Related Analogues Research Articles

Lipoprotein(a) as a predictive marker of coronary artery calcification (CAC). The results from the STAR-Lp(a) cohort study.

Abstract Background Lipoprotein(a) [Lp(a)] concentration is an independent risk factor for cardiovascular disease, including atherosclerosis. Purpose The aim of the study was to assess the relationship between the elevated Lp(a) levels, and the risk of developing atherosclerosis assessed using coronary artery calcium (CAC) score. Methods The analysis was conducted among 553 primary prevention patients (65.7% women, the average age was 65.8±10.1 years) from the outpatient specialist care who underwent coronary computed tomographic angiography (CTA). This group accounted for 22.3% of all patients (n=2475) included in the registry. Lp(a) levels were assessed in three groups: <30 mg/dL (<75 nmol/l) (normal level), 30-50 mg/dL (75-125 nmol/l) (moderate cardiovascular risk) and >50 (>125 nmol/l) (high cardiovascular risk). Patients were divided into groups: with normal CAC score (CAC=0), with CAC 1-100 (presence of atherosclerotic), and those with CAC>100 (advanced atherosclerosis). Statistical analysis was performed using STATISTICA 13.1. Quantitative variables were known by providing descriptive statistics (mean and standard deviation [SD]). The chi-square test was used to assess the relationship between quantitative variables and Mann-Whitney and Kruskal Wallis in the case of qualitative variables. Pearson's correlation coefficient was used to measure correlation. To determine the effect of factors on the probability of occurrence CAC=0 a multivariate logistic regression model was built. P<0.05 was judged as significant. Results Positive significant correlation between CAC score and age was revealed (r=0.266, p<0.001). An analogous relationship was observed regarding to glucose level (r=-0.123, p=0.012). This was not observed for Lp(a). However, we showed a significant relationship between the level of Lp(a) and CAC score (r=0.113, p=0.009) (Fig. 1). Lp(a) levels increased with the CAC score increase. For every 10 mg/dL (25 nmol/l) of Lp(a), CAC score increases by 15.7±0.57 (p=0.006). The mean CAC among patients with normal Lp(a) level was 203.1 (±412.6) and respectively 206.6 (±460.1) in those with moderate cardiovascular risk and 335.6 (±784.9) for people with high risk (p=0.183). In the regression model the factors determining the absence of atherosclerosis (CAC=0; "power of zero") included female gender (OR = 4.05; 95CI: 2.48-6.59), age under 65 (OR = 0.31; 95CI: 0.07-1.34 for aged 40-65), and Lp(A)≤50 mg/dl (≤125 nmol/l) (OR=2.26; 95CI: 1.12-4.61). People with hypertension had a significantly lower odds of CAC=0 (OR=0.58; 95CI: 0.38-0.89). Conclusions The study showed a significant linear relationship between increased Lp(a) levels, and the progression of atherosclerosis expressed by the CAC score. Results confirm some existing recommendations that if an elevated Lp(a) level is found in a patient for primary prevention, a CT scan of the coronary arteries with assessment of the CAC score should be considered for more appropriate risk stratification.

Structure-activity relationship of amino acid analogs to probe the binding pocket of sodium-coupled neutral amino acid transporter SNAT2.

The sodium-coupled neutral amino acid transporter SNAT2 (SLC38A2) has been shown to have important physiological functions and is implicated in various diseases like cancer. However, few compounds targeting this transporter have been identified and little is known about the structural requirements for SNAT2 binding. In this study, the aim was to establish the basic structure-activity relationship for SNAT2 using amino acid analogs. These analogs were first studied for their ability to inhibit SNAT2-mediated 3H-glycine uptake in hyperosmotically treated PC-3 cells. Then to identify substrates a FLIPR membrane potential assay and o-phthalaldehyde derivatization of intracellular amino with subsequent quantification using HPLC-Fl was used. The results showed that ester derivatives of the C-terminus maintained SNAT2 affinity, suggesting that the negative charge was less important. On the other hand, the positive charge at the N-terminus of the substrate and the ability to donate at least two hydrogen bonds to the binding site appeared important for SNAT2 recognition of the amine. Side chain charged amino acids generally had no affinity for SNAT2, but their non-charged derivatives were able to inhibit SNAT2-mediated 3H-glycine uptake, while also showing that amino acids of a notable length still had affinity for SNAT2. Several amino acid analogs appeared to be novel substrates of SNAT2, while γ-benzyl L-glutamate seemed to be inefficiently translocated by SNAT2. Elaborating on this structure could lead to the discovery of non-translocated inhibitors of SNAT2. Thus, the present study provides valuable insights into the basic structural binding requirements for SNAT2 and can aid the future discovery of compounds that target SNAT2.

