Synergistic effect of tryptamine-urea derivatives to overcome the chromosomally-mediated colistin resistance in Klebsiella pneumoniae.

Colistin is considered as the last-resort antibiotics to treat multi-drug resistant Gram-negative bacterial infections in humans. However, the clinical use of colistin was limited because of the apparition of chromosomal mutations and mobile colistin resistance genes in bacterial isolates. One promising strategy is to combine existing antibiotics with promising non-antibiotics to overcome the widespread emergence of antibiotic-resistant pathogens. Moreover, colistin resistance would be regulated by two component systems PhoP/PhoQ which leads to permanent synthesis of cationic groups compensating for Mg2+ deficiency. In this study, the synthesis of a small library of tryptamine urea derivatives was carried out. In addition, antibiotic susceptibility, antibiotic adjuvant screening and checkerboard assays were used to investigate the antibacterial activity of these synthesized compounds and the potential synergistic activity of their combination with colistin. Conformational analysis of the docked binding modes of the active compound in the predicted binding pocket of bacterial response regulator PhoP were carried out, to see if the active compound inhibits PhoP which is involved in colistin resistance. Finally, hemolytic activity studies have been conducted on the most active compound.

Recent advances in the development of bacterial response regulators inhibitors as antibacterial and/or antibiotic adjuvant agent: A new approach to combat bacterial resistance.

The number of new antibacterial agents currently being discovered is insufficient to combat bacterial resistance. It is extremely challenging to find new antibiotics and to introduce them to the pharmaceutical market. Therefore, special attention must be given to find new strategies to combat bacterial resistance and prevent bacteria from developing resistance. Two-component system is a transduction system and the most prevalent mechanism employed by bacteria to respond to environmental changes. This signaling system consists of a membrane sensor histidine kinase that perceives environmental stimuli and a response regulator which acts as a transcription factor. The approach consisting of developing response regulators inhibitors with antibacterial activity or antibiotic adjuvant activity is a novel approach that has never been previously reviewed. In this review we report for the first time, the importance of targeting response regulators and summarizing all existing studies carried out from 2008 until now on response regulators inhibitors as antibacterial agents or / and antibiotic adjuvants. Moreover, we describe the antibacterial activity and/or antibiotic adjuvants activity against the studied bacterial strains and the mechanism of different response regulator inhibitors when it's possible.

Synthesis of amino juglone derivatives with adjuvant activity against clinical isolated methicillin-resistant staphylococcus aureus strains.

1,4-naphthoquinones hydroxyderivatives belong to an important class of natural products and have been known as a favored scaffold in medicinal chemistry due to their multiple biological properties. Juglone is one of the most important 1,4-naphthoquinone extracted from juglandaceae family showing a good antibacterial activity. In this study, we report the synthesis of aminojuglone derivatives through Michael addition reaction using Cerium (III) chloride heptahydrate (CeCl3·7H2O) as catalyst. The synthesized aminojuglone derivatives were evaluated for their antibacterial properties against sensitive, clinical resistant Gram-positive and Gram-negative bacterial strains. Compound 3c showed a good antibacterial activity similar to cloxacillin (2 µg/mL) against the clinically resistant S.aureus. The antibiotic adjuvant activity of compounds was evaluated in combination with three clinically use antibiotics. The combination of compounds 3a, 3b, 3e, 3 h-3 l, 3n and 3o with cloxacillin showed remarkable adjuvant activity against clinically resistant S. aureus (66-fold potentiation of cloxacillin activity). 3e is the only compound consistent with the concept of antibiotic adjuvant, presenting insufficient antibacterial activity (MIC > 128 µg/mL) and potentiate the activity of cloxacillin (66-fold) with synergistic effect. A structural characterization of 3e was carried out for the first time using X-ray diffraction technic. Moreover, compound 3e did not show a cytotoxic activity on sheep red blood cells.

Antibacterial Activity and Untargeted Metabolomics Profiling of Acalypha arvensis Poepp.

