Development of an mRNA-based therapeutic vaccine mHTV-03E2 for high-risk HPV-related malignancies.

Human papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventive vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.

Amur Grape VaMYB4a-VaERF054-Like Module Regulates Cold Tolerance Through a Regulatory Feedback Loop.

Cold stress can limit the growth and development of grapevines, which can ultimately reduce productivity. However, the mechanisms by which grapevines respond to cold stress are not yet fully understood. Here, we characterized an APETALA2/ethylene response factor (AP2/ERF) which was shown to be a target gene of our previously identified VaMYB4a from Amur grape. We further investigated the molecular interactions between VaMYB4a and VaERF054-like transcription factors in grapes and their role in cold stress tolerance. Our results demonstrated that VaMYB4a directly binds to and activates the VaERF054-like gene promoter, leading to its enhanced expression. Moreover, we also explored the influence of ethylene precursors and inhibitors on VaERF054-like expression and grape cold tolerance. Our findings indicate that VaERF054-like contribute to cold tolerance in grapes through modulation of the ethylene pathway and the CBF signal pathway. Overexpression of VaERF054-like in Vitis vinifera 'Chardonnay' calli and transgenic grape lines resulted in increased freezing stress tolerance, confirming its role in the cold stress response. We further confirmed the interaction between VaMYB4a and VaERF054-like in vivo and in vitro. The co-transformation of VaMYB4a and VaERF054-like in grape calli demonstrates a synergistic interaction, enhancing the cold tolerance through a regulatory feedback mechanism. Our finding provides new insights into grape cold tolerance mechanisms, potentially contributing to the development of cold-resistant grape varieties.

Clinicopathological and prognostic features of colorectal mucinous adenocarcinomas: a systematic review and meta-analysis.

BACKGROUND: Many studies have explored the clinicopathological features and prognosis between colorectal mucinous adenocarcinoma (MAC) and adenocarcinoma (AC) and have given different results. This meta-analysis summarizes previous evidence and evaluates the clinicopathological and prognostic features of MAC relative to AC in colorectal cancers (CRCs). METHODS: The meta-analysis was conducted by searching the databases of PubMed, China National Knowledge Infrastructure (CNKI), WANFANG data, Embase, and Web of Science. Pooled odds ratios (ORs) and hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated to assess the clinicopathological and prognostic differences between MAC and AC. RESULTS: Fifty-six studies involving 803157 patients met the inclusion criteria and were included in this meta-analysis. The clinicopathological features of MAC were greatly different from AC, except for lymphatic invasion (OR = 1.07, 95% CI: 0.99-1.15, P = 0.09) and perineural invasion (OR = 0.92, 95% CI: 0.79-1.06, P = 0.09). Further investigation found that MAC predicted poor OS (HR = 1.04, 95% CI: 1.03-1.04, P < 0.01), but not DFS in CRCs (HR = 1.01,95% CI: 0.88- 1.17, P = 0.85). Subgroup analysis found that MAC was obviously correlated with OS in patients with different recruitment time, with tumor located in rectum, from different regions, with different sample sizes and with TNM stage in II, and calculated by different data types(P < 0.01). CONCLUSIONS: This study shows that MAC displays obviously different clinicopathological features compared with AC. And MAC has a poor OS relative to AC but the DFS was comparable.

Hypercholesterolemia and the Increased Risk of Vascular Dementia: a Cholesterol Perspective.