A simple and efficient solution scheme of coupling method between phase field regularized cohesive zone model and linear elastic model for fracture

To improve computational efficiency, in this work, a coupling scheme between a phase field regularized cohesive zone model and a linear elastic model is proposed. According to the crack pattern, the entire solution domain is partitioned into different subregions, the phase field regularized cohesive zone model is applied only in the subregion where the crack appears, the linear elastic model is considered in the remaining region, combining the characteristics and advantages of the two models to improve computational efficiency. Secondly, in the light of the similarity between the phase field model governing equation and the heat transfer equation, the analogous relationships for different coefficients are given, and the coupling model is implemented using an equivalent thermal coupling framework, avoiding post-processing of complex element. Finally, the validity of the presented model is verified by some typical examples. The results indicate that the coupling model can be used to study the complex fracture process under different failure modes. Its load displacement response, energy characteristic and crack pattern are in line with that of the pure phase field regularized cohesive zone model and are in agreement with experiment and literature results. Meanwhile, compared to pure phase field model, the proposed coupling model consumes lower time cost.

Nucleoside Scaffolds and Carborane Clusters for Boron Neutron Capture Therapy: Developments and Future Perspective.

Nucleosides containing carboranes are one of the most important boron delivery agents for boron neutron capture therapy, BNCT, which are good substrates of hTK1. The development of several nucleosides containing carboranes at early stages led to the discovery of the first generation of 3CTAs by incorporating a hydrocarbon spacer between the thymidine scaffold and carborane cluster and attaching dihydroxylpropyl group on the second carbon (C2) atom of the carborane cluster (e.g., N5 and N5-2OH). Phosphorylation rate, tumor cellular uptake, and retention have been evaluated in parallel to change the length of the tether arm of spacers in these compounds. Many attempts were reported and discussed to overcome the disadvantage of the first generation of 3CTAs by a) incorporating modified spacers between thymidine and carborane clusters, such as ethyleneoxide, polyhydroxyl, triazole, and tetrazole units, b) attaching hydrophilic groups at C2 of the carborane cluster, c) transforming lipophilic closo-carboranes to hydrophilic nidocarborane. The previous modifications represented the second generation of 3CTAs to improve the hydrogen bond formation with the hTK1 active site. Moreover, amino acid prodrugs were developed to enhance biological and physicochemical properties. The structure-activity relationship (SAR) of carboranyl thymidine analogues led to the roadmap for the development of the 3rd generation of the 3CTAs for BNCT.

3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies.

The apicoplast is an essential organelle for the viability of apicomplexan parasites Plasmodium falciparum or Toxoplasma gondii, which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active at low nM concentrations on several blood stages of Plasmodiumsuch as early rings and gametocytes. Nevertheless, its precise biological targets remain unknown. Here, we described the synthesis and the evaluation of new heteroaromatic analogues of plasmodione, active on asexual blood P. falciparum stages and T. gondii tachyzoites. Using a bioimaging-based analysis, we followed the morphological alterations of T. gondii tachyzoites and revealed a specific loss of the apicoplast upon drug treatment. Lipidomic and fluxomic analyses determined that drug treatment severely impacts apicoplast-hosted FASII activity in T. gondii tachyzoites, further supporting that the apicoplast is a primary target of plasmodione analogues. To follow the drug localization, "clickable" analogues of plasmodione were designed as tools for fluorescence imaging through a Cu(I)-catalyzed azide-alkyne cycloaddition reaction. Short-time incubation of two probes with P. falciparum trophozoites and T. gondii tachyzoites showed that the clicked products localize within, or in the vicinity of, the apicoplast of both Apicomplexa parasites. In P. falciparum, the fluorescence signal was also associated with the mitochondrion, suggesting that bioactivation and activity of plasmodione and related analogues are potentially associated with these two organelles in malaria parasites.