The search for potent antimicrobial compounds is critical in the face of growing antibiotic resistance. This study explores Acalypha arvensis Poepp. (A. arvensis), a Caribbean plant traditionally used for disease treatment. The dried plant powder was subjected to successive extractions using different solvents: hexane (F1), dichloromethane (F2), methanol (F3), a 50:50 mixture of methanol and water (F4), and water (F5). Additionally, a parallel extraction was conducted using a 50:50 mixture of methanol and chloroform (F6). All the fractions were evaluated for their antimicrobial activity, and the F6 fraction was characterized using untargeted metabolomics using SPME-GC×GC-TOFMS. The extracts of A. arvensis F3, F4, and F5 showed antibacterial activity against Staphylococcus aureus ATCC 25923 (5 mg/mL), MRSA BA22038 (5 mg/mL), and Pseudomonas aeruginosa ATCC 27853 (10 mg/mL), and fraction F6 showed antibacterial activity against Staphylococcus aureus ATCC 29213 (2 mg/mL), Escherichia coli ATCC 25922 (20 mg/mL), Pseudomonas aeruginosa ATCC 27853 (10 mg/mL), Enterococcus faecalis ATCC 29212 (10 mg/mL), Staphylococcus aureus 024 (2 mg/mL), and Staphylococcus aureus 003 (2 mg/mL). Metabolomic analysis of F6 revealed 2861 peaks with 58 identified compounds through SPME and 3654 peaks with 29 identified compounds through derivatization. The compounds included methyl ester fatty acids, ethyl ester fatty acids, terpenes, ketones, sugars, amino acids, and fatty acids. This study represents the first exploration of A. arvensis metabolomics and its antimicrobial potential, providing valuable insights for plant classification, phytochemical research, and drug discovery.

Green methodologies for the synthesis of 2-aminothiophene.

Pollution and the rising energy demand have prompted the design of new synthetic reactions that meet the principles of green chemistry. In particular, alternative synthesis of 2-aminothiophene have recently focused interest because 2-aminothiophene is a unique 5-membered S-heterocycle and a pharmacophore providing antiprotozoal, antiproliferative, antiviral, antibacterial or antifungal properties. Here, we review new synthetic routes to 2-aminothiophenes, including multicomponent reactions, homogeneously- or heterogeneously-catalyzed reactions, with focus on green pathways.

Catalyst-Free Site Selective Hydroxyalkylation of 5-Phenylthiophen-2-amine with α-Trifluoromethyl Ketones through Electrophilic Aromatic Substitution.

An original and effective approach for achieving trifluoromethyl hydroxyalkylation of 5-phenylthiophen-2-amine using α-trifluoromethyl ketones is described. In the last few years, reaction of Friedel-Crafts had been widely used to realize hydroxyalkylation on heterocycles such as indoles or thiophenes by means of Lewis acid as catalyst. Additionally, amine functions are rarely free when carbonyl reagents are used because of their tendency to form imines. This is the first time that a site-selective electrophilic aromatic substitution on C3 atom of an unprotected 5-phenylthiophen-2-amine moiety is reported. The liberty to allow reaction in neutral conditions between free amine is valuable in a synthesis pathway. The reaction proceeds smoothly using an atom-economical metal-and catalyst-free methodology in good to excellent yields. A mechanism similar to an electrophilic aromatic substitution has been proposed.

Synthesis of histidine kinase inhibitors and their biological properties.

Infections caused by multidrug-resistant bacteria represent a significant and ever-increasing cause of morbidity and mortality. There is thus an urgent need to develop efficient and well-tolerated antibacterials targeting unique cellular processes. Numerous studies have led to the identification of new biological targets to fight bacterial resistance. Two-component signal transduction systems are widely employed by bacteria to translate external and cellular signals into a cellular response. They are ubiquitous in bacteria, absent in the animal kingdom and are integrated into various virulence pathways. Several chemical series, including isothiazolidones, imidazolium salts, benzoxazines, salicylanilides, thiophenes, thiazolidiones, benzimidazoles, and other derivatives deduced by different approaches have been reported in the literature to have histidine kinase (HK) inhibitory activity. In this review, we report on the design and the synthesis of these HKs inhibitors and their potential to serve as antibacterial agents.

Improved synthesis, resolution, absolute configuration determination and biological evaluation of HLM006474 enantiomers.

An improved green synthesis of the E2F inhibitor HLM0066474 is described, using solvent-free and microwave irradiation conditions. The two enantiomers are separated using semi-preparative separation on Chiralpak ID and their absolute configuration is determined by vibrational circular dichroism (VCD) analysis. Biological evaluation of both enantiomers on E2F1 transcriptional activity reveals that the (+)-R, but not the (-)-S enantiomer is biologically active in repressing E2F1 transcriptional activity.

Ethynylglycine synthon, a useful precursor for the synthesis of biologically active compounds: an update. Part II: synthetic uses of ethynylglycine synthon.

The ethynylglycine synthon {(R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyl-oxazolidine} is a chiral compound with valuable synthetic interest. An update (covering literature from 2005 to 2017) on the different synthetic utilities is reviewed and discussed.

Advances in the synthesis of α-quaternary α-ethynyl α-amino acids.

α-Quaternary α-ethynyl α-amino acids are an important class of non-proteinogenic amino acids that play an important role in the development of peptides and peptidomimetics as therapeutic agents and in the inhibition of enzyme activities. This review provides an overview of the literature concerning synthesis and applications of α-quaternary α-ethynyl α-amino acids covering the period from 1977 to 2015.

Ethynylglycine synthon, a useful precursor for the synthesis of biologically active compounds: an update: part I: preparations of ethynylglycine synthon.

