Relationship between epicardial adipose tissue measured by computed tomography and premature ventricular complexes originating from different sites.

AIMS: This study aims to explore the association between the features of epicardial adipose tissue (EAT) in different zones and premature ventricular complexes (PVCs) originating from different sites by computed tomography (CT). METHODS AND RESULTS: A total of 136 patients who underwent radiofrequency ablation for PVCs were incorporated in this study. One hundred and thirty-six matched controls were included in this study using the case-control method (1:1 matching). PVCs were classified into four subgroups: (1) right ventricular outflow tract (RVOT-PVCs), (2) non-RVOT of the right ventricle (RV-PVCs), (3) left ventricular outflow tract (LVOT-PVCs), and (4) non-LVOT of the left ventricle (LV-PVCs). The volume and density of EAT were quantified by CT. Patients with PVCs had a significantly higher volume and lower density of EAT than the controls (P < 0.001). The LVOT-PVCs and LV-PVCs had a higher left ventricle periventricular EAT volume (LV-EATv) proportion (P < 0.05). The right ventricle periventricular EAT volume (RV-EATv) proportion was higher in ROVT-PVCs and LVOT-PVCs (P < 0.05). RVOT-PVC patients had a higher volume ratio and a smaller density differential (P < 0.05). Patients with LVOT-PVCs had a lower volume ratio and the LV-PVCs showed a greater density differential (P < 0.05). CONCLUSION: Higher volume and lower density of EAT were significantly associated with frequent PVCs. The RVOT-PVC patients had a higher volume ratio and a smaller density differential. The LVOT-PVCs had a lower volume ratio and the LV-PVCs showed a greater density differential. These suggest a link between EAT structural properties and PVCs and a potential role for regional EAT in the development of PVCs.

Self-reported sleep pattern and recurrence of atrial fibrillation after catheter ablation.

BACKGROUND: Increasing evidence has shown the relationship between sleep and the recurrence of atrial fibrillation (AF). However, the association of different sleep patterns with AF recurrence after catheter ablation was rarely studied. We aimed to assess the role of different sleep behaviors in the risk of AF recurrence after catheter ablation. METHODS AND RESULTS: A total of 416 consecutive participants from Zhongda hospital of Southeast University were finally analyzed. Sleep patterns were defined by chronotype, sleep duration, insomnia, snoring, and daytime sleepiness. A total of 208 patients (50.0%) had a healthy sleep pattern within a mean follow-up of 32.42 ± 18.18 months. The observed number of patients with AF recurrence was 10 (50.0%), 80 (42.6%), and 40 (19.2%) in unhealthy, intermediate and healthy sleep groups, respectively (p < .01). After adjusting covariates, unhealthy sleep pattern was significantly associated with AF recurrence [hazard ratio = 3.47 (95% confidence interval CI: 1.726-6.979, p < .001)]. Sleep disorders such as inadequate sleep time (time <7 h or >8 h), insomnia and excessive sleepiness during daytime were associated with a higher risk of recurrence. Otherwise, improvement in sleep seemed to be associated with decreased risk of AF recurrence. CONCLUSION: This retrospective study indicates that adherence to a healthy sleep pattern is associated with a lower risk of AF recurrence. Also, improved sleep before ablation is associated with a lower risk of AF recurrence.

Effects of Chronic Remote Ischemic Conditioning on Atrial Fibrillation Burden in Patients with Permanent Pacemakers.