AANAT kinetics of CoASH-targeted electrophiles of tryptamine and related analogs

Arylalkylamine N-acetyltransferase (AANAT) catalyzes the rate-limiting step in melatonin synthesis and is a potential target for disorders involving melatonin overproduction, such as seasonal affective disorder. Previously described AANAT inhibitor bromoacetyltryptamine (BAT) and benzothiophenes analogs were reported to react with CoASH to form potent bisubstrate inhibitors through AANAT’s alkyltransferase function, which is secondary to its role as an acetyltransferase. We replaced the bromoacetyl group in BAT with various Michael acceptors to mitigate possible off-target activity of its bromoacetyl group. Additionally, we modified the length of the carbon linker between the Michael acceptor and indole bicycle of tryptamine to determine its effect on potency. An AANAT enzymatic assay showed a two-carbon linker present in BAT was optimal, while none of the new warheads had activity. Kinetic analysis indicated that these Michael acceptors reacted with CoASH much slower than BAT and not within the timeframe of our enzymatic assay. Additionally, we confirmed earlier reports that the acetyltransferase function of AANAT follows an ordered bi bi mechanism in which AcCoA binds before serotonin. In contrast, BAT’s alkyltransferase kinetics revealed a bi uni mechanism in which BAT binds to AANAT before CoASH. Our model combines both functions of AANAT into one kinetic mechanism.

Dual Kv7.2/3-TRPV1 modulators inhibit nociceptor hyperexcitability and alleviate pain without target-related side effects.

Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either limited in efficacy or cause intolerable side effects. Diverse mechanisms contribute to the basic phenomena of nociceptor hyperexcitability that initiates and maintains pain. Two prominent players in the modulation of nociceptor hyperexcitability are the transient receptor potential vanilloid type 1 (TRPV1) ligand-gated ion channel and the voltage-gated potassium channel, Kv7.2/3, that reciprocally regulate neuronal excitability. Across many drug development programs targeting either TRPV1 or Kv7.2/3, significant evidence has been accumulated to support these as highly relevant targets; however, side effects that are poorly separated from efficacy have limited the successful clinical translation of numerous Kv7.2/3 and TRPV1 drug development programs. We report here the pharmacological profile of 3 structurally related small molecule analogues that demonstrate a novel mechanism of action (MOA) of dual modulation of Kv7.2/3 and TRPV1. Specifically, these compounds simultaneously activate Kv7.2/3 and enable unexpected specific and potent inhibition of TRPV1. This in vitro potency translated to significant analgesia in vivo in several animal models of acute and chronic pain. Importantly, this specific MOA is not associated with any previously described Kv7.2/3 or TRPV1 class-specific side effects. We suggest that the therapeutic potential of this MOA is derived from the selective and specific targeting of a subpopulation of nociceptors found in rodents and humans. This efficacy and safety profile supports the advancement of dual TRPV1-Kv7.2/3 modulating compounds into preclinical and clinical development for the treatment of chronic pain.

Plasmodium SEY1 is a novel druggable target that contributes to imidazolopiperazine mechanism of action.

The precise mode of action of ganaplacide (KAF156), a phase III antimalarial candidate, remains elusive. Here we employ omics-based methods with the closely related chemical analog, GNF179, to search for potential Plasmodium targets. Ranking potential targets derived from chemical genetics and proteomic affinity chromatography methodologies identifies SEY1, or Synthetic Enhancement of YOP1, which is predicted to encode an essential dynamin-like GTPase implicated in homotypic fusion of endoplasmic reticulum (ER) membranes. We demonstrate that GNF179 decreases Plasmodium SEY1 melting temperature. We further show that GNF179 binds to recombinant Plasmodium SEY1 and subsequently inhibits its GTPase activity, which is required for maintaining ER architecture. Using ultrastructure expansion microscopy, we find GNF179 treatment changes parasite ER and Golgi morphology. We also confirm that SEY1 is an essential gene in P. falciparum. These data suggest that SEY1 may contribute to the mechanism of action of imidazolopiperazines and is a new and attractive druggable target.

