Malaria is one of the world's most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds from the roots of Echinops hoehnelii were tested for their antimalarial activity using the standard four-day suppressive method in Plasmodium berghei-infected mice. The 80% methanol extract exhibited suppression of 4.6%, 27.8%, 68.5% and 78.7% at dose of 50, 100, 200 and 400 mg/kg respectively. The dichloromethane fraction displayed chemosuppression of 24.9, 33.5 and 43.0% dose of 100, 200 and 400 mg/kg of body weight. Five acetylenicthiophenes were isolated from the dichloromethane fraction of which 5-(penta-1,3-diynyl)-2-(3,4-dihydroxybut-1-ynyl)-thiophene decreased the level of parasitaemia by 43.2% and 50.2% while 5-(penta-1,3-diynyl)-2-(3-chloro-4-acetoxy-but-1-yn)-thiophene suppressed by 18.8% and 32.7% at 50 and 100 mg/kg, respectively. The study confirmed the traditional claim of the plant to treat malaria and could be used as a new lead for the development of antimalarial drugs.

With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino-thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure-activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent respiration.

We report a new class of thiophene (TP) compounds that kill Mycobacterium tuberculosis by the previously uncharacterized mechanism of Pks13 inhibition. An F79S mutation near the catalytic Ser55 site in Pks13 conferred TP resistance in M. tuberculosis. Overexpression of wild-type Pks13 resulted in TP resistance, and overexpression of the Pks13(F79S) mutant conferred high resistance. In vitro, TP inhibited fatty acyl-AMP loading onto Pks13. TP inhibited mycolic acid biosynthesis in wild-type M. tuberculosis, but it did so to a much lesser extent in TP-resistant M. tuberculosis. TP treatment was bactericidal and equivalent to treatment with the first-line drug isoniazid, but it was less likely to permit emergent resistance. Combined isoniazid and TP treatment resulted in sterilizing activity. Computational docking identified a possible TP-binding groove within the Pks13 acyl carrier protein domain. This study confirms that M. tuberculosis Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway.

Brominated anthraquinones can be synthesized directly from bromothiophenes when these are reacted with 1,4-naphthoquinones in the presence of meta-chloroperoxybenzoic acid. The bromoanthraquinones are versatile building blocks in the preparation of arylated anthraquinones and of extended pi-systems with interspersed anthraquinone units.

p38α mitogen-activated protein kinase (MAPK) plays a role in several cellular processes and consequently has been a therapeutic target in inflammatory diseases, cancer, and cardiovascular disease. A number of known p38α MAPK inhibitors contain vicinal 4-fluorophenyl/4-pyridyl rings connected to either a 5- or 6-membered heterocycle. In this study, a small library of substituted thiophene-based compounds bearing the vicinal 4-fluorophenyl/4-pyridyl rings was designed using computational docking as a visualisation tool. Compounds were synthesised and evaluated in a fluorescence polarisation binding assay. The synthesised analogues had a higher binding affinity to the active phosphorylated form of p38α MAPK than the inactive nonphosphorylated form of the protein. 4-(2-(4-fluorophenyl)thiophen-3-yl)pyridine had a K i value of 0.6 μm to active p38α MAPK highlighting that substitution of the core ring to a thiophene retains affinity to the enzyme and can be utilised in p38α MAPK inhibitors. This compound was further elaborated using a substituted phenyl ring in order to probe the second hydrophobic pocket. Many of these analogues exhibited low micromolar affinity to active p38α MAPK. The suppression of neonatal rat fibroblast collagen synthesis was also observed suggesting that further development of these compounds may lead to potential therapeutics having cardioprotective properties.

Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (-)-usnic acid and studied their ability to inhibit the main protease of SARS-CoV-2. Substances containing unsubstituted thiophene groups or methyl- or bromo-substituted thiophene moieties showed moderate activity. Derivatives containing nitro substituents in the thiophene heterocycle-just as pure (+)- and (-)-usnic acids-showed no anti-3CLpro activity. Kinetic parameters of the most active compound, (+)-3e, were investigated, and molecular modeling of the possible interaction of the new thiazolo-thiophenes with the active site of the main protease was carried out. We evaluated the binding energies of the ligand and protein in a ligand-protein complex. Active compound (+)-3e was found to bind with minimum free energy; the binding of inactive compound (+)-3g is characterized by higher values of minimum free energy; the positioning of pure (+)-usnic acid proved to be unstable and is accompanied by the formation of intermolecular contacts with many amino acids of the catalytic binding site. Thus, the molecular dynamics results were consistent with the experimental data. In an in vitro antiviral assay against six strains (Wuhan, Delta, and four Omicron sublineages) of SARS-CoV-2, (+)-3e demonstrated pronounced antiviral activity against all the strains.