This study aimed to evaluate the effects of chronic remote ischemic conditioning (CRIC) on atrial fibrillation burden in patients with an implanted pacemaker. Sixty-six patients with permanent pacemakers were randomly divided into the CRIC group and control group after 4 weeks of screening. CRIC treatment was performed twice daily for 12 weeks. The remote ischemic conditioning protocol consisted of 4 × 5 minutes inflation/deflation of the blood pressure cuff applied in the upper arm to create intermittent arm ischemia. Sixty-one patients (31 patients in the CRIC group and 30 patients in the control group) completed the study. CRIC was well tolerated by patients after 12 weeks of treatment. The burden of atrial fibrillation (AF) in the CRIC group decreased significantly at 4 weeks compared with that at 0 weeks (14.7% ± 18.5% versus 17.0% ± 20.7%, P < 0.001), which further decreased at 12 weeks compared with that at 0 weeks (8.6% ± 10.2% versus 17.0% ± 20.7%, P < 0.001) and that at 4 weeks (8.6% ± 10.2% versus 14.7% ± 18.5%, P < 0.001), which was not observed in the control group. AF burden also reduced significantly after 12-week CRIC compared with that in the control group (8.6% ± 10.2% versus 17.6% ± 19.5%, P = 0.013). Repeated measurement ANOVA showed that the changes in AF burden were associated with CRIC instead of time (P < 0.01). In addition, there were trends that the longest duration of AF and cumulative numbers of atrial high-rate episodes (AHREs) reduced after 12-week CRIC. This study suggests that a 12-week course of CRIC treatment could reduce AF burden in patients with permanent pacemakers, supporting the widespread use of CRIC in the daily lives of these patients, which needs to be verified in the future.

WiSE CRT Is Beneficial for Heart Failure Patients as a Rescue Therapy: Evidence From a Meta-Analysis.

Background: Leadless endocardial left ventricular (LV) pacing resynchronization therapy is a novel solution for patients with heart failure (HF) in whom conventional cardiac resynchronization therapy (CRT) failed. Methods: PubMed and the Cochrane Library were searched for relevant cohort studies. Clinical outcomes of interest such as ejection fraction (EF), QRS duration (QRSd), and left ventricular end-systolic volume (LVESV) were extracted and analyzed. Results: Five studies involving 175 HF patients for WiSE CRT were included, and patients were followed-up for 6 months. The implanted success rate ranged from 76.5 to 100%. WiSE CRT resulted in significantly narrower QRSd [mean difference (MD): -38.21 ms, 95% confidence interval (CI): -44.36 to -32.07, p < 0.001], improved left ventricular ejection fraction (MD: 6.07%, 95% CI: 4.43 to 7.71, I2 = 0%, p < 0.001), reduced left ventricular end-systolic volume (MD: -23.47 ml, 95% CI: -37.18 to -9.13, p < 0.001), and reduced left ventricular end-diastolic volume (MD: -24.02 ml, 95% CI: -37.01 to -11.03, p = 0.02). Conclusion: Evidence from current studies suggests that leadless endocardial LV pacing resynchronization is effective for HF patients who failed conventional CRT or needed a device upgrade, and it may be an interesting rescue therapy.

Exosomal miR-17-3p Alleviates Programmed Necrosis in Cardiac Ischemia/Reperfusion Injury by Regulating TIMP3 Expression.

OBJECTIVE: Myocardial ischemia/reperfusion (I/R) injury can aggravate myocardial injury. Programmed necrosis plays a crucial role in this injury. However, the role of exosomal miRNAs in myocardial I/R injury remains unclear. Therefore, this study is aimed at exploring the function and mechanism of exosomal miR-17-3p in myocardial I/R injury. METHODS: The myocardial I/R injury animal model was established in C57BL/6 mice. Exosomes were identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. Programmed necrosis was detected by PI staining. Heart function and myocardial infarct size were evaluated using echocardiography and triphenyl tetrazolium chloride (TTC) staining, respectively. Histopathological changes were visualized by hematoxylin and eosin (H&E) and Masson staining. The regulation of TIMP3 expression by miR-17-3p was verified using a dual-luciferase reporter assay. Lactate dehydrogenase (LDH) and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assays (ELISA). TIMP3 expression was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: We demonstrated that miR-17-3p was significantly downregulated in peripheral blood exosomes after cardiac I/R injury. Further analysis indicated that exosomal miR-17-3p attenuated H2O2-induced programmed necrosis in cardiomyocytes in vitro. Moreover, TIMP3 was a target for miR-17-3p. TIMP3 affected H2O2-induced programmed necrosis in cardiomyocytes. This effect was modulated by miR-17-3p in vitro. Furthermore, exosomal miR-17-3p greatly alleviated cardiac I/R injury in vivo. CONCLUSIONS: The present study demonstrated that exosomal miR-17-3p alleviated the programmed necrosis associated with cardiac I/R injury by regulating TIMP3 expression. These findings could represent a potential treatment for I/R injury.

