Subtemporal Approach for the Treatment of Ruptured and Unruptured Distal Basilar Artery Aneurysms: Is There a Contemporary Use?

BACKGROUND AND OBJECTIVES: Distal basilar artery aneurysms (DBAs) are high-risk lesions for which endovascular treatment is preferred because of their deep location, yet indications for open clipping nonetheless remain. The subtemporal approach allows for early proximal control and direct visualization of critical posterior perforating arteries, especially for posterior-projecting aneurysms. Our objective was to describe our clinical experience with the subtemporal approach for clipping DBAs in the evolving endovascular era. METHODS: This was a retrospective, single-institution case series of patients with DBAs treated with microsurgery over a 21-year period (2002-2023). Demographic, clinical, and surgical data were collected for analysis. RESULTS: Twenty-seven patients underwent clipping of 11 ruptured and 16 unruptured DBAs with a subtemporal approach (24 female; mean age 53 years). Ten patients had expanded craniotomies for treatment of additional aneurysms. The aneurysm occlusion rate was 100%. Good neurological outcomes as defined by the modified Rankin Scale score ≤2 and Glasgow Outcome Scale score ≥4 were achieved in 21/27 patients (78%). Two patients died before hospital discharge, one from vasospasm-induced strokes and another from an intraoperative myocardial infarction. CONCLUSION: These results demonstrate that microsurgical clip ligation of DBAs using the subtemporal approach remains a viable option for complex lesions not amenable to endovascular management.

Novel Natural Inhibitors for Glioblastoma by Targeting Epidermal Growth Factor Receptor and Phosphoinositide 3-kinase.

BACKGROUND/AIM: Glioblastoma is an extensively malignant neoplasm of the brain that predominantly impacts the human population. To address the challenge of glioblastoma, herein, we have searched for new drug-like candidates by extensive computational and biochemical investigations. METHOD: Approximately 950 compounds were virtually screened against the two most promising targets of glioblastoma, i.e., epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K). Based on highly negative docking scores, excellent binding capabilities and good pharmacokinetic properties, eight and seven compounds were selected for EGFR and PI3K, respectively. RESULTS: Among those hits, four natural products (SBEH-40, QUER, QTME-12, and HCFR) exerted dual inhibitory effects on EGFR and PI3K in our in-silico analysis; therefore, their capacity to suppress the cell proliferation was assessed in U87 cell line (type of glioma cell line). The compounds SBEH-40, QUER, andQTME-12 exhibited significant anti-proliferative capability with IC50 values of 11.97 ± 0.73 µM, 28.27 ± 1.52 µM, and 22.93 ± 1.63 µM respectively, while HCFR displayed weak inhibitory potency (IC50 = 74.97 ± 2.30 µM). CONCLUSION: This study has identified novel natural products that inhibit the progression of glioblastoma; however, further examinations of these molecules are required in animal and tissue models to better understand their downstream targeting mechanisms.

Urease and human glioblastoma (U87) cells growth inhibitory iridoid glycoside acetates from Nyctanthes arbor-tristis Linn.

The present study was undertaken on the chemical constituents of ethanol extract of aerial parts of Nyctanthes arbor-tristis Linn., and their determination of growth inhibitory activity against glioblastoma multiforme cell line (U87) and urease inhibitory activity. Six constituents were isolated including two new arbortristoside F tetraacetate (1) and arbortristoside G heptaacetate (2) and four known arborside A tetraacetate (3), arborside C pentaacetate (4), 6,7-di-O-acetyl-6ß-hydroxyloganin hexaacetate (5) and nyctanthoside heptaacetate (6) iridoid glycoside acetates. Their structures were elucidated using spectroscopic methods, including 1D and 2D NMR and mass analyses. Compounds 3 and 6 showed significant growth inhibition of U87 cell line (76.41 and 87.62% inhibition) respectively while 2, 4 and 5 showed moderate inhibition. 3 and 6 showed notable urease inhibition (IC50 = 17.2 ± 0.4 and 17.2 ± 0.7 µM) respectively, and IC50 of 2, 4 and 5 were 23.8 - 56.3 µM. Compound 1 was inactive.

Circular Differential Photocurrent Mapping of Hot Electron Response from Individual Plasmonic Nanohelicoids.

