Dimeric peptoids as antibacterial agents.

Building upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal interplay between hydrophobicity and cationicity in optimizing efficacy against specific bacteria. The bromophenyl dimeric guanidinium peptoid compound 10j showed excellent activity against S. aureus 38 and E. coli K12 with MIC of 0.8 µg mL-1 and 6.2 µg mL-1, respectively. Further investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes, as suggested by tethered bilayer lipid membranes (tBLMs) and cytoplasmic membrane permeability studies. Notably, these promising antibacterial agents exhibited negligible toxicity against mammalian red blood cells. Additionally, the study explored the potential of 12 active compounds to disrupt established biofilms of S. aureus 38. The most effective biofilm disruptors were ethyl and octyl-naphthyl guanidinium peptoids (10c and 10 k). These compounds 10c and 10 k disrupted the established biofilms of S. aureus 38 with 51 % at 4x MIC (MIC = 17.6 µg mL-1 and 11.2 µg mL-1) and 56 %-58 % at 8x MIC (MIC = 35.2 µg mL-1 and 22.4 µg mL-1) respectively. Overall, this research contributes insights into the design principles of cationic dimeric peptoids and their antibacterial activity, with implications for the development of new antibacterial compounds.

Mindful attention is inversely associated with pain via mediation by psychological distress in orthopedic patients.

BACKGROUND: Orthopedic patients report pain as their main symptom complaint. Subjective pain experience is correlated with self-reported psychological state, such as distress. PURPOSE: This study tests whether scores from a measure of mindful attention are associated with subjective pain levels and whether psychological distress scores function as a mediation path. METHODS: During routine visits to a single orthopedic clinic in East Los Angeles, California, 525 patients were recruited to participate in the study. Participants reported on measures of pain (Universal Pain Assessment Tool [UPAT]), mindful attention (Five-Facet Mindfulness Questionnaire [FFMQ]), and psychological distress (Depression, Anxiety, Stress Scale [DASS]). We used Pearson correlations to examine relationships between FFMQ and UPAT scores and mediation analyses to test indirect effects of DASS scores as a mediation path. RESULTS: The average age of the sample was 54 years (range 18-98 years), 61% were male, and 64% were non-Hispanic White individuals. The locations of injury were the shoulder (72%), elbow (21%), and clavicle or wrist (7%). Ninety-one percent reported mild or greater pain in the prior 2 weeks (mean = 4.2 ± 2.5, range 0-10), and 49% reported mild or more severe distress symptoms (DASS: 13.0 ± 11.5). FFMQ scores inversely predicted UPAT scores (ß = -0.22, P < .01), mediated through DASS scores. DASS subscale scores for depression (ß = -0.10, P = .02) and stress (ß = -0.08, P = .04) but not anxiety (ß = -0.03, P = .33) produced significant indirect effects. FFMQ acting-with-awareness and non-judging subscales had the largest effect on depression and stress DASS subscale scores. CONCLUSIONS: We find statistical support to suggest that distress-particularly depressed mood and stress-mediates the association between mindful attention and pain intensity among orthopedic patients. A disposition of mindful attention might counter distress ailments that exacerbate subjective pain, and this has possible implications for mindfulness training interventions offered to orthopedic patients.

Novel quinazolinone disulfide analogues as pqs quorum sensing inhibitors against Pseudomonas aeruginosa.

It is well established that the quorum sensing (QS) in Pseudomonas aeruginosa is primarily responsible for the synthesis and the release of several virulence factors including pyocyanin and are involved in biofilm formation. In the Pseudomonas quinolone signal (PQS) system, autoinducers such as PQS and HHQ bind and activate the transcription regulator protein receptor PqsR (MvfR). Targeting PqsR with competitive inhibitors could be a promising strategy to inhibit QS in P. aeruginosa to overcome antimicrobial resistance. In this study, we have designed and synthesized a series of novel quinazolinone disulfide-containing competitive inhibitor of PqsR. The most potent analogue 8q efficiently inhibited the pqs system with an IC50 value of 4.5 µM. It also showed complete suppression of pyocyanin production and a significant reduction in biofilm formation by P. aeruginosa (PAO1) with low cytotoxicity. Additionally, 8q produced synergy in combination with known antibiotics such as ciprofloxacin and tobramycin. Finally, molecular docking analysis suggested that compound 8q could bind with the ligand-binding domain of PqsR in a similar fashion to the native ligand.