Risk factors of left atrial appendage thrombus in patients with non-valvular atrial fibrillation.

OBJECTIVE: To investigate the risk factors of left atrial appendage thrombus (LAAT) in patients with non-valvular atrial fibrillation (AF). METHODS: We collected the clinical data of patients with non-valvular AF who underwent transesophageal echocardiography (TEE) at the Zhongda Hospital of Southeast University between January 2016 and June 2019. The patients were divided into two groups, LAAT and non-LAAT. We performed comparative analysis, receiver operating characteristic (ROC) curve analysis and logistic regression analysis to estimate the risk factors of LAAT. RESULTS: A total of 442 patients with non-valvular AF were enrolled in the study. LAAT was detected by TEE in 20 cases (4.7%). Compared with patients without LAAT, patients with LAAT had higher CHA2DS2-VASc scores (3 vs 2, p = 0.001), higher values of D-dimer (180.0 vs 90.0 µg/L, p = 0.003), larger LA anteroposterior diameters (50.5 vs 41.0 mm, p < 0.001) and higher ratios of non-paroxysmal AF (85.0% vs 23.6%, p < 0.001). ROC curve analysis revealed that the cutoff value of LA anteroposterior diameter was 49.5 mm. After adjusting for other confounders, logistic regression analysis showed that enlarged LA (anteroposterior diameter ≥49.5 mm) and non-paroxysmal AF were independently associated with higher risks of LAAT (OR = 7.28, 95% CI: 2.36-22.47; OR = 8.89, 95% CI: 2.33-33.99, respectively). The proportions of LAAT in patients with larger LA (anteroposterior diameter ≥49.5 mm), non-paroxysmal AF and both larger LA and non-paroxysmal AF were 30% (12/40), 15.2% (17/112) and 39.1% (9/23), respectively. CONCLUSION: Enlarged LA (anteroposterior diameter ≥49.5 mm) and non-paroxysmal AF were independent risk factors of LAAT in non-valvular AF patients.

Exchange proteins directly activated by cAMP mediate cardiac repolarization and arrhythmogenesis during chronic heart failure.

Most sudden cardiac death in chronic heart failure (CHF) is caused by malignant ventricular arrhythmia (VA); however, the molecular mechanism remains unclear. This study aims to explore the effect of exchange proteins directly activated by cAMP (Epac) on VA in CHF and the potential molecular mechanism. Transaortic constriction was performed to prepare CHF guinea pigs. Epac activation model was obtained with 8-pCPT administration. Programmed electrical stimulation (PES) was performed to detect effective refractory period (ERP) or induce VA. Isolated adult cardiomyocytes were treated with 8-pCPT and (or) the Epac inhibitor. Cellular electrophysiology was examined by whole-cell patch clamp. With Epac activation, corrected QT duration was lengthened by 12.6%. The 8-pCPT increased action potential duration (APD) (APD50: 236.9 ± 18.07 ms vs. 328.8 ± 11.27 ms, p < 0.05; APD90: 264.6 ± 18.22 ms vs. 388.6 ± 6.47 ms, p < 0.05) and decreased rapid delayed rectifier potassium (IKr) current (tail current density: 1.1 ± 0.08 pA/pF vs. 0.7 ± 0.03 pA/pF, p < 0.05). PES induced more malignant arrhythmias in the 8-pCPT group than in the control group (3/4 vs. 0/8, p < 0.05). The selective Epac1 inhibitor CE3F4 rescued the drop in IKr after 8-pCPT stimulation (tail current density: 0.5 ± 0.02 pA/pF vs. 0.6 ± 0.03 pA/pF, p < 0.05). In conclusion, Epac1 regulates IKr, APD, and ERP in guinea pigs, which could contribute to the proarrhythmic effect of Epac1 in CHF.

CLOCK-BMAL1 regulates circadian oscillation of ventricular arrhythmias in failing hearts through ß1 adrenergic receptor.