PURPOSE OF REVIEW: Vascular dementia (VaD) is the second most prevalent type of dementia after Alzheimer's disease.Hypercholesterolemia may increase the risk of dementia, but the association between cholesterol and cognitive function is very complex. From the perspective of peripheral and brain cholesterol, we review the relationship between hypercholesterolemia and increased risk of VaD and how the use of lipid-lowering therapies affects cognition. RECENT FINDINGS: Epidemiologic studies show since 1980, non-HDL-C levels of individuals has increased rapidly in Asian countries.The study has suggested that vascular risk factors increase the risk of VaD, such as disordered lipid metabolism. Dyslipidemia has been found to interact with chronic cerebral hypoperfusion to promote inflammation resulting in cognitive dysfunction in the brain.Hypercholesterolemia may be a risk factor for VaD. Inflammation could potentially serve as a link between hypercholesterolemia and VaD. Additionally, the potential impact of lipid-lowering therapy on cognitive function is also worth considering. Finding strategies to prevent and treat VaD is critical given the aging of the population to lessen the load on society. Currently, controlling underlying vascular risk factors is considered one of the most effective methods of preventing VaD. Understanding the relationship between abnormal cholesterol levels and VaD, as well as discovering potential serum biomarkers, is important for the early prevention and treatment of VaD.

Effect of acupuncture anesthesia on inflammatory response and cellular immunity in patients with osteoporotic fractures.

Osteoporotic vertebral compression fractures (OVCFs) occur frequently in the elderly, with percutaneous vertebroplasty (PVP) being the major clinical treatment at present. How to improve the patient's surgical cooperation while ensuring surgical safety is the focus of clinical research. This study explores the influence of acupuncture anesthesia (AA) on the safety, inflammatory response, and cellular immunity of OVCF patients undergoing PVP, which may provide a more reliable safety guarantee for future treatment of OVCFs. The results showed that patients using AA had lower postoperative Visual Analogue Scale (VAS) scores and incidence of postoperative adverse reactions, a smaller anesthetic dosage, but an extended duration of anesthesia; moreover, the postoperative inflammatory response was markedly alleviated and the stability of T lymphocyte subsets was obviously enhanced. Therefore, AA has high clinical application value in PKP treatment of OVCFs in the future.

Novel antibody-antibiotic conjugate using KRM-1657 as payload eliminates intracellular MRSA in vitro and in vivo.

Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S.aureus within host cells may cause long-term colonization and clinical failure. Current treatments have poor efficacy in clearing intracellular bacteria. Antibody-antibiotic conjugates (AACs) is a novel strategy for eliminating intracellular bacteria. Herein, we use KRM-1657 as payload of AAC for the first time, and we conjugate it with anti S. aureus antibody via a dipeptide linker (Valine-Alanine) to obtain a novel AAC (ASAK-22). The ASAK-22 exhibits good in vitro pharmacokinetic properties and inhibitory activity against intracellular MRSA, with 100 µg/mL of ASAK-22 capable of eliminating intracellular MRSA to the detection limit. Furthermore, the in vivo results demonstrate that a single administration of ASAK-22 significantly reduces the bacterial burden in the bacteremia model, which is superior to the vancomycin treatment.

Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Clinical Impact of Operating Room Nursing Pathways on Hospitalization Duration and Consciousness Status in Patients Undergoing Emergency Craniocerebral Injury Surgery.

Background: Craniocerebral injuries carry high disability and mortality rates. In clinical practice, timely determination of the condition and immediate rescue interventions are crucial for patients with emergency craniocerebral injuries. Nurses play a pivotal role in providing proactive nursing services to save patients' lives. Objective: This study aims to examine the practical implications of implementing operating room nursing pathways in the care of patients undergoing emergency craniocerebral injury surgery. Design: A randomized controlled study was conducted. Setting: The study was conducted at the Department of Operating Room at Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine. Participants: A total of 80 patients undergoing emergency craniocerebral injury surgery in our hospital from August 2020 to August 2022 were included. They were randomly divided into control and observation groups through a lottery, with 40 cases in each. Interventions: The control group received conventional nursing, while the observation group received operating room nursing pathways. Primary Outcome Measures: (1) Surgical preparation time, surgical time, and hospitalization time; (2) Pupil scores; (3) Brain injury grading; and (4) Nursing satisfaction score. Results: The observation group exhibited a significant decrease in surgical preparation time and hospitalization time compared to the control group (P < .05). After the intervention, severe craniocerebral injury pupil scores in the observation group showed improvement compared to the control group (P < .05). The total satisfaction rate in the observation group (92.5%) was higher than that in the control group (80.0%) (P = .012). Conclusions: The application of operating room nursing pathways in patients undergoing emergency craniocerebral injury surgery can lead to a shortened length of stay, substantial improvement in patients' consciousness status, and high satisfaction rates from both patients and their family members. This intervention holds significant clinical value and merits further promotion.