Microwaves (MW) are often the most efficient, in terms of heat exchange and conversion rate, of all the energy sources used to promote chemical reactions thanks to fast volumetric dielectric heating, and metal-catalyzed synthetic reactions under heterogeneous conditions are an eloquent example. We herein report a MW-assisted green protocol for the C-H arylation of thiophenes with substituted aryl halides. This sustainable protocol carried out in γ-valerolactone (GVL) is catalyzed by Pd nanoparticles embedded in cross-linked β-cyclodextrin. In view of the excellent results achieved with activated substrates, the one-pot synthesis of a 4(3H)-quinazolinone derivative has been accomplished. A pressure-resistant MW reactor, equipped with multiple gas inlets, was used for sequential (i) C-H arylation, (ii) reduction, and (iii) carbonylation in the presence of the same catalyst, but under different gas atmospheres. The robust heterogeneous Pd catalyst showed limited metal leaching in GVL, making this an efficient MW-assisted process with high atom economy.

The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform-mediated functions.

Allosteric enhancers for the A1 adenosine receptor represent a novel and unique drug design strategy to augment the response to endogenous adenosine in a site- and event-specific manner. We have previously investigated a detailed structure-activity relationship study around a wide series of 2-amino-3-aroyl-4-[(4-arylpiperazin-1-yl)methyl]thiophene derivatives as potent allosteric enhancers of the A1 adenosine receptor. In this manuscript we report our investigation on the influence on allosteric enhancer activity of further substitution at the 4-position of the 2-amino-3-(4-chlorobenzoyl)-thiophene system to explore bulk tolerance by replacement of the arylpiperazine moiety with a series of fused indole nuclei corresponding to 1,2,3,4-tetrahydropyrazino[1,2-a]indole, 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole, tetrahydro-γ-carboline, tetrahydroisoquinoline, spiro-1,3-benzodioxolepiperidine, aliphatic tertiary amine, N-alkylaniline, aryl ether and aryl thioether templates. The 1,2,3,4-tetrahydropyrazino[1,2-a]indole derivatives 3a-c and 3e were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor. This study also shows that it is possible to obtain a good separation between allosteric enhancement and antagonistic activity at the A1 adenosine receptor.

Utilising cavitation for enhancing oxidative desulphurization has been investigated for nearly-two decades with recent investigations shifting focus from low-capacity acoustic cavitation (AC) to scalable hydrodynamic cavitation (HC). This work focuses on developing a viable means for removing thiophene's from fuels. In the first phase of this work, use of vortex based HC devices for removal of single and dual ring thiophenes from dodecane was investigated. HC was shown to be able to remove single ring thiophene from dodecane without using any external catalyst or additives. However, in absence of catalyst or additives, it was not possible to remove dual ring thiophenes such as dibenzothiophene using HC. Therefore, in the second phase of this work, various strategies based on use of catalyst or additives to augment cavitation based process were investigated. AC based experiments were opted for shortlisting suitable catalysts and additives for intensifying cavitation based processes. The influence of using oxidant (H2O2) and carboxylic acid catalysts on efficacy of removal of dual ring thiophenes is presented. Several conditions were tested, and the optimal volumetric ratios of 0.95 v/v % H2O2 and 6.25 v/v % HCOOH was identified and utilised throughout the remainder of the study. Regeneration of extractant which accumulates oxidised sulphur species from dodecane was also investigated using AC. The additives and process conditions reported in this work are useful for enhancing desulphurization performance.

This report examines the assembly of chalcogenide organic molecules on various surfaces, focusing on cases when chemisorption is accompanied by carbon-chalcogen atom-bond scission. In the case of alkane and benzyl chalcogenides, this induces formation of a chalcogenized interface layer. This process can occur during the initial stages of adsorption and then, after passivation of the surface, molecular adsorption can proceed. The characteristics of the chalcogenized interface layer can be significantly different from the metal layer and can affect various properties such as electron conduction. For chalcogenophenes, the carbon-chalcogen atom-bond breaking can lead to opening of the ring and adsorption of an alkene chalcogenide. Such a disruption of the π-electron system affects charge transport along the chains. Awareness about these effects is of importance from the point of view of molecular electronics. We discuss some recent studies based on X-ray photoelectron spectroscopy that shed light on these aspects for a series of such organic molecules.