The incidence of ventricular arrhythmias (VAs) in chronic heart failure (CHF) exhibits a notable circadian rhythm, for which the underlying mechanism has not yet been well defined. Thus, we aimed to investigate the role of cardiac core circadian genes on circadian VAs in CHF. First, a guinea pig CHF model was created by transaortic constriction. Circadian oscillation of core clock genes was evaluated by RT-PCR and was found to be unaltered in CHF (P > 0.05). Using programmed electrical stimulation in Langendorff-perfused failing hearts, we discovered that the CHF group exhibited increased VAs with greater incidence at CT3 compared to CT15 upon isoproterenol (ISO) stimulation. Circadian VAs was blunted by a ß1-AR-selective blocker rather than a ß2-AR-selective blocker. Circadian oscillation of ß1-AR was retained in CHF (P > 0.05) and a 4-h phase delay between ß1-AR and CLOCK-BMAL1 was recorded. Therefore, when CLOCK-BMAL1 was overexpressed using adenovirus infection, an induced overexpression of ß1-AR also ensued, which resulted in prolonged action potential duration (APD) and enhanced arrhythmic response to ISO stimulation in cardiomyocytes (P < 0.05). Finally, chromatin immunoprecipitation and luciferase assays confirmed that CLOCK-BMAL1 binds to the enhancer of ß1-AR gene and upregulates ß1-AR expression. Therefore, in this study, we discovered that CLOCK-BMAL1 regulates the expression of ß1-AR on a transcriptional level and subsequently modulates circadian VAs in CHF.

Identifying a marked inflammation mediated cardiac dysfunction during the development of arthritis in collagen-induced arthritis mice.

OBJECTIVES: Systemic inflammation is very closely linked to the increased risk of cardiovascular diseases (CVD) in rheumatoid arthritis (RA). We investigated the cardiac changes during the development of arthritis in collagen-induced arthritis (CIA) mice to explore the potential role of inflammation on cardiac dysfunction in RA. METHODS: Arthritis severity was evaluated using clinical indices, micro-computed tomography and histopathology. Cardiac function was determined by transthoracic echocardiography at weeks 5, 7, 9 and 11 after immunisation in mice. At week 7 (day 50), mice joints and hearts were removed for pathological study, and cardiomyocytes and cardiac fibroblasts were isolated using Langendorff perfusion method ex vivo to measure the expression of inflammatory and cardiac-related genes by real time PCR. The expression of key molecule in cardiac dysfunction (ß-MHC) was also tested in H9c2 cardiomyocyte treated with sera derived from CIA mice or RA patients. RESULTS: At day 50 after immunisation, cardiac function in CIA mice was prominently reduced as evidenced by decreased ejection fraction (EF) and fractional shortening (FS), increased left ventricular end-systolic volume (LVESV) and internal systolic diameter (LVIDs). Accordingly, enhanced inflammatory cell infiltration and fibrosis were identified in ventricular tissues pathologically, and increased inflammatory gene expression including TNF-α, IL-6, IL-17 and MMP3 was detected in isolated ventricular cardiomyocytes and cardiac fibroblasts from CIA mice. Furthermore, H9c2 cells treated with sera from CIA mice or RA patients exhibited high levels of ß-MHC. CONCLUSIONS: Joint inflammation is associated with an obvious cardiac dysfunction and enhanced inflammation infiltration and inflammatory cytokine production in cardiomyocytes and cardiac fibroblasts during CIA development. Our data provide the direct evidence that inflammation contributes to the development of cardiac diseases in RA patients.

Cardiac electrical and mechanical synchrony of super-responders to cardiac resynchronization therapy.