A Multimodal, In Vivo Approach for Assessing Structurally and Phenotypically Related Neuroactive Molecules.

A recently reported behavioral screen in larval zebrafish for phenocopiers of known anesthetics and associated drugs yielded an isoflavone. Related isoflavones have also been reported as GABAA potentiators. From this, we synthesized a small library of isoflavones and incorporated an in vivo phenotypic approach to perform structure-behavior relationship studies of the screening hit and related analogs via behavioral profiling, patch-clamp experiments, and whole brain imaging. This revealed that analogs effect a range of behavioral responses, including sedation with and without enhancing the acoustic startle response. Interestingly, a subset of compounds effect sedation and enhancement of motor responses to both acoustic and light stimuli. Patch clamp recordings of cells with a human GABAA receptor confirmed that behavior-modulating isoflavones modify the GABA signaling. To better understand these molecules' nuanced effects on behavior, we performed whole brain imaging to reveal that analogs differentially effect neuronal activity. These studies demonstrate a multimodal approach to assessing activities of neuroactives.

Structure-Activity Relationship of Inositol Thiophosphate Analogs as Allosteric Activators of Clostridioides difficile Toxin B.

Clostridioides difficile is a bacterium that causes life-threatening intestinal infections. Infection symptoms are mediated by a toxin secreted by the bacterium. Toxin pathogenesis is modulated by the intracellular molecule, inositol-hexakisphosphate (IP6). IP6 binds to a cysteine protease domain (CPD) on the toxin, inducing autoproteolysis, which liberates a virulence factor in the cell cytosol. We developed second-generation IP6 analogs designed to induce autoproteolysis in the gut lumen, prior to toxin uptake, circumventing pathogenesis. We synthesized a panel of thiophosphate-/sulfate-containing IP6 analogs and characterized their toxin binding affinity, autoproteolysis induction, and cation interactions. Our top candidate was soluble in extracellular cation concentrations, unlike IP6. The IP6 analogs were more negatively charged than IP6, which improved affinity and stabilization of the CPD, enhancing toxin autoproteolysis. Our data illustrate the optimization of IP6 with thiophosphate biomimetic which are more capable of inducing toxin autoproteolysis than the native ligand, warranting further studies in vivo.

Previously unmeasured genetic diversity explains part of Lewontin's paradox in a -mer-based meta-analysis of 112 plant species.

At the molecular level, most evolution is expected to be neutral. A key prediction of this expectation is that the level of genetic diversity in a population should scale with population size. However, as was noted by Richard Lewontin in 1974 and reaffirmed by later studies, the slope of the population size-diversity relationship in nature is much weaker than expected under neutral theory. We hypothesize that one contributor to this paradox is that current methods relying on single nucleotide polymorphisms (SNPs) called from aligning short reads to a reference genome underestimate levels of genetic diversity in many species. To test this idea, we calculated nucleotide diversity ( ) and -mer-based metrics of genetic diversity across 112 plant species, amounting to over 205 terabases of DNA sequencing data from 27,488 individual plants. We then compared how these different metrics correlated with proxies of population size that account for both range size and population density variation across species. We found that our population size proxies scaled anywhere from about 3 to over 20 times faster with -mer diversity than nucleotide diversity after adjusting for evolutionary history, mating system, life cycle habit, cultivation status, and invasiveness. The relationship between -mer diversity and population size proxies also remains significant after correcting for genome size, whereas the analogous relationship for nucleotide diversity does not. These results suggest that variation not captured by common SNP-based analyses explains part of Lewontin's paradox in plants.

