl groups are twisted out of the plane of the central acetamide group, with N—C—C—C and C—C—C—C torsion angles of −58.8 (3) and 65.0 (2)°, respectively] linked by inter­molecular N—H⋯O and O—H⋯O hydrogen bonds

Natural product polyamines that inhibit human carbonic anhydrases

Natural product compound collections have proven an effective way to access chemical diversity and recent findings have identified phenolic, coumarin, and polyamine natural products as atypical chemotypes that inhibit carbonic anhydrases (CAs). CA enzymes are implicated as targets of variable drug therapeutic classes and the discovery of selective, drug-like CA inhibitors is essential. Just two natural product polyamines, spermine and spermidine, have until now been investigated as CA inhibitors. In this study, five more complex natural product polyamines 1–5, derived from either marine sponge or fungi, were considered for inhibition of six different human CA isozymes of interest in therapeutic drug development. All compounds share a simple polyamine core fragment, either spermine or spermidine, yet display substantially different structure activity relationships for CA inhibition. Notably, polyamines 1–5 were submicromolar inhibitors of the cancer drug target CA IX, this is more potent than either spermine or spermidine

Selective protein unfolding: a universal mechanism of action for the development of irreversible inhibitors

High-throughput differential scanning fluorimetry of GFP-tagged proteins (HT-DSF-GTP) was applied for the identification of novel enzyme inhibitors acting by a mechanism termed: selective protein unfolding (SPU). Four different protein targets were interrogated with the same library to identify target-selective hits. Several hits selectively destabilized bacterial biotin protein ligase. Structure–activity relationship data confirmed a structure-dependent mechanism of protein unfolding. Simvastatin and altenusin were confirmed to irreversibly inactivate biotin protein ligase. The principle of SPU combined with HT-DSF-GTP affords an invaluable and innovative workflow for the identification of new inhibitors with potential applications as antimicrobials and other biocides

Natural product-based phenols as novel probes for mycobacterial and fungal carbonic anhydrases

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Type III secretion inhibitors for the management of bacterial plant diseases

Altres ajuts: COST Action SUSTAIN (FA1208) from the European Union.The identification of chemical compounds that prevent and combat bacterial diseases is fundamental for crop production. Bacterial virulence inhibitors are a promising alternative to classical control treatments, because they have a low environmental impact and are less likely to generate bacterial resistance. The major virulence determinant of most animal and plant bacterial pathogens is the type III secretion system (T3SS). In this work, we screened nine plant extracts and 12 isolated compounds-including molecules effective against human pathogens-for their capacity to inhibit the T3SS of plant pathogens and for their applicability as virulence inhibitors for crop protection. The screen was performed using a luminescent reporter system developed in the model pathogenic bacterium Ralstonia solanacearum. Five synthetic molecules, one natural product and two plant extracts were found to down-regulate T3SS transcription, most through the inhibition of the regulator hrpB. In addition, for three of the molecules, corresponding to salicylidene acylhydrazide derivatives, the inhibitory effect caused a dramatic decrease in the secretion capacity, which was translated into impaired plant responses. These candidate virulence inhibitors were then tested for their ability to protect plants. We demonstrated that salicylidene acylhydrazides can limit R. solanacearum multiplication in planta and protect tomato plants from bacterial speck caused by Pseudomonas syringae pv. tomato. Our work validates the efficiency of transcription reporters to discover compounds or natural product extracts that can be potentially applied to prevent bacterial plant disease

De quelques catéchismes créoles anciens: oublis, pertes, disparitions, réapparitions, découvertes

Il existe, dans le très vaste domaine des études postcoloniales, des territoires contigus ou semblables qui connaissent des phénomènes communs mais aux histoires très différentes, sinon radicalement opposées : tels les catéchismes - en langues romanes - fruit de la colonisation. Plus précisément, à l’histoire des catéchismes issus de la colonisation hispano-américaine, s’oppose l’histoire des catéchismes issus de la colonisation française, de l’Amérique et d’ailleurs. Ces derniers arrivent un siècle et demi environ après les espagnols et se manifestent de tout autre manière ; différents en sont l’époque, la scène et les acteurs : les destinateurs mais surtout les destinataires. Ce travail se propose de retracer l’histoire souvent aventureuse des plus anciens catéchismes des colonies ou ex-colonies françaises de la Caraïbe et de l’Océan Indien ; écrits en créole ou, parfois, en d’autres langues autochtones, ils constituent aussi des témoignages linguistiques absolument précieux. Rédigés généralement sur place, mais non toujours publiés, leur histoire est faite d’oublis, pertes, disparitions, réapparitions et découvertes. - - - In the wide field of postcolonial studies, there exist related or similar areas whose stories are nevertheless very different, if not indeed opposed. This is the case of catechisms in Romance languages (or of Romance origin), outcomes of European colonization. In particular, contradictions between the history of catechisms from Hispanic-American colonization and the catechisms produced by French colonization, in America and elsewhere. The latter appear a century and a half after the Spanish texts, and exhibit completely distinct characteristics: different periods, settings, actors, and especially recipients. I set out to recount the often adventurous history of the oldest catechisms in the French colonies, or ex-colonies, of the Caribbean and the Indian Ocean. Written in Creole or sometimes other indigenous languages, they are precious linguistic records. Compiled in the colonies, but not always published, these texts are often forgotten, lost, misplaced, resurfaced, discovered