BACKGROUND: Super-responders (SRs) to cardiac resynchronization therapy (CRT) regain near-normal or normal cardiac function. The extent of cardiac synchrony of SRs and whether continuous biventricular (BIV) pacing is needed remain unknown. The aim of this study was to evaluate the cardiac electrical and mechanical synchrony of SRs. METHODS: We retrospectively analyzed CRT recipients between 2008 and 2016 in 2 centers to identify SRs, whose left ventricular (LV) ejection fraction was increased to ≥50% at follow-up. Cardiac synchrony was evaluated in intrinsic and BIV-paced rhythms. Electrical synchrony was estimated by QRS duration and LV mechanical synchrony by single-photon emission computed tomography myocardial perfusion imaging. RESULTS: Seventeen SRs were included with LV ejection fraction increased from 33.0 ±â€Š4.6% to 59.3 ±â€Š6.3%. The intrinsic QRS duration after super-response was 148.8 ±â€Š30.0 ms, significantly shorter than baseline (174.8 ±â€Š11.9 ms, P = 0.004, t = -3.379) but longer than BIV-paced level (135.5 ±â€Š16.7 ms, P = 0.042, t = 2.211). Intrinsic LV mechanical synchrony significantly improved after super-response (phase standard deviation [PSD], 51.1 ±â€Š16.5° vs. 19.8 ±â€Š8.1°, P < 0.001, t = 5.726; phase histogram bandwidth (PHB), 171.7 ±â€Š64.2° vs. 60.5 ±â€Š22.9°, P < 0.001, t = 5.376) but was inferior to BIV-paced synchrony (PSD, 19.8 ±â€Š8.1° vs. 15.2 ±â€Š6.4°, P = 0.005, t = 3.414; PHB, 60.5 ±â€Š22.9° vs. 46.0 ±â€Š16.3°, P = 0.009, t = 3.136). CONCLUSIONS: SRs had significant improvements in cardiac electrical and LV mechanical synchrony. Since intrinsic synchrony of SRs was still inferior to BIV-paced rhythm, continued BIV pacing is needed to maintain longstanding and synchronized contraction.

Pathway-based analysis of genome-wide association study of circadian phenotypes.

Sleepiness affects normal social life, which attracts more and more attention. Circadian phenotypes contribute to obvious individual differences in susceptibility to sleepiness. We aimed to identify candidate single nucleotide polymorphisms (SNPs) which may cause circadian phenotypes, elucidate the potential mechanisms, and generate corresponding SNP-gene-pathways. A genome-wide association studies (GWAS) dataset of circadian phenotypes was utilized in the study. Then, the Identify Candidate Causal SNPs and Pathways analysis was employed to the GWAS dataset after quality control filters. Furthermore, genotype-phenotype association analysis was performed with HapMap database. Four SNPs in three different genes were determined to correlate with usual weekday bedtime, totally providing seven hypothetical mechanisms. Eleven SNPs in six genes were identified to correlate with usual weekday sleep duration, which provided six hypothetical pathways. Our results demonstrated that fifteen candidate SNPs in eight genes played vital roles in six hypothetical pathways implicated in usual weekday bedtime and six potential pathways involved in usual weekday sleep duration.

CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway.

The heterodimerized transcription factors CLOCK-BMAL1 regulate the cardiomyocyte circadian rhythms. The L-type calcium currents play important role in the cardiac electrogenesis and arrhythmogenesis. Whether and how the CLOCK-BMAL1 regulate the cardiac L-type calcium channels are yet to be determined. The functions of the L-type calcium channels were evaluated with patch clamping techniques. Recombinant adenoviruses of CLOCK and BMAL1 were used in the expression experiments. We reported that the expressions and functions of CACNA1C (the α-subunit of the L-type calcium channels) showed circadian rhythms, with the peak at zeitgeber time 3 (ZT3). The endocardial action potential durations 90 (APD90) were correspondingly longer at ZT3. The protein levels of the phosphorylated Akt at threonine 308 (pAkt T308) also showed circadian rhythms. Overexpressions of CLOCK-BMAL1 significantly reduced the levels of CACNA1C while increasing the levels of pAkt T308 and pik3r1. Furthermore, the inhibitory effects of CLOCK-BMAL1 on CACNA1C could be abolished by the Akt inhibitor MK2206 or the PDK1 inhibitor GSK2334470. Collectively, our findings suggested that the expressions of the cardiac CACNA1C were under the CLOCK-BMAL1 regulation, probably through the PI3K-Akt signal pathway.

Andrographolide Attenuates LPS-Induced Cardiac Malfunctions Through Inhibition of IκB Phosphorylation and Apoptosis in Mice.