Screening, Growing, and Validation by Catalog: Using Synthetic Intermediates from Natural Product Libraries to Discover Fragments for an Aspartic Protease Through Crystallography

Fragment screening directly on protein crystals has been applied using AnalytiCon’s collection of intermediates that have been utilized to generate libraries of larger synthetic natural product-like molecules. The fragments with well-balanced physicochemical properties show an impressively high hit rate for a screen using the aspartic protease endothiapepsin. The subsequent validation and expansion of the discovered fragment hits benefits from AnalytiCon’s comprehensive library design. Since the screened fragments are intermediates that share a common core with larger and closely related analogs with modulated substitution patterns, they allow for the retrieval of off-the-shelf follow-up compounds, which enable the development of design strategies for fragment optimization. A promising bicyclic core scaffold found in several fragment hits could be validated by selecting a set of enlarged follow-up compounds. Due to unexpected changes in binding mode and no significant improvement in ligand efficiency, this series was quickly deemed unsuitable and therefore discontinued. The structures of follow-up compounds of two other fragments helped to evaluate a putative fusion of two overlapping fragment hits. A design concept on how to fuse the two fragments could be proposed and helps to plan a suitable substitution pattern and promising central bridging element.

Three-fold π delocalisation bonding pattern in bowl-like B70 cluster: an all-boron analogue of the nanographene molecule C48H18

A chemical bonding model for the quasi-planar bowl-like B70 cluster has been presented using the canonical molecular orbital (CMO) and the adaptive natural density partitioning (AdNDP) analyses at the density functional theory (DFT) level. Chemical bonding analysis indicates that the bowl-like B70 is an all-boron analogues of one planar nanographene molecule (C48H18) featuring concentric triple π delocalisation with 6π, 12π and 30π electrons for the inner, middle and outer boron ribbons, respectively. The bonding nature of C48H18 is fully elucidated herein firstly. The infrared spectra of B70 are predicted to facilitate the future experimental characterisations. This research enriches the analogous relationship between planar boron clusters and their polycyclic aromatic hydrocarbons (PAHs) counterparts. The bowl-shaped B70 is the largest boron analogue of PAH reported to date. The unique bonding picture of concentric, three-fold π delocalisation has not been discussed previously in the literature.

In vitro trypanocidal activities and structure-activity relationships of ciprofloxacin analogs.

Tropical diseases, such as African trypanosomiasis, by their nature and prevalence lack the necessary urgency regarding drug development, despite the increasing need for novel, structurally diverse antitrypanosomal drugs, using different mechanisms of action that would improve drug efficacy and safety. Traditionally antibacterial agents, the fluoroquinolones, reportedly possess in vitro trypanocidal activities against Trypanosoma brucei organisms. During our research, the fluroquinolone, ciprofloxacin (1), and its analogs (2-24) were tested against bloodstream forms of T. brucei brucei, T. b. gambiense, T. b. rhodesiense, T. evansi, T. equiperdum, and T. congolense and Madin-Darby bovine kidney cells (cytotoxicity). Ciprofloxacin [CPX (1)] demonstrated selective trypanocidal activity against T. congolense (IC50 7.79µM; SI 39.6), whereas the CPX derivatives (2-10) showed weak selective activity (25 < IC50 < 65µM; 2 < SI < 4). Selectivity and activity of the CPX and 1,2,3-triazole (TZ) hybrids (11-24) were governed by their chemical functionality at C-3 (carboxylic acid, or 4-methylpiperazinyl amide) and their electronic effect (electron-donating or electron-withdrawing para-benzyl substituent), respectively. Trypanocidal hits in the micromolar range were identified against bloodstream forms of T. congolense [CPX (1); CPX amide derivatives 18: IC50 8.95µM; SI 16.84; 22: IC50 5.42µM; SI 25.2] and against T. brucei rhodesiense (CPX acid derivative 13: IC50 4.51µM; SI 10.2), demonstrating more selectivity toward trypanosomes than mammalian cells. Hence, the trypanocidal hit compound 22 may be optimized by retaining the 4-methylpiperazine amide functional group (C-3) and the TZ moiety at position N-15 and introducing other electron-withdrawing ortho-, meta-, and/or para-substituents on the aryl ring in an effort to improve the pharmacokinetic properties and increase the trypanocidal activity.

Investigation on the Anticancer Activity of [6]-Gingerol of Zingiber officinale and its Structural Analogs against Skin Cancer.