Improved Resting-State Functional MRI Using Multi-Echo Echo-Planar Imaging on a Compact 3T MRI Scanner with High-Performance Gradients.

In blood-oxygen-level-dependent (BOLD)-based resting-state functional (RS-fMRI) studies, usage of multi-echo echo-planar-imaging (ME-EPI) is limited due to unacceptable late echo times when high spatial resolution is used. Equipped with high-performance gradients, the compact 3T MRI system (C3T) enables a three-echo whole-brain ME-EPI protocol with smaller than 2.5 mm isotropic voxel and shorter than 1 s repetition time, as required in landmark fMRI studies. The performance of the ME-EPI was comprehensively evaluated with signal variance reduction and region-of-interest-, seed- and independent-component-analysis-based functional connectivity analyses and compared with a counterpart of single-echo EPI with the shortest TR possible. Through the multi-echo combination, the thermal noise level is reduced. Functional connectivity, as well as signal intensity, are recovered in the medial orbital sulcus and anterior transverse collateral sulcus in ME-EPI. It is demonstrated that ME-EPI provides superior sensitivity and accuracy for detecting functional connectivity and/or brain networks in comparison with single-echo EPI. In conclusion, the high-performance gradient enabled high-spatial-temporal resolution ME-EPI would be the method of choice for RS-fMRI study on the C3T.

Antimicrobial Peptidomimetics Prevent the Development of Resistance against Gentamicin and Ciprofloxacin in Staphylococcus and Pseudomonas Bacteria.

Bacteria readily acquire resistance to traditional antibiotics, resulting in pan-resistant strains with no available treatment. Antimicrobial resistance is a global challenge and without the development of effective antimicrobials, the foundation of modern medicine is at risk. Combination therapies such as antibiotic-antibiotic and antibiotic-adjuvant combinations are strategies used to combat antibiotic resistance. Current research focuses on antimicrobial peptidomimetics as adjuvant compounds, due to their promising activity against antibiotic-resistant bacteria. Here, for the first time we demonstrate that antibiotic-peptidomimetic combinations mitigate the development of antibiotic resistance in Staphylococcus aureus and Pseudomonas aeruginosa. When ciprofloxacin and gentamicin were passaged individually at sub-inhibitory concentrations for 10 days, the minimum inhibitory concentrations (MICs) increased up to 32-fold and 128-fold for S. aureus and P. aeruginosa, respectively. In contrast, when antibiotics were passaged in combination with peptidomimetics (Melimine, Mel4, RK758), the MICs of both antibiotics and peptidomimetics remained constant, indicating these combinations were able to mitigate the development of antibiotic-resistance. Furthermore, antibiotic-peptidomimetic combinations demonstrated synergistic activity against both Gram-positive and Gram-negative bacteria, reducing the concentration needed for bactericidal activity. This has significant potential clinical applications-including preventing the spread of antibiotic-resistant strains in hospitals and communities, reviving ineffective antibiotics, and lowering the toxicity of antimicrobial chemotherapy.

Rational Design, Synthesis, and Anti-Proliferative Evaluation of Novel 4-Aryl-3,4-Dihydro-2H-1,4-Benzoxazines.

A synthetic pathway to a novel 4-aryl-3,4-dihydro-2H-1,4-benzoxazine scaffold was developed and a series of compounds based on the scaffold were synthesised as potential anticancer agents. The 4-aryl-substituted compounds were prepared via Buchwald-Hartwig cross-coupling between substituted bromobenzenes and various 1,4-benzoxazines, which in turn were generated from a cascade hydrogenation and reductive amination one-pot reaction. These analogues exhibited moderate to good potency against various cancer cell lines. Structure-activity relationship analysis indicated that the inclusion of hydroxyl groups on ring A and ring B was beneficial to biological activity, while having a para-amino group on ring C significantly enhanced potency. Molecule 14f displayed the most potent anticancer activity (IC50 = 7.84-16.2 µM against PC-3, NHDF, MDA-MB-231, MIA PaCa-2, and U-87 MG cancer cell lines), indicating its potential as a lead compound for further structural optimisation. All the synthesised compounds were fully characterised with NMR, HMRS, and IR. The novel benzoxazine scaffold described in this study holds promise and deserves further in-depth studies.

Inhibitors of bacterial RNA polymerase transcription complex.