BACKGROUND/AIMS: Cardiac malfunction is a common complication in sepsis and significantly increases the mortality of patients in septic shock. However, no studies have examined whether andrographolide (And) reduces LPS-induced myocardial malfunction. METHODS: Left ventricular systolic and diastolic functions were examined using echocardiography. TNF-α and IL-1ß protein levels were detected by an enzyme-linked immunosorbent assay (ELISA). NO oxidation products were determined using Griess reagent. Protein expression levels of inhibitors of NF-κBα (IκB) and phospho-IκB were determined via Western blot. Oxidative injury was determined by measuring myocardial lipid peroxidation and superoxide dismutase activity. Cardiac apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nickend-labeling (TUNEL) and cardiac caspase 3/7 activity. RESULTS: And blunted LPS-induced myocardial malfunctions in mice. LPS induced TNF-α, IL-1ß, and NO production as well as I-κB phosphorylation. Cardiac apoptosis was attenuated via incubation with And, but the extent of oxidative injury remained unaffected. CONCLUSION: And prevents LPS-induced cardiac malfunctions in mice by inhibiting TNF-α, IL-1ß, and NO production, IκB phosphorylation, and cardiac apoptosis, indicating that And may be a potential agent for preventing myocardial malfunction during sepsis.

Design, synthesis and antimicrobial activities of nitroimidazole derivatives containing 1,3,4-oxadiazole scaffold as FabH inhibitors.

Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities, recently found application in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. In order to search for novel antibacterial agents, we designed and synthesized a series of secnidazole analogs based on oxadiazole scaffold (4-21). Among these compounds, 4 and 7-21 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. This new nitroimidazole derivatives class demonstrated strong antibacterial activities. Escherichia coli ß-ketoacyl-acyl carrier protein synthase III (FabH) inhibitory assay and docking simulation indicated that the compounds 2-(2-methoxyphenyl)-5-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-1,3,4-oxadiazole (11) with MIC of 1.56-3.13 µg/mL against the tested bacterial strains and 2-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-5-(2-methylbenzyl)-1,3,4-oxadiazole (12) with MIC of 1.56-6.25 µg/mL were most potent inhibitors of Escherichia coli FabH.

Synthesis, molecular modeling and biological evaluation of chalcone thiosemicarbazide derivatives as novel anticancer agents.

A series of novel chalcone thiosemicarbazide derivatives (4a-4x) have been designed, synthesized, structurally determined, and their biological activities were also evaluated as potential EGFR kinase inhibitors. All the synthesized compounds are first reported. Among the compounds, compound 4r showed the most potent biological activity (IC(50) = 0.78 ± 0.05 µM for HepG2 and IC(50) = 0.35 µM for EGFR), which is comparable to the positive controls. Docking simulation was also performed to position compound 4r into the EGFR active site to determine the probable binding model. Antiproliferative assay results demonstrated that some of these compounds possessed good antiproliferative activity against HepG2. Compound 4r with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent.

Synthesis, antibacterial activities and molecular docking studies of Schiff bases derived from N-(2/4-benzaldehyde-amino) phenyl-N'-phenyl-thiourea.

A series of novel Schiff base derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of FabH. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their E. coli FabH inhibitory activity. Compound 3v showed the most potent antibacterial activity with MIC of 1.56-6.25 µg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 4.3 µM. Docking simulation was performed to position compound 3v into the E. coli FabH active site to determine the probable binding conformation.

Synthesis, molecular modeling and biological evaluation of ß-ketoacyl-acyl carrier protein synthase III (FabH) as novel antibacterial agents.

A series of novel cinnamic acid secnidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of FabH. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their E. coli FabH inhibitory activity. Compound 3n showed the most potent antibacterial activity with MIC of 1.56-6.25 µg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 2.5 µM. Docking simulation was performed to position compound 3n into the E. coli FabH active site to determine the probable binding conformation.

Design, synthesis and biological evaluation of urea derivatives from o-hydroxybenzylamines and phenylisocyanate as potential FabH inhibitors.

FabH, ß-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and Gram-negative bacteria. A series of o-hydroxybenzylamines 1-16 and its corresponding new urea derivatives 17-32 were synthesized and fully characterized by spectroscopic methods and elemental analysis. This new urea derivatives class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 1-(5-bromo-2-hydroxybenzyl)-1-(4-fluorophenyl)-3-phenylurea (18) and 1-(5-bromo-2-hydroxybenzyl)-1-(4-chlorophenyl)-3-phenylurea (20) were potent inhibitors of E. coli FabH.