Skin cancer is the most common type of cancer caused by the uncontrolled growth of abnormal cells in the epidermis and the outermost skin layer. This study aimed to study the anti-skin cancer potential of [6]-Gingerol and 21 related structural analogs using in vitro</i> and in silico</i> studies. The ethanolic crude extract of the selected plant was subjected to phytochemical and GC-MS analysis to confirm the presence of the [6]-gingerol. The anticancer activity of the extract was evaluated by MTT (3-[4, 5-dimethylthiazol-2-y]-2, 5-diphenyl tetrazolium bromide) assay using the A431 human skin adenocarcinoma cell line. The GC-MS analysis confirmed the presence of [6]-Gingerol compound, and its promising cytotoxicity IC50 was found at 81.46 ug/ml in the MTT assay. Furthermore, the in silico studies used [6]-Gingerol and 21 structural analogs collected from the PubChem database to investigate the anticancer potential and drug-likeliness properties. Skin cancer protein, DDX3X, was selected as a target that regulates all stages of RNA metabolism. It was docked with 22 compounds, including [6]-Gingerol and 21 structural analogs. The potent lead molecule was selected based on the lowest binding energy value. Thus, the [6]-Gingerol and its structure analogs could be used as lead molecules against skin cancer and future drug development process.

Bis-sulfonamido-2-phenylbenzoxazoles Validate the GroES/EL Chaperone System as a Viable Antibiotic Target.

We recently reported on small-molecule inhibitors of the GroES/GroEL chaperone system as potential antibiotics against Escherichia coli and the ESKAPE pathogens but were unable to establish GroES/GroEL as the cellular target, leading to cell death. In this study, using two of our most potent bis-sulfonamido-2-phenylbenzoxazoles (PBZs), we established the binding site of the PBZ molecules using cryo-EM and found that GroEL was the cellular target responsible for the mode of action. Cryo-EM revealed that PBZ1587 binds at the GroEL ring-ring interface (RRI). A cellular reporter assay confirmed that PBZ1587 engaged GroEL in cells, but cellular rescue experiments showed potential off-target effects. This prompted us to explore a closely related analogue, PBZ1038, which is also bound to the RRI. Biochemical characterization showed potent inhibition of Gram-negative chaperonins but much lower potency of chaperonin from a Gram-positive organism, Enterococcus faecium. A cellular reporter assay showed that PBZ1038 also engaged GroEL in cells and that the cytotoxic phenotype could be rescued by a chromosomal copy of E. faecium GroEL/GroES or by expressing a recalcitrant RRI mutant. These data argue that PBZ1038's antimicrobial action is exerted through inhibition of GroES/GroEL, validating this chaperone system as an antibiotic target.

Sensitive quantification of mevalonate pathway intermediates and prediction of relative novel analogs by chemical derivatization-based LC-MS/MS

The mevalonate (MVA) pathway plays a crucial role in the occurrence and progression of various diseases, such as osteoporosis, breast cancer, and lung cancer, etc. However, determining all the MVA pathway intermediates is still challenging due to their high polarity, low concentration, chelation effect with metal compartments, and poor mass spectrometric response. In this study, we established a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method coupled with N2, N2, N4, N4-tetramethyl-6-(4-(piperazin-1-ylsulfonyl) phenyl)-1,3,5-triazine-2,4-diamine (Tmt-PP) labeling for the simultaneous analysis of all MVA intermediates in biospecimens. Chemical derivatization significantly improved the chromatographic retention, peak shape, and detection sensitivity of the analytes. Moreover, we employed a method named mass spectrum calculation to achieve the absolute quantification of the isomers, i.e., isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). The established method was fully qualified and applied to explore the difference of these metabolites in cisplatin-resistant non-small cell lung cancer (NSCLC) cells. Additionally, several MVA intermediate analogs, including isopentenyl monophosphate or dimethylallyl monophosphate (IMP/DMAMP), geranyl monophosphate (GMP), 5-triphosphomevalonate (MTP), and isopentenyl triphosphate or dimethylallyl triphosphate (ITP/DMATP), were identified for the first time using a knowledge-driven prediction strategy. We further explored the tissue distribution of these novel metabolites. Overall, this work developed a sensitive quantification method for all MVA intermediates, which will enhance our understanding of the role of this pathway in various health and disease conditions. The novel metabolites we discovered warrant further investigations into their biosynthesis and biological functions.