A series of hybrid compounds that incorporated anthranilic acid with activated 1H-indoles through a glyoxylamide linker were designed to target bacterial RNA polymerase holoenzyme formation using computational docking. Synthesis, in vitro transcription inhibition assays, and biological testing of the hybrids identified a range of potent anti-transcription inhibitors with activity against a range of pathogenic bacteria with MICs as low as 3.1 µM. A structure activity relationship study identified the key structural components necessary for inhibition of both bacterial growth and transcription. Correlation of in vitro transcription inhibition activity with in vivo mechanism of action was established using fluorescence microscopy and resistance passaging using Gram-positive bacteria showed no resistance development over 30 days. Furthermore, no toxicity was observed from the compounds in a wax moth larvae model, establishing a platform for the development of a series of new antibacterial drugs with an established mode of action.

Bioinspired Polydopamine Coatings Facilitate Attachment of Antimicrobial Peptidomimetics with Broad-Spectrum Antibacterial Activity.

The prevention and treatment of biofilm-mediated infections remains an unmet clinical need for medical devices. With the increasing prevalence of antibiotic-resistant infections, it is important that novel approaches are developed to prevent biofilms forming on implantable medical devices. This study presents a versatile and simple polydopamine surface coating technique for medical devices, using a new class of antibiotics-antimicrobial peptidomimetics. Their unique mechanism of action primes them for activity against antibiotic-resistant bacteria and makes them suitable for covalent attachment to medical devices. This study assesses the anti-biofilm activity of peptidomimetics, characterises the surface chemistry of peptidomimetic coatings, quantifies the antibacterial activity of coated surfaces and assesses the biocompatibility of these coated materials. X-ray photoelectron spectroscopy and water contact angle measurements were used to confirm the chemical modification of coated surfaces. The antibacterial activity of surfaces was quantified for S. aureus, E. coli and P. aeruginosa, with all peptidomimetic coatings showing the complete eradication of S. aureus on surfaces and variable activity for Gram-negative bacteria. Scanning electron microscopy confirmed the membrane disruption mechanism of peptidomimetic coatings against E. coli. Furthermore, peptidomimetic surfaces did not lyse red blood cells, which suggests these surfaces may be biocompatible with biological fluids such as blood. Overall, this study provides a simple and effective antibacterial coating strategy that can be applied to biomaterials to reduce biofilm-mediated infections.

Cholic Acid-Based Antimicrobial Peptide Mimics as Antibacterial Agents.

There is a significant and urgent need for the development of novel antibacterial agents to tackle the increasing incidence of antibiotic resistance. Cholic acid-based small molecular antimicrobial peptide mimics are reported as potential new leads to treat bacterial infection. Here, we describe the design, synthesis and biological evaluation of cholic acid-based small molecular antimicrobial peptide mimics. The synthesis of cholic acid analogues involves the attachment of a hydrophobic moiety at the carboxyl terminal of the cholic acid scaffold, followed by the installation of one to three amino acid residues on the hydroxyl groups present on the cholic acid scaffold. Structure-activity relationship studies suggest that the tryptophan moiety is important for high antibacterial activity. Moreover, a minimum of +2 charge is also important for antimicrobial activity. In particular, analogues containing lysine-like residues showed the highest antibacterial potency against Gram-positive S. aureus. All di-substituted analogues possess high antimicrobial activity against both Gram-positive S. aureus as well as Gram-negative E. coli and P. aeruginosa. Analogues 17c and 17d with a combination of these features were found to be the most potent in this study. These compounds were able to depolarise the bacterial membrane, suggesting that they are potential antimicrobial pore forming agents.

Perceptions of older adults? Measuring positive, negative, and physical descriptors using the stereotype content and strength survey.

The COVID-19 pandemic has disproportionately impacted the health of older adults. In addition to a higher risk for serious illness and death, the societal value of senescent adults was challenged. There have been conflicting results reported in the research literature regarding positive and negative stereotypes of older adults, and areliable and valid assessment tool to measure content (existence of astereotype) and strength (intensity of astereotype) is unavailable. To address issues with instruments employed to measure ageist stereotypes, researchers developed the Stereotypes Content and Strength Survey. University students (n=483) were directed to "think about their perceptions of older adults" and indicate how many they believed could be described using the terms listed on a5-point Likert-type scale from none-all. Response categories for each descriptive item were dichotomized into 1 = "some, most or all" and 0 = "none or few." Based on an odds analyses of 117 items, 84 met the content criteria to be considered astereotype regarding older adults. Using the criteria for strength, items were categorized into 36 "strong," 25 "moderate," and 23 "weak" stereotypes. Assessing the content and strength of stereotypic beliefs using this procedure may contribute to major bias influencing ageist perceptions.