Comparative investigations on the incorporation of biogenic Fe products into anaerobic granular sludge of different sources: Fe loading capacity, physicochemical properties, microbial community and long-term methanogenesis performance.

Anaerobic granular sludge (AGS) has been regarded as the core of lots of advanced anaerobic reactors. Formation of biogenic Fe products and their incorporation into AGS could influence interspecies electron transfer and methanogenesis performance. In this study, with anaerobic granular sludge (AGS) from different sources (brewery, chemical plant, paper mill, citric acid factory, and food factory) as the research targets, the formation of biogenic iron products in AGS through the biologically induced mineralization process was studied. Furthermore, the influences of physicochemical properties and microbial community on methanogenesis were investigated. Results showed that all the AGS of different sources possessed the capacity to form biogenic Fe products through dissimilatory iron-reduction process, and diverse Fe minerals including magnetite (Fe3O4), hematite (Fe2O3), goethite (FeOOH), siderite (FeCO3) and wustite (FeO) were incorporated into AGS. The AGS loaded with Fe minerals (Fe-AGS) showed increased conductivity, magnetism and zeta-potential comparing to the control. Those Fe-AGS of different sources demonstrated different methanogenesis performance during the long-term operation (50 days). Methane production was increased for the Fe-AGS of citric acid (6.99-32.50%), food (8.33-37.46%), chemical (2.81-7.22%) and brewery plants (2.27-2.81%), but decreased for the Fe-AGS of paper mill (54.81-72.2%). The changes of microbial community and microbial correlations in AGS as a response to Fe minerals incorporation were investigated. For the Fe-AGS samples with enhanced methane production capability, it was widely to find the enriched populations of fermentative and dissimilatory iron reducing bacteria Clostridium_sensu_stricto_6, Bacteroidetes_vadinHA17 and acetoclastic methanogens Methanosaeta, and positive correlations between them. This study provides comprehensive understanding on the effects of incorporation biogenic Fe products on AGS from different sources.

Impact of resampling interpolation FIR filter in the practical Kramers-Kronig receiver.

The practical Kramers-Kronig (KK) receiver has been a competitive receiving technique in the data-center, medium reach, and even long-haul metropolitan networks. Nevertheless, an extra digital resampling operation is required at both ends of the KK field reconstruction algorithm due to the spectrum broadening caused by adopting the nonlinear function. Generally, the digital resampling function can be implemented by using linear interpolation (LI-ITP), the Lagrange cubic interpolation (LC-ITP), the spline cubic interpolation (SC-ITP), time-domain anti-aliasing finite impulse response (FIR) filter method (TD-FRM) scheme, and fast Fourier transform (FFT)-based scheme. However, the performance and the computational complexity analysis of different resampling interpolation schemes in the KK receiver have not been thoroughly investigated yet. Different from the interpolation schemes of conventional coherent detection, the interpolation function of the KK system is followed by the nonlinear operation, which will broaden the spectrum significantly. Due to the frequency-domain transfer function of different interpolation schemes, the broadened spectrum will have a potential spectrum aliasing, which will cause serious inter-symbol interference (ISI) and further impair the KK phase retrieval performance. We experimentally investigate the performance of different interpolation schemes under different digital up-sampling rates (i.e. the computational complexity) as well as the cut-off frequency, the tap number of the anti-aliasing filter, and the shape factor of the TD-FRM scheme in a 112-Gbit/s SSB DD 16-QAM system over 1920-km Raman amplification (RFA)-based standard single-mode fiber (SSMF). The experimental results involve that the TD-FRM scheme outperforms other interpolation schemes and the complexity is reduced by at least 49.6%. In fiber transmission results, take 20% soft decision-forward error correction (SD-FEC) of 2×10-2 as the threshold, the LI-ITP and LC-ITP schemes only reach 720-km while others can reach up to 1440-km.