Microwave Spectroscopy of Chiral Astrochemical Candidate Vinyloxirane: The Missing Gauche Conformer.

The recent detection of a chiral molecule, propylene oxide, in the interstellar medium provides impetus for investigation of related analogues as candidates for discovery of a second chiral species. Vinyloxirane (VO) shares many of the characteristics of propylene oxide that favored its remote detection such as modest size, appreciable dipole moment and modest adsorption to water ice. The microwave spectrum of vinyloxirane at room temperature has been studied in the 18 - 26 GHz region. Rotational transitions of the previously undetected gauche-1 conformer have been assigned and fitted. The quantum number range of anti conformer transitions has been greatly expanded, providing improved molecular constants. Vibrational satellite transitions were assigned and fitted for the lowest frequency ν27 torsion mode, for 2ν27, and for the ν26 C=CC bend of anti VO, along with ν27 satellites of gauche-1. The rovibrational analyses were assisted by anharmonic vibrational calculations at B3LYP-D3/aug-cc-PVTZ, B2PLYPD3/cc-pVTZ, and DSDPBEP86/cc-pVTZ levels. Experimental peak intensities provide a population ratio Ngauche-1/Nanti of 0.36 ± 0.06, corresponding to a Gibbs free energy difference of 2.5 ± 0.4 kJ mol-1 in favor of the anti conformer, in agreement with the density functional theory results. In the gauche-1 conformer, the torsional angle between vinyl group and oxirane ring, τC=CCM, is optimized at -35° to favor an intramolecular CvinylH11...O interaction. The gauche-2 conformer with τC=CCM of + 74° suffers from CvinylH11...HCcyclopropyl repulsion so that it is calculated to be 8-9 kJ mol-1 higher than gauche-1. Reinterpretation of earlier Raman spectra suggests that the gauche-2 conformer had not been observed as reported.

Inoculation theory

ABSTRACT Inoculation theory is a theory of resistance to influence that builds on analogous relationships with medical vaccination. In short: Exposure to weakened forms of challenges motivates resistance to stronger challenges encountered later. Throughout its 60 + year lifespan, scholars have applied inoculation theory as a messaging strategy across issues and contexts, including politics, health, and commerce. Additionally, inoculation theory scholarship has clarified how inoculation messaging confers resistance, moving beyond the traditional components (threat and refutational preemption) to consider other factors, including emotions. This article reviews key findings in inoculation theory research and then proposes particularly promising areas for future research.

Thiazolidinedione as a Promising Medicinal Scaffold for the Treatment of Type 2 Diabetes.

Thiazolidinediones, also known as glitazones, are considered as biologically active scaffold and a well-established class of anti-diabetic agents for the treatment of type 2 diabetes mellitus. Thiazolidinediones act by reducing insulin resistance through elevated peripheral glucose disposal and glucose production. These molecules activate peroxisome proliferated activated receptor (PPARγ), one of the sub-types of PPARs, and a diverse group of its hybrid have also shown numerous therapeutic activities along with antidiabetic activity. The objective of this review was to collect and summarize the research related to the medicinal potential, structure-activity relationship and safety aspects of thiazolidinedione analogues designed and investigated in type 2 diabetes during the last two decades. The mentioned objective was achieved by collecting and reviewing the research manuscripts, review articles, and patents from PubMed, Science Direct, Embase, google scholar and journals related to the topic from different publishers like Wiley, Springer, Elsevier, Taylor and Francis, Indian and International government patent sites etc. Results: The thiazolidinedione scaffold has been a focus of research in the design and synthesis of novel derivatives for the management of type 2 diabetes, specifically in the case of insulin resistance. The complications like fluid retention, idiosyncratic hepatotoxicity, weight gain and congestive heart failure in the case of trosiglitazone, and pioglitazone have restricted their use. The newer analogues have been synthesized by different research groups to attain better efficacy and less side effects. Thus, the potential of thiazolidinediones in terms of their chemical evolution, action on nuclear receptors, aldose reductase and free fatty acid receptor 1 is well established. The newer TZD analogues with better safety profiles and tolerability will soon be available in the market for common use without further delay.