Sports mega-events and changing world order.

Processes of making, sustaining, reforming, and un-making world orders are constants in global politics and development. Understood in the neo-Gramscian tradition pioneered by Robert Cox, ideas, institutions, and material capabilities combine to shape the range of possibilities for more and less stable orders. Sports mega-events (SMEs)-most prominently, the Olympic Games-have played an underappreciated role in this process. This paper examines the ways in which the Olympics manifested and supported the rise of globalized neoliberal hegemony in the early 1980s, the reconfiguration and erosion of this order through the 1990s and 2000s, and efforts to fundamentally revise this order in the new millennium. Particular emphasis is placed on the dual role of SMEs and the Olympics as manifestations of conspicuous consumption and the pursuit of prestige on the one hand, and as focal points for sanctions campaigns and boycotts on the other.

Mindfulness-Based Intervention Effects on Substance Use and Relapse Among Women in Residential Treatment: A Randomized Controlled Trial With 8.5-Month Follow-Up Period From the Moment-by-Moment in Women's Recovery Project.

OBJECTIVE: We tested the efficacy of Moment-by-Moment in Women's Recovery (MMWR), a mindfulness training program adapted for ethnoculturally diverse women with complex social and clinical histories in residential treatment for substance use disorder, on substance use and relapse outcomes. METHODS: Participants were randomized to MMWR (n = 100; 60% Hispanic/Latina, 18% non-Hispanic Black) or the attention control condition, Neurobiology of Addiction (n = 100; 56% Hispanic/Latina, 21% non-Hispanic Black). Substance use outcomes (days until first use, days of use, and relapse status: abstained, lapsed, relapsed) were obtained from interviewer-assisted timeline followback for an 8.5-month follow-up period spanning the intervention start through the 6-week intervention period and 7 months after the intervention ended. RESULTS: An intent-to-treat survival analyses showed that time delay to first marijuana use favored MMWR (hazard ratio = 0.44, 95% confidence interval = 0.20-0.98, p = .049) with a medium-to-large effect size. In negative binomial hurdle models, the MMWR group showed fewer days of marijuana use at 3.5 months (B = -1.71, SE = 0.79, incidence rate ratio = 0.18, p = .030) and a trend at 7 months after the intervention (B = -0.90, standard error = 0.55, incidence rate ratio = 0.41, p = .10). For marijuana, mindfulness practice time during the intervention predicted time delay to first use (B = 0.28, p = .006) and total abstinence days (B = 0.34, p = .002) across the 7 months after MMWR. No other substance use outcomes showed differential response to MMWR relative to controls. Only in MMWR, number of study intervention sessions attended (dose) correlated with a greater length of time to alcohol intoxication (r = .48, p < .001), fewer days of alcohol intoxication (r = -.24, p = .020), and greater improvement in mindfulness skills (r = .61, p < .01). CONCLUSIONS: MMWR added to an ongoing intensive residential treatment program serving vulnerable women is protective against marijuana use but no other substance use outcomes. Mindfulness practice time predicted a delay in time to first marijuana use. MMWR class attendance, an indicator of intervention dose, appears protective of alcohol intoxication at follow-up; thus, extended MMWR exposure might be useful.

SMART syndrome: retrospective review of a rare delayed complication of radiation.