Chiral plasmonic nanocrystals have recently attracted increasing attention in circular polarization-dependent photocatalysis driven by hot carriers. While being concealed in traditional ensemble measurements, the individual chiral photocatalytic activity of nanocrystals can exclusively be revealed by directly correlating the circular differential photocurrent response to helical morphologies using single-particle techniques. Herein, we develop a method named circular differential photocurrent mapping (CDPM) and demonstrate that CDPM can be used to characterize the circular differential hot electron (CDHE) response from individual Au nanohelicoids (AuNHs) on a TiO2 photoanode in a photoelectrochemical cell. The single-particle circular differential scattering and CDHE measurements were interpreted with calculations performed on a model in direct correlation to the helical morphologies of the nanocrystal. While CDHE response was found inactive at a dipolar resonance of 750 nm, helicity-convoluted sites of HE generation were identified on the AuNH at a specific higher-order mode of 550 nm, resulting in a significant response of CDHE in association with the handedness of the AuNH. Details of circular differential contributions were further resolved by examining the efficiencies of individual AuNHs in terms of g-factors. Our study provides a powerful microscopic method at the single-particle level for the photocatalytic characterization of chiral nanocrystals, gaining fundamental insights into the photocatalysis of chirality, especially toward plasmon-induced asymmetrical photochemistry or photoelectrochemistry.

Electrochemical sensing of B-complex vitamins: current challenges and future prospects with microfluidic integration.

Vitamins are crucial micronutrients found in limited quantities in food, living organisms, and soil. Since most vitamins are not produced within the human body, a lack of these essential nutrients can result in various physiological disorders. Analyzing vitamins typically involves costly, time-consuming methods, requiring skilled personnel, automated equipment, and dedicated laboratory setups. The pressing need is for the development of efficient, portable, and user-friendly detection techniques that are cost-effective, addressing the challenges associated with traditional analytical approaches. In recent years, electrochemical sensors and electrochemical microfluidic devices have garnered prominence owing to their remarkable sensitivity, quick analysis, cost-effectiveness, and facile fabrication procedures. Electrochemical sensing and microfluidics are two distinct fields that are often integrated to create powerful and versatile sensing devices. The connection between them leverages the advantages of both fields to create highly efficient, miniaturized, and portable analytical systems. This interdisciplinary approach has led to the development of innovative devices with broad applications in various scientific, medical, and environmental domains. This review begins by outlining the importance of vitamins in human nutrition and health and emphasizing the need for precise and reliable sensing techniques. Owing to the limited literature available on electrochemical detection of vitamin B complexes, this review offers an in-depth analysis of modern electrochemical sensing of water-soluble vitamins, focusing on B1, B2, B6, B9, and B12. The challenges faced by researchers are addressed, including selectivity, sensitivity, interference, matrix effects, and calibration, while also exploring promising prospects such as nanomaterial integration, miniaturization, microfluidics-based IoTs, and innovative sensor designs.

Computational prediction of workability and mechanical properties of bentonite plastic concrete using multi-expression programming.

Bentonite plastic concrete (BPC) demonstrated promising potential for remedial cut-off wall construction to mitigate dam seepage, as it fulfills essential criteria for strength, stiffness, and permeability. High workability and consistency are essential attributes for BPC because it is poured into trenches using a tremie pipe, emphasizing the importance of accurately predicting the slump of BPC. In addition, prediction models offer valuable tools to estimate various strength parameters, enabling adjustments to BPC mixing designs to optimize project construction, leading to cost and time savings. Therefore, this study explores the multi-expression programming (MEP) technique to predict the key characteristics of BPC, such as slump, compressive strength (fc), and elastic modulus (Ec). In the present study, 158, 169, and 111 data points were collected from the experimental studies for the slump, fc, and Ec, respectively. The dataset was divided into three sets: 70% for training, 15% for testing, and another 15% for model validation. The MEP models exhibited excellent accuracy with a correlation coefficient (R) of 0.9999 for slump, 0.9831 for fc, and 0.9300 for Ec. Furthermore, the comparative analysis between MEP models and conventional linear and non-linear regression models revealed remarkable precision in the predictions of the proposed MEP models, surpassing the accuracy of traditional regression methods. SHapley Additive exPlanation analysis indicated that water, cement, and bentonite exert significant influence on slump, with water having the greatest impact on compressive strength, while curing time and cement exhibit a higher influence on elastic modulus. In summary, the application of machine learning algorithms offers the capability to deliver prompt and precise early estimates of BPC properties, thus optimizing the efficiency of construction and design processes.

Biochemical and In Silico Studies on Triazole Derivatives as Tyrosinase Inhibitors: Potential Treatment of Hyperpigmentation Related Skin Disorders.