Cu-Catalyzed Decarboxylative Annulation of N-Phenylglycines with Maleimides: Synthesis of 1H-Pyrrolo[3,4-c]quinoline-1,3(2H)-diones.

A novel protocol for the construction of functionalized 1H-pyrrolo[3,4-c]quinoline-1,3(2H)-diones (PQLs, 3) from N-phenylglycines and maleimides was developed. The cascade reaction was enabled by heating a mixture of the two substrates in the presence of di-tert-butyl peroxide (DTBP) as an oxidant and anhydrous CuBr as a catalyst in chlorobenzene. Consequently, a diverse series of PQLs 3 were synthesized in moderate-to-good yields (43-73%). The synthesis of the PQLs was enabled via a one-pot cascade reaction that proceeded through subsequent oxidative decarboxylation, 1,2-addition, intramolecular cyclization, tautomerization, and aromatization reactions. This protocol can be used for the synthesis of functionalized PQLs via a one-pot oxidative decarboxylation annulation reaction rather than through a series of multistep reactions, making it suitable for both combinatorial and parallel syntheses of PQLs.

Crystalline versus Amorphous: High-Performance Hafnium Phosphonate Framework for the Separation of Uranium and Transuranium Elements.

Metal phosphonate frameworks (MPFs) consisting of tetravalent metal ions and aryl-phosphonate ligands feature a large affinity for actinides and excellent stabilities in harsh aqueous environments. However, it remains elusive how the crystallinity of MPFs influences their performance in actinide separation. To this end, we prepared a new category of porous, ultrastable MPF with different crystallinities for uranyl and transuranium separation. The results demonstrated that crystalline MPF was generally a better adsorbent for uranyl than the amorphous counterpart and ranked as the top-performing one for uranyl and plutonium in strong acidic solutions. A plausible uranyl sequestration mechanism was unveiled by using powder X-ray diffraction in tandem with vibrational spectroscopy, thermogravimetry, and elemental analysis.

Defunctioning stoma and anastomotic stricture in rectal cancer surgery: a propensity score matching study.

BACKGROUND: In cases of rectal cancer surgery, patients at high risk of anastomotic leakage often receive a defunctioning stoma (DS). However, its role in postoperative anastomotic strictures (AS) remains unclear. This study aimed to investigate the correlation between DS and AS and outcomes of transanal endoscopic microsurgery (TEM) in treating rectal AS. METHODS: This retrospective study was conducted from January 2019 to September 2021 and included patients who underwent rectal cancer surgery. A 1:1 ratio was used for propensity score matching (PSM). Univariate analyses were performed to identify statistically significant variables, and multivariate analyses were conducted to determine the factors affecting AS. RESULTS: This study included 383 patients. The results of the univariate analysis suggested that surgery time (HR 4.597, 95% CI 1.563-13.525, P=0.006), postoperative anastomotic leakage (HR 11.830, 95% CI 3.773-37.094, P<0.001), and DS (HR 15.475, 95% CI 6.042-39.641, P<0.001) were significantly associated with AS. In the multivariate analysis, postoperative anastomotic leakage (HR 7.596, 95% CI 1.987-29.044, P= 0.003) and DS (HR 11.252, 95% CI 4.113-30.779, P<0.001) were identified as significant risk factors for AS. After matching, the univariate analysis revealed that postoperative anastomotic leakage (HR 8.333, 95% CI 1.541-45.052, P= 0.014) and DS (HR 9.965, 95% CI 2.200-45.142, P= 0.003) were associated with AS. The multivariate analysis indicated that postoperative anastomotic leakage (HR 14.549, 95% CI 1.765-119.913, P= 0.013) and DS (HR 12.450, 95% CI 2.418-64.108, P= 0.003) were significant risk factors for AS. CONCLUSIONS: This study provides evidence that DS is independently associated with AS, and postoperative anastomotic leakage increases the risk of AS. Furthermore, this study suggests that TEM could be a valuable treatment option for AS.