BACKGROUND: SMART (stroke-like migraine attacks after radiation therapy) is a rare, delayed complication of brain radiation. In this study, we wanted to review the spectrum of symptoms, neuroradiological findings, autoimmune status, and outcomes in SMART syndrome patients. METHODS: We conducted a retrospective cohort study of all consecutive adult patients (≥18 years) diagnosed with SMART syndrome at Mayo Clinic, Rochester between January 1995 and December 2018. RESULTS: We identified 25 unique patients with SMART syndrome and a total of 31 episodes and 15 (60%) patients were male. The median age at onset was 46 (interquartile range [IQR] 43-55) years and the median latency of onset after the initial radiation was 21.6 (IQR 14.4-28.2) years. Magnetic resonance imaging (MRI) showed gyral edema and enhancement in all cases with the temporal (25, 80.6%) and parietal (23, 74.2%) lobes being the most commonly affected. The median follow-up of the patients in our cohort was 10 (IQR 6-32) weeks. On univariate analysis, factors associated with an increased risk of recurrent SMART episodes were female gender (odds ratio [OR] 8.1, 95% confidence interval [95% CI] 1.1-52.6, p = 0.019) and absence of electrographic seizure discharges during initial symptoms (OR 7.4, 95% CI 1.1-45.9, p = 0.032). We could not identify an autoimmune etiology. Longer duration of symptoms (>10 weeks) correlated with an older age (p = 0.049), temporal lobe involvement (p < 0.001), and diffusion restriction (p = 0.043). CONCLUSIONS: SMART is a syndrome with characteristic imaging findings and clinical features. Incomplete recovery by 10 weeks occurred in one-third of individuals and was associated with older age, temporal lobe involvement, and restricted diffusion on MRI.

Orthogonal Syntheses of γ-Carbolinone and Spiro[pyrrolidinone-3,3']indole Derivatives in One Pot through Reaction Telescoping.

Herein we report a series of telescoping methodologies for one pot synthesis of biologically relevant γ-carboline derivatives 6 and spiro[pyrrolidinone-3,3']indole 7. Initially the three consecutive steps of cyclopropanation, phthalimide deprotection, and Boc-deprotection have been congregated in a single reaction vessel to afford a ∼1:1 mixture of 6 and 7. Next, careful optimization of the reaction sequence and the conditions generated an orthogonal approach to access compounds 6 and 7 exclusively. Air oxidation of the γ-carbolinones 6 afforded aromatic γ-carbolines 8.

Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa.

The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be utilized as quorum sensing inhibitors to treat P. aeruginosa infections. In this study, we report the synthesis of novel thioether-linked dihydropyrrol-2-one (DHP) analogues as PqsR antagonists. Compound 7g containing a 2-mercaptopyridyl linkage effectively inhibited the pqs system with an IC50 of 32 µM in P. aeruginosa PAO1. Additionally, these inhibitors significantly reduced bacterial aggregation and biofilm formation without affecting planktonic growth. The molecular docking study suggest that these inhibitors bind with the ligand binding domain of the MvfR as a competitive antagonist.

Clinical 7-T MRI for neuroradiology: strengths, weaknesses, and ongoing challenges.

Since the relatively recent regulatory approval for clinical use in both Europe and North America, 7-Tesla (T) MRI has been adopted for clinical practice at our institution. Based on this experience, this article reviews the unique features of 7-T MRI neuroimaging and addresses the challenges of establishing a 7-T MRI clinical practice. The underlying fundamental physics principals of high-field strength MRI are briefly reviewed. Scanner installation, safety considerations, and artifact mitigation techniques are discussed. Seven-tesla MRI case examples of neurologic diseases including epilepsy, vascular abnormalities, and tumor imaging are presented to illustrate specific applications of 7-T MRI. The advantages of 7-T MRI in conjunction with advanced neuroimaging techniques such as functional MRI are presented. Seven-tesla MRI produces more detailed information and, in some cases, results in specific diagnoses where previous 3-T studies were insufficient. Still, persistent technical issues for 7-T scanning present ongoing challenges for radiologists.

Higher temporal resolution multiband fMRI provides improved presurgical language maps.

PURPOSE: We investigated the hypothesis that increasing fMRI temporal resolution using a multiband (MB) gradient echo-echo planar imaging (GRE-EPI) pulse sequence provides fMRI language maps of higher statistical quality than those acquired with a traditional GRE-EPI sequence. METHODS: This prospective study enrolled 29 consecutive patients receiving language fMRI prior to a potential brain resection for tumor, AVM, or epilepsy. A 4-min rhyming task was performed at 3.0 Tesla with a traditional GRE-EPI pulse sequence (TR = 2000, TE = 30, matrix = 64/100%, slice = 4/0, FOV = 24, slices = 30, time points = 120) and an additional MB GRE-EPI pulse sequence with an acceleration factor of 6 (TR = 333, TE = 30, matrix 64/100%, slice = 4/0, FOV = 24, time points = 720). Spatially filtered t statistical maps were generated. Volumes of interest (VOIs) were drawn around activations at Broca's, dorsolateral prefrontal cortex, Wernicke's, and the visual word form areas. The t value maxima were measured for the overall brain and each of the VOIs. A paired t test was performed for the corresponding traditional and MB GRE-EPI measurements. RESULTS: The mean age of subjects was 42.6 years old (18-75). Sixty-two percent were male. The average overall brain t statistic maxima for the MB pulse sequence (t = 15.4) was higher than for the traditional pulse sequence (t = 9.3, p = < .0001). This also held true for Broca's area (p < 0.0001), Wernicke's area (p < .0001), dorsolateral prefrontal cortex (p < .0001), and the visual word form area (p < .0001). CONCLUSION: A MB GRE-EPI fMRI pulse sequence employing high temporal resolution provides clinical fMRI language maps of greater statistical significance than those obtained with a traditional GRE-EPI sequence.