INTRODUCTION: Tyrosinase is a versatile, glycosylated copper-containing oxidase enzyme that mainly catalyzes the biosynthesis of melanin in mammals. Its overexpression leads to the formation of excess melanin, resulting in hyperpigmentary skin disorders, such as dark spots, melasma, freckles, etc. Therefore, inhibition of tyrosinase is a therapeutic approach for the treatment of hyperpigmentation. METHOD: The current study focused on evaluating tyrosinase inhibitory activities of triazole derivatives 1-20, bearing different substituents on the phenyl ring. 17 derivatives have shown a potent tyrosinase inhibition with IC50 values between 1.6 to 13 µM, as compared to the standard drug, i.e., kojic acid (IC50 = 24.1 ± 0.5 µM). Particularly, compounds 11 and 15 displayed 12 times more potent inhibitory effects than the kojic acid. RESULT: The structure-activity relationship revealed that substituting halogens at the C-4 position of the benzene ring renders remarkable anti-tyrosinase activities. Compounds 1-3 and 8 showed a competitive type of inhibition, while compounds 5, 11, and 15 showed a non-competitive mode of inhibition. Next, we performed molecular docking analyses to study the binding modes and interactions between the ligands (inhibitors) and the active site of the tyrosinase enzyme (receptor). Besides this, we have assessed the toxicity profile of inhibitors on the BJ human fibroblast cell line. CONCLUSION: The majority of the newly identified tyrosinase inhibitors were found to be noncytotoxic. The results presented herein form the basis of further studies on triazole derivatives as potential drug leads against tyrosinase-related diseases.

Anti-inflammatory and urease inhibitory iridoid glycosides from Nyctanthes arbor-tristis Linn.

ETHNOPHARMACOLOGICAL RELEVANCE: Nyctanthes arbor-tristis Linn. has been used by Ayruvedic physicians for the cure of different diseases including ulcers, gastric and inflammatory diseases. AIM OF THE STUDY: To isolate and identify compounds from this source and investigate their therapeutic potential for the treatment of gastric ulcer and related disorders. MATERIAL AND METHODS: The ethanol extract of fresh aerial parts of N. arbor-tristis was used in the present studies which was subjected to a bio-assay guided fractionation followed by chromatographic separations. The structures of pure compounds were elucidated using various spectroscopic techniques. The inhibition of urease enzyme was evaluated by weatherburn indophenol method. Molecular docking studies were determined by using Molecular Operating Environment (MOE) version 2020.0901 version. The intracellular ROS production from phagocytes was determined by chemiluminescence assay and NO generation was detected by Griess method. The proinflammatory cytokine TNF-α was quantified by ELISA. Cytotoxic activity was assessed by MTT assay. RESULTS: One previously undescribed iridoid glycoside arborside F (1) and four known iridoid glycosides arborside A (2), arborside C (3), loganin (4) and 7-O-trans-cinnamoyl-6ß-hydroxyloganin (5) were isolated and characterized in the present studies and their urease inhibitory activity was determined. Among these, 2 and 5 showed strong urease inhibition (IC50 = 12.1 ± 1.74 and 14.1 ± 0.59 µM respectively) (standard acetohydroxamic acid IC50 = 20.3 ± 0.42 µM), whereas rest of compounds showed moderate to low inhibition. Kinetic studies revealed that compounds 2 and 5 possess competitive type of inhibition. Molecular docking showed polar and non-polar interactions of compounds 2 and 5 with urease enzyme residues. Compounds 2 and 3 showed inhibition of ROS from whole blood (IC50 = 1.6 ± 0.3 and 2.5 ± 0.09 µg/mL respectively) and PMNs (IC50 = 1.5 ± 0.03 and 1.4 ± 0.0 µg/mL respectively). Compound 2 significantly inhibited nitric oxide and proinflammatory cytokine TNF-α (IC50 = 18.2 ± 3.0 and 73.8 ± 6.6 µg/mL respectively). Compounds 1, 4 and 5 were inactive on ROS. All isolated compounds were non-toxic on normal mouse fibroblasts (NIH-3T3) cells. CONCLUSIONS: The ethno pharmacological repute of N. arbor-tristis in treating gastric and anti-inflammatory ailments is supported by present studies which resulted in isolation of a potent urease inhibitory and anti-inflammatory agent arborside A (2) a potential anti-ulcer and anti-inflammatory drug lead.

Key dependent information confidentiality scheme based on deoxyribonucleic acid (DNA) and circular shifting.

In this era of advanced information technology, the exploration and development of novel mechanisms to ensure information confidentiality have consistently captivated the attention of upcoming researchers. In this article, we present a pioneering approach that combines DNA sequencing with a four-dimensional (4D) hyperchaotic map to bolster the security of digital information. Our primary focus is on the design of a robust and secure scheme for encrypting color images, leveraging DNA cryptography and hyperchaos. By extracting three distinct DNA sequences, we generate encryption keys through the integration of DNA computing and 4D hyperchaotic maps. Notably, these keys are intricately linked to the plaintext and vary with any alterations in the input. Consequently, the proposed encryption method stands resilient against an array of potential cryptographic attacks. To gauge the algorithm's security, we subject it to rigorous standard statistical analysis. Our findings underscore the efficiency and robustness of the proposed framework, establishing its potential for facilitating secure communication.

Intelligent prediction modeling for flexural capacity of FRP-strengthened reinforced concrete beams using machine learning algorithms.

Fiber-reinforced polymers (FRP) are widely utilized to improve the efficiency and durability of concrete structures, either through external bonding or internal reinforcement. However, the response of FRP-strengthened reinforced concrete (RC