Hydrodynamic Cavitation (HC) offers an attractive platform for intensifying oxidative desulphurization of fuels. In the first part of this work, we present new results on oxidising single ring thiophene in a model fuel over the extended range of volume fraction of organic phase from 2.5 to 80 v/v %. We also present influence of type and scale of HC device on performance of oxidative desulphurization. Further experiments revealed that oxidising radicals generated in-situ by HC alone were not able to oxidise dual ring thiophenes. External catalyst (formic acid) and oxidising agents (hydrogen peroxide, H2O2) were therefore used with HC. Based on our prior work with acoustic cavitation (AC), the volumetric ratios for H2O2 and formic acid were identified as 0.95 v/v % and 6.25 v/v % respectively. The data of oxidation of dual ring thiophenes with n-dodecane and n-hexane as model fuels and typical transport fuels (diesel, kerosene, and petrol) using these oxidant and catalyst is presented. The observed performance with HC was compared with results obtained from a stirred tank and AC set-up. The presented data indicates that HC is able to intensify oxidation of sulphur species. The presented results provide a sound basis for further developments on HC based oxidative desulphurization processes.

Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led to identification of thiophene PF-07208254, which improved cardiometabolic endpoints in mice. Structure-activity relationship studies led to identification of a thiazole series of BDK inhibitors; however, these inhibitors did not improve metabolism in mice upon chronic administration. While the thiophenes demonstrated sustained branched chain ketoacid (BCKA) lowering and reduced BDK protein levels, the thiazoles increased BCKAs and BDK protein levels. Thiazoles increased BDK proximity to BCKDH-E2, whereas thiophenes reduced BDK proximity to BCKDH-E2, which may promote BDK degradation. Thus, we describe two BDK inhibitor series that possess differing attributes regarding BDK degradation or stabilization and provide a mechanistic understanding of the desirable features of an effective BDK inhibitor.

The screening of Chinese medicinal herbs for insecticidal principles showed that the essential oil of Echinops grijsii Hance roots possessed significant larvicidal activity against mosquitoes. The essential oil was extracted via hydrodistillation and its constituents were determined by gas chromatography-mass spectrometry (GC-MS) analysis. GC-MS analyses revealed the presence of 31 components, with 5-(3-buten-1-yn-1-yl)-2,2'-bithiophene (5-BBT, 27.63%), αterthienyl (α-T, 14.95%),1,8-cineole (5.56%) and cis-β-ocimene (5.01%) being the four major constituents. Based bioactivity-directed chromatographic separation of the essential oil led to the isolation of 5-BBT, 5-(4-isovaleroyloxybut-1-ynyl)-2,2'-bithiophene (5-IBT) and αT as active compounds. The essential oil of E. grijsii exhibited larvicidal activity against the fourth instar larvae of Aedes albopictus, Anopheles sinensis and Culex pipiens pallens with LC50 values of 2.65 μg/mL, 3.43 μg/mL and 1.47 μg/mL, respectively. The isolated thiophenes, 5-BBT and 5-IBT, possessed strong larvicidal activity against the fourth instar larvae of Ae. albopictus(LC50 = 0.34 μg/mL and 0.45 μg/mL, respectively) and An. sinensis(LC50 = 1.36 μg/mL and 5.36 μg/mL, respectively). The two isolated thiophenes also had LC50 values against the fourth instar larvae of C. pipiens pallens of 0.12 μg/mL and 0.33 μg/mL, respectively. The findings indicated that the essential oil of E. grijsii roots and the isolated thiophenes have an excellent potential for use in the control of Ae.albopictus, An. sinensis and C. pipiens pallens larvae and could be used in the search for new, safer and more effective natural compounds as larvicides.

The tick Rhipicephalus sanguineus is the species with the largest worldwide distribution and is proven to be involved in the transmission of pathogens such as Babesia canis, Ehrlichia canis, Coxiella burnetii, Rickettsia ricketsii, Rickettsia conorii, among others. Studies have demonstrated acquisition of resistance to some of the active principles used in commercial formulations of acaricides. Tagetes patula (Asteraceae) is a plant with highlighted economic and commercial importance due to the production of secondary metabolites with insecticide and acaricide potential, mainly flavonoids, thiophenes and terpenes.