The ethynylglycine synthon {(R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyloxazolidine} is a chiral compound with valuable synthetic interest. An update on the different routes for its synthesis is reviewed and discussed.

Volatile Organic Compounds Emitted by Flowers: Ecological Roles, Production by Plants, Extraction, and Identification.

Volatile organic compounds (VOCs) with a large chemical diversity are emitted by plant flowers. These compounds play an important role in the ecology of plants. This review presents the different ecological roles of VOCs present in the odor plumes of plant flowers, such as pollination, defense, adaptation to their environment, and communication with other organisms. The production and accumulation sites of VOCs in plants with their spatial and temporal variations, including environmental issues, are also summarized. To evaluate the qualitative and quantitative chemical composition of VOCs, several methods of extraction and analysis were used. Headspace (HS) sampling coupled with solid phase microextraction (SPME) is now well-developed for the extraction process. Parameters are known, and several fibers are now available to optimize this extraction. Most of the time, SPME is coupled with gas chromatography-mass spectrometry (GC-MS) to determine the structural identification of the VOCs, paying attention to the use of several complementary methods for identification like the use of databases, retention indices, and, when available, comparison with authentic standards analyses. The development of the knowledge on VOCs emitted by flowers is of great importance for plant ecology in the context of environmental and climate changes.

Determination of the maximum bioaccumulation capacity of various metals in leaves of two Tillandsia species.

Tillandsia species are plants from the Bromeliaceae family which display biomonitoring capacities in both active and passive modes. The bioaccumulation potential of Tillandsia aeranthos (Loisiel.) Desf. and Tillandsia bergeri Mez acclimated to Southern/Mediterranean Europe has never been studied. More generally, few studies have detailed the maximum accumulation potential of Tillandsia leaves through controlled experiments. The aim of this study is to evaluate the maximum accumulation values of seven metals (Co, Cu, Mn, Ni, Pb, Pt, and Zn) in T. aeranthos and T. bergeri leaves. Plants were immersed in different mono elemental metallic solutions of Co (II), Cu (II), Mn (II), Ni (II), Pb (II), Pt (IV), and Zn (II) ions at different concentrations. In addition, cocktail solutions of these seven metals at different concentrations were prepared to study the main differences and the potential selectivity between metals. After exposure, the content of these metals in the leaves were measured by inductively coupled plasma-optical emission spectrometry. Data sets were evaluated by a fitted regression hyperbola model and principal component analysis, maximum metal loading capacity, and thermodynamic affinity constant were determined. The results showed important differences between the two species, with T. bergeri demonstrating higher capacity and affinity for metals than T. aeranthos. Furthermore, between the seven metals, Pb and Ni showed higher enrichment factors (EF). T. bergeri might be a better bioaccumulator than T. aeranthos with marked selectivity for Pb and Ni, metals of concern in air quality biomonitoring.

Survey on the Traditional Use of Medicinal Herbs in Haiti: A Study on Knowledge, Practices, and Efficacy Prevention.

The use of medicinal herbs is highly developed in Haiti. However, there is a significant lack of knowledge in the literature on medicinal plants and their uses. The objective of this study was to determine the knowledge and practices of Haitian families for the prevention/treatment of COVID-19, influenza, and respiratory diseases, as well as the mode of preparation and administration of the plants. Individuals were interviewed using the TRAMIL questionnaire as the information holder. The data obtained were analyzed by calculating 5 indices (relative frequency of citation, use value, the family use value, informant consensus factor, and fidelity level). The study surveyed 120 Haitians and collected 75 plants from 43 botanical families. The botanical family most used for all these preventions and remedies is the Lamiaceae. The highest ranked species with a relative frequency of citation value > 0.3. Infusion, decoction, and in the form of punch are the methods used for the remedies. The study found that the use of herbal remedies is still prevalent in the study area, and many of the commonly used plants have been scientifically validated. However, some plants, such as Samyda rosea Sims, lack sufficient research and are recommended for further investigation.

An overview on the antibacterial properties of juglone, naphthazarin, plumbagin and lawsone derivatives and their metal complexes.

Bacterial resistance development represents a serious threat to human health across the globe and has become a very serious clinical problem for many classes of antibiotics. Hence, there is a constant and urgent need for the discovery and development of new effective antibacterial agents to stem the emergence of resistant bacteria. 1,4-naphthoquinones are an important class of natural products and have been known for decades as a privileged scaffold in medicinal chemistry regarding their many biological properties. The significant biological properties of specific 1,4-naphthoquinones hydroxyderivatives have drawn the attention of researchers in order to find new derivatives with an optimized activity, mainly as antibacterial agents. Based on juglone, naphthazarin, plumbagin and lawsone moieties, structural optimization was realized with the purpose of improving the antibacterial activity. Thereupon, relevant antibacterial activities have been observed on different panels of bacterial strains including resistant ones. In this review, we highlight the interest of developing new 1,4-naphthoquinones hydroxyderivatives and some metal complexes as promising antibacterial agents alternatives. Here, we thoroughly report for the first time both the antibacterial activity and the chemical synthesis of four different 1,4-naphthoquinones (juglone, naphthazarin, plumbagin and lawsone) from 2002 to 2022 with an emphasis on the structure-activity relationship, when applicable.