Efficacy and safety of erythropoietin in isolated spinal metastasis patients with total en bloc spondylectomy surgery: a case-control study.

OBJECTIVE: The purpose of our study is to identify the effect of short-term and high-dose use of erythropoietin (EPO) in spinal isolated metastatic patients with Total en bloc spondylectomy (TES) surgery by assessing hematological parameters, transfusion volume, postoperative complications, recurrence-free survival (RFS), and overall survival (OS). METHODS: From January 2015 and January 2022, 93 isolated spinal metastasis patients were selected and separated into 2 groups based on the treatment method used (EPO + TXA (Tranexamic acid) group, n = 47; and TXA group, n = 46). Indexes for evaluation included hemoglobin (Hb), hematocrit (Hct), red blood cells (RBC), RFS, OS, postoperative complications, postoperative Frankel Grade, drainage volume, transfusion rate, and mean units transfused. RESULTS: The average follow-up duration was 38.13 months. There was no significant difference (P > 0.05) in RFS, OS, postoperative complications, postoperative Frankel Grade, drainage volume, and transfusion rate between the two groups. However, patients in EPO + TXA group have significantly higher Hb, Hct, and RBC values than those in the TXA group on postoperative days 1, 2, 3, and 5. Moreover, the mean transfusion volume in EPO + TXA group was significantly lower than those in the TXA group (P = 0.011). CONCLUSIONS: Perioperative short-term and high-dose administration of EPO could improve the anemia-related hematological parameters and reduce the requirement for blood transfusion without increasing the risk of deep vein thrombosis and tumor progression in solitary spinal metastatic patients with TES surgery.

Identity-Guided Spatial Attention for Vehicle Re-Identification.

In vehicle re-identification, identifying a specific vehicle from a large image dataset is challenging due to occlusion and complex backgrounds. Deep models struggle to identify vehicles accurately when critical details are occluded or the background is distracting. To mitigate the impact of these noisy factors, we propose Identity-guided Spatial Attention (ISA) to extract more beneficial details for vehicle re-identification. Our approach begins by visualizing the high activation regions of a strong baseline method and identifying noisy objects involved during training. ISA generates an attention map to mask most discriminative areas, without the need for manual annotation. Finally, the ISA map refines the embedding feature in an end-to-end manner to improve vehicle re-identification accuracy. Visualization experiments demonstrate ISA's ability to capture nearly all vehicle details, while results on three vehicle re-identification datasets show that our method outperforms state-of-the-art approaches.

Development and Psychometric Properties of a Scale Measuring Barriers to Perioperative Hypothermia Prevention for Anesthesiologists and Nurses.

PURPOSE: To develop a scale that measures barriers to perioperative hypothermia prevention (BPHP) as perceived by anesthesiologists and nurses. DESIGN: A methodological and prospective psychometric study. METHODS: Based on the theoretical domains framework, the item pool was created through a literature review, qualitative interviews, and expert consultation. The scale was pretested with a sample of 154 key stakeholders in perioperative temperature management and then field tested with 416 anesthesiologists and nurses working at three hospitals in Southeast China. Item analysis, and reliability and validity analysis were performed. FINDINGS: The average content validity index was 0.94. According to exploratory factor analysis, seven factors were obtained that could explain 70.283% of the total variance. Confirmatory factor analysis showed excellent or acceptable goodness-of-fit indices. The reliability analysis demonstrated that the scale had high internal consistency and temporal stability, with Cronbach's α, split-half coefficient and test-retest values of 0.926, 0.878 and 0.835, respectively. CONCLUSIONS: The BPHP scale meets the psychometric criteria for reliability and validity and promises to be a useful quality measure for IPH management during the perioperative period. Further investigations on educational or resource needs and the development of an optimal perioperative hypothermia prevention protocol to narrow the gap between research evidence and clinical practice should be performed.