Four new thiophenes, (3''R)-pluthiophenol (1), (3''R)-pluthiophenol-4''-acetate (2), 3''-ethoxy-(3''S)-pluthiophenol (3), 3''-ethoxy-(3''S)-pluthiophenol-4''-acetate (4), together with twenty-five known compounds were obtained from the 70% ethanol-water extract of the aerial parts of Pluchea indica Less. Their structures were elucidated by spectroscopic methods. Among the known isolates, compounds 7, 8, 11, 14, 15, 18, 20, 23, 25⁻27 were isolated from Asteraceae family firstly, while compounds 6, 9, 10, 12, 13, 16, 19, 21, 28 were isolated from Pluchea genus for the first time. Meanwhile, compounds 1, 2, 10, 13, 18, 23 displayed significant inhibitory activities on LPS-induced NO production at 40 µM from RAW 264.7 macrophages, while compounds 3, 4, 26⁻29 possessed moderate inhibitory effects.

Direct trifluoromethylation of unactivated aromatic rings at metabolically susceptible positions is highly desirable in pharmaceutical applications. By incorporating thiophenes into the backbone of triphenylamine to enlarge its π-system, a new approach for constructing coordination polymers is reported for direct trifluoromethylation without prefunctionalization of the aryl precursors. The improved light-harvesting ability and well-modulated excited state redox potential of the designed polymers endow the generated CF3 radicals with suitable reactivity and enhance radical adduct oxidation in pores. The well-configurated interactions between the organic ligands distort the coordination geometry to create active interaction sites within the coordination polymer; thus, the substrates could be docked near the photoredox-active centres. The synergistic electronic and spatial effects in the confined pores balance the contradictory demands of electronic effects and reaction dynamics, achieving regio- and diastereoselective discrimination among reaction sites with unremarkable electronic/steric differences.

Four derivatives of dithieno[2,3-d;2',3'-d']benzo[1,2-b;3,4-b']dithiophene (DTmBDT) have been synthesized to investigate the correlation between molecular structure, thin-film organization, and charge-carrier transport. Phenyl or thiophene end-capped derivatives at alpha positions of the outer thiophenes of DTmBDT present vastly different optoelectronic properties in comparison with bay-position alkyl-chain-substituted DTmBDT, which was additionally confirmed by density functional theory simulations. The film morphology of the derivatives strongly depends on alkyl substituents, aromatic end-caps, and substrate temperature. Field-effect transistors based on DTmBDT derivatives with bay-substituted alkyl chains show the best performance within this studied series with a hole mobility up to 0.75 cm2/V s. Attachment of aromatic end-caps disturbs the ordering, limiting the charge-carrier transport. Higher substrate temperature during deposition of the DTmBDT derivatives with aromatic end-caps results in larger domains and improved the transistor mobilities but not beyond the alkylated DTmBDT.

Pluchea indica Less. is a medicine and food dual-use plant, which belongs to the Pluchea genus, Asteraceae family. Its main constituents are quinic acids, flavonoids, thiophenes, phenolic acids, as well as sesquiterpenes. In order to provide a comprehensive chemical profiling of P. indica, an orthogonal chromatography combining reverse-phase chromatography BEHC18 column with a normal-phase chromatography silica column as the separation system and a ESI-Q-Orbitrap MS as the detector in both positive and negative ion modes were used. According to the retention time (tR) and the exact mass-to-charge ratio (m/z), 67 compounds were unambiguously identified by comparing to the standard references. Moreover, 47 compounds were tentatively speculated on the basis of the rules of MS/MS fragmentation pattern and chromatographic elution order generalized from the above-mentioned reference standards. Among them, 10 of them were potentially novel.

Eclipta prostrata (L.) L. (Syn.: Eclipta alba (L.) Hassak, Family: Asteraceae) is an important medicinal plant in the tropical and subtropical regions. It is widely used in treating various diseases of skin, liver and stomach in India, Nepal, Bangladesh, and other countries. The main aim of this review was to collect and analyze the available information on traditional uses, phytoconstituents, and biological activities of E. prostrata. The scientific information was collected from the online bibliographic databases such as Scopus, MEDLINE/PubMed, Google Scholar, SciFinder, etc. and books and proceedings. The active phytochemicals were coumestan derivatives, phenolic acid derivatives, flavonoids, triterpenoid and steroid saponins, substituted thiophenes, etc. Various extracts and isolated compounds of E. prostrata showed a wide range of biological activities such as antimicrobial, anticancer, hepatoprotective, neuroprotective and hair growth promoting activities. Relatively a few studies have been performed to reveal the exact phytoconstituents responsible for their corresponding pharmacological activities. Future studies should focus on detailed mechanism based studies using animal models and clinical studies.