Phytochemical and Biological Study of Trophic Interaction between Pseudosphinx Tetrio L. Larvae and Allamanda Cathartica L.

In this article, we propose to explore the chemical interaction between Pseudosphinx tetrio L. and Allamanda cathartica L. using different analytical methods, including an innovative electrochemical approach (called electrochemical ecology) and multivariate analysis, and we investigate the potential antimicrobial effects (antibacterial and antifungal activities) of this interaction in order to gain a better understanding of their specific interaction. The analytical study presents a similar chemical profile between the leaves of healthy and herbivorous A. cathartica and the excretions of the caterpillars. The similar analytical profile of the leaves of A. cathartica and the excretions of P. tetrio, and the difference with the caterpillar bodies, suggests a selective excretion of compounds by the caterpillar. The measured antimicrobial activities support the physicochemical tests. The natural products found selectively in the excretions (rather than in the body) could explain the ability of P. tetrio to feed on this toxic Apocynaceae species.

ß-Cell-Specific E2f1 Deficiency Impairs Glucose Homeostasis, ß-Cell Identity, and Insulin Secretion.

The loss of pancreatic ß-cell identity has emerged as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cell-autonomous role of the cell-cycle regulator and transcription factor E2F1 in the maintenance of ß-cell identity, insulin secretion, and glucose homeostasis. We show that the ß-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, altered endocrine cell mass, downregulation of many ß-cell genes, and concomitant increase of non-ß-cell markers. Mechanistically, epigenomic profiling of the promoters of these non-ß-cell upregulated genes identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, promoters of downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that specific E2f1 transcriptional, cistromic, and epigenomic signatures are associated with these ß-cell dysfunctions, with E2F1 directly regulating several ß-cell genes at the chromatin level. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of ß-cell identity genes. Our data suggest that E2F1 is critical for maintaining ß-cell identity and function through sustained control of ß-cell and non-ß-cell transcriptional programs. ARTICLE HIGHLIGHTS: ß-Cell-specific E2f1 deficiency in mice impairs glucose tolerance. Loss of E2f1 function alters the ratio of α- to ß-cells but does not trigger ß-cell conversion into α-cells. Pharmacological inhibition of E2F activity inhibits glucose-stimulated insulin secretion and alters ß- and α-cell gene expression in human islets. E2F1 maintains ß-cell function and identity through control of transcriptomic and epigenetic programs.

Chemoenzymatic routes to enantiomerically pure 2-azatyrosine and 2-, 3- and 4-pyridylalanine derivatives.

Enantiomerically pure 2-, 3- or 4-pyridylalanine (pya) and 2-azatyrosine (azatyr) are known to present various biological activities. After incorporation into appropriate peptide sequences, these heterocyclic non natural α-amino acids could behave as new substrates or inhibitors of elastase from Pseudomonas aeruginosa. This enzyme is known to be involved in nosocomial infections and infections related to the cystic fibrosis disease. New efficient chemoenzymatic preparations of those compounds using α-chymotrypsin (α-CT) are presented.

Recent contribution of medicinally active 2-aminothiophenes: A privileged scaffold for drug discovery.

In medicinal chemistry, 2-aminothiophene is a central five-membered heterocyclic core that is mostly synthesized using Gewald methodology. Its incorporation into a molecule can confer broad biological activities, making 2-aminothiophene an attractive scaffold for drug discovery. Another interesting feature of 2-aminothiophene moiety is its ability to act as synthon for the synthesis of biological active thiophene-containing heterocycles, conjugates or hybrids. Compounds from the 2-aminothiophene family are promising selective inhibitors and modulators in medicinal chemistry, and even exhibit effective pharmacological properties in the various clinical phases of appropriate diseases. Likewise, the biological actions of 2-aminothiophenes or their 2-N-substituted analogs are still being investigated because of their diverse mechanisms of action (e.g., pharmacophore and pharmacokinetic properties). In this review, we focus on the structure-activity relationship, the synthesis and the biological activities of 2-aminothiophene derivatives, including antiprotozoal, antiproliferative, antiviral, antibacterial, antifungal, channel and cannabinoid receptor inhibitors. Most perspective drug-candidate hits were selected for discussion and described, along with additional synthetic pathways. Since there has been several contributions in this field recently, we emphasized on the literature dedicated to 2-aminothiophenes and 2-N-substituted derivatives which have been published from 2017 to 2022.