Polyphenylglyoxamide-Based Amphiphilic Small Molecular Peptidomimetics as Antibacterial Agents with Anti-Biofilm Activity.

The rapid emergence of drug-resistant bacteria is a major global health concern. Antimicrobial peptides (AMPs) and peptidomimetics have arisen as a new class of antibacterial agents in recent years in an attempt to overcome antibiotic resistance. A library of phenylglyoxamide-based small molecular peptidomimetics was synthesised by incorporating an N-alkylsulfonyl hydrophobic group with varying alkyl chain lengths and a hydrophilic cationic group into a glyoxamide core appended to phenyl ring systems. The quaternary ammonium iodide salts 16d and 17c showed excellent minimum inhibitory concentration (MIC) of 4 and 8 µM (2.9 and 5.6 µg/mL) against Staphylococcus aureus, respectively, while the guanidinium hydrochloride salt 34a showed an MIC of 16 µM (8.5 µg/mL) against Escherichia coli. Additionally, the quaternary ammonium iodide salt 17c inhibited 70% S. aureus biofilm formation at 16 µM. It also disrupted 44% of pre-established S. aureus biofilms at 32 µM and 28% of pre-established E. coli biofilms 64 µM, respectively. A cytoplasmic membrane permeability study indicated that the synthesised peptidomimetics acted via disruption and depolarisation of membranes. Moreover, the quaternary ammonium iodide salts 16d and 17c were non-toxic against human cells at their therapeutic dosages against S. aureus.

Synthesis and Characterisation of Novel Tricyclic and Tetracyclic Furoindoles: Biological Evaluation as SAHA Enhancer against Neuroblastoma and Breast Cancer Cells.

The dihydropyranoindole structures were previously identified as promising scaffolds for improving the anti-cancer activity of histone deacetylase inhibitors. This work describes the synthesis of related furoindoles and their ability to synergize with suberoylanilide hydroxamic acid (SAHA) against neuroblastoma and breast cancer cells. The nucleophilic substitution of hydroxyindole methyl esters with α-haloketones yielded the corresponding arylether ketones, which were subsequently cyclized to tricyclic and tetracyclic furoindoles. The furoindoles showed promising individual cytotoxic efficiency against breast cancer cells, as well as decent SAHA enhancement against cancer cells in select cases. Interestingly, the best IC50 value was obtained with the non-cyclized intermediate.

Natural Product Rottlerin Derivatives Targeting Quorum Sensing.

Rottlerin is a natural product consisting of chalcone and flavonoid scaffolds, both of which have previously shown quorum sensing (QS) inhibition in various bacteria. Therefore, the unique rottlerin scaffold highlights great potential in inhibiting the QS system of Pseudomonas aeruginosa. Rottlerin analogues were synthesised by modifications at its chalcone- and methylene-bridged acetophenone moieties. The synthesis of analogues was achieved using an established five-step synthetic strategy for chalcone derivatives and utilising the Mannich reaction at C6 of the chromene to construct morpholine analogues. Several pyranochromene chalcone derivatives were also generated using aldol conditions. All the synthetic rottlerin derivatives were screened for QS inhibition and growth inhibition against the related LasR QS system. The pyranochromene chalcone structures displayed high QS inhibitory activity with the most potent compounds, 8b and 8d, achieving QS inhibition of 49.4% and 40.6% and no effect on bacterial growth inhibition at 31 µM, respectively. Both compounds also displayed moderate biofilm inhibitory activity and reduced the production of pyocyanin.