Differential Use of Signal Peptides and Membrane Domains Is a Common Occurrence in the Protein Output of Transcriptional Units

Membrane organization describes the orientation of a protein with respect to the membrane and can be determined by the presence, or absence, and organization within the protein sequence of two features: endoplasmic reticulum signal peptides and alpha-helical transmembrane domains. These features allow protein sequences to be classified into one of five membrane organization categories: soluble intracellular proteins, soluble secreted proteins, type I membrane proteins, type II membrane proteins, and multi-spanning membrane proteins. Generation of protein isoforms with variable membrane organizations can change a protein's subcellular localization or association with the membrane. Application of MemO, a membrane organization annotation pipeline, to the FANTOM3 Isoform Protein Sequence mouse protein set revealed that within the 8,032 transcriptional units (TUs) with multiple protein isoforms, 573 had variation in their use of signal peptides, 1,527 had variation in their use of transmembrane domains, and 615 generated protein isoforms from distinct membrane organization classes. The mechanisms underlying these transcript variations were analyzed. While TUs were identified encoding all pairwise combinations of membrane organization categories, the most common was conversion of membrane proteins to soluble proteins. Observed within our high-confidence set were 156 TUs predicted to generate both extracellular soluble and membrane proteins, and 217 TUs generating both intracellular soluble and membrane proteins. The differential use of endoplasmic reticulum signal peptides and transmembrane domains is a common occurrence within the variable protein output of TUs. The generation of protein isoforms that are targeted to multiple subcellular locations represents a major functional consequence of transcript variation within the mouse transcriptome

Red Fluorescent Chlamydia trachomatis Applied to Live Cell Imaging and Screening for Antibacterial Agents

In this study, we describe the application of a transformed Chlamydia trachomatis strain constitutively expressing the red fluorescent protein mCherry, to allow real-time monitoring of the infection cycle and screening for agents that block replication of C. trachomatis. The red fluorescent C. trachomatis strain was detected autonomously without antibody staining and was equally susceptible to doxycycline as the wild type strain. A high-throughput screening assay was developed using the transformed strain and automated fluorescence microscopy. The assay was used in a pilot screen of a 349 compound library containing natural products from Australian flora and fauna. Compounds with anti-chlamydial activity were tested for dose response and toxicity to host cells and two non-toxic compounds had 50% effective concentration (EC50) values in the low micromolar range. Natural products are valuable sources for drug discovery and the identified Chlamydia growth inhibition may be starting points for future drug development. Live cell imaging was used to visualize growth of the red fluorescent C. trachomatis strain over time. The screening assay reduced workload and reagents compared to an assay requiring immunostaining and could further be used to monitor the development of Chlamydia inclusions and anti-chlamydial effect in real time

The natural stilbenoid (-)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7, and B.1.351 variants

Antivirals are urgently needed to combat the global SARS-CoV-2/COVID- 19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host angiotensin-converting enzyme II (ACE2) receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here, we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (-)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry. For example, (-)-hopeaphenol disrupted RBD/ACE2 binding with a 50% inhibitory concentration (IC50) of 0.11 mM, in contrast to an IC50 of 28.3 mM against the unrelated host ligand/receptor binding pair PD-1/PD-L1 (selectivity index, 257.3). When assessed against the USA-WA1/2020 variant, (-)-hopeaphenol also inhibited entry of a VSVDG-GFP reporter pseudovirus expressing SARS-CoV-2 spike into ACE2-expressing Vero-E6 cells and in vitro replication of infectious virus in cytopathic effect and yield reduction assays (50% effective concentrations [EC50s], 10.2 to 23.4 mM) without cytotoxicity and approaching the activities of the control antiviral remdesivir (EC50s, 1.0 to 7.3 mM). Notably, (-)-hopeaphenol also inhibited two emerging variants of concern, B.1.1.7/Alpha and B.1.351/Beta in both viral and spike-containing pseudovirus assays with similar or improved activities over the USA-WA1/2020 variant. These results identify (-)-hopeaphenol and related stilbenoid analogues as potent and selective inhibitors of viral entry across multiple SARS-CoV-2 variants of concern