MOFs with 12-Coordinate 5f-Block Metal Centers.

We have constructed an unprecedented MOF platform that accommodates a range of 5f-block metal ions (Th4+, U4+, Np4+, Pu4+) as the primary building block. The isoreticular actinide metal-organic frameworks (An-MOFs) exhibit periodic trends in the 12-coordinate metal environment, ligand configuration, and resulting ultramicroporosity. It holds potential in distinguishing neighboring tetravalent actinides. The metal ionic radius, carboxylate bite angle, anthracene plane twisting, interligand interactions, and countercation templating collectively determine an interplay between solvation, modulation, and complexation, resulting in a coordination saturation of the central actinide, while lanthanide counterparts are stabilized by the formation of a dimer-based motif. Quantum chemical calculations indicate that this large coordination number is only feasible in the high-symmetry environment provided by the An-MOFs. This category of MOFs not only demonstrates autoluminescence (4.16 × 104 counts per second per gram) but also portends a wide-bandgap (2.84 eV) semiconducting property with implications for a multitude of applications such as hard radiation detection.

Multispectral higher-order Fano resonant metasurface based on periodic twisted DNA-like split ring arrays with three modulation methods.

The active modulation of the Fano resonance is rare but desirable. However, recent studies mostly focused on a single modulation method and few reported the use of three photoelectric control methods. A tunable graphene DNA-like metamaterial modulator with multispectral Fano resonance is demonstrated. In experimentally fabricated metamaterials with six photoelectric joint modulation patterns, each joint shows different optoelectrical response characteristics. Ultrahigh modulation depth (MD) up to 982% was achieved at 1.5734 THz with a 1.040 A external laser pump by involving combined optoelectrical methods. These results show that the metasurface modulator is a promising platform for higher-order Fano resonance modulation and communication fields.

Cu-Catalyzed Oxidative [3 + 2] Annulation of 2-(Pyridine-2-yl)acetates with Maleimides: Synthesis of 1H-Pyrrolo[3,4-b]indolizine-1,3-diones.

A novel protocol for the construction of highly functionalized indolizine derivatives, that is, 1H-pyrrolo[3,4-b]indolizine-1,3-diones (PIZDOs, 3) from 2-(pyridine-2-yl)acetates and maleimides via a regioselective oxidative [3 + 2] annulation was developed. The cascade oxidative reaction was enabled by heating a mixture of the two substrates in the presence of Ag2CO3 as an oxidant and Cu(OAc)·H2O as a catalyst in chlorobenzene. Consequently, a series of PIZDOs 3 were synthesized with high regioselectivity in moderate yields. This protocol can be used in the synthesis of functionalized PIZDOs via the one-pot oxidative annulation reaction rather than through multistep reactions, which is suitable for both combinatorial and parallel syntheses of PIZDOs.

Design, synthesis and biological evaluation of nitrofuran-1,3,4-oxadiazole hybrids as new antitubercular agents.

Three series of novel nitrofuran-1,3,4-oxadiazole hybrids were designed and synthesized as new anti-TB agents. The structure activity relationship study indicated that the linkers and the substituents on the oxadiazole moiety greatly influence the activity, and the substituted benzenes are more favoured than the cycloalkyl or heterocyclic groups. Besides, the optimal compound in series 2 was active against both MTB H37Rv strain and MDR-MTB 16883 clinical isolate and also displayed low cytotoxicity, low inhibition of hERG and good oral PK, indicating its promising potential to be a lead for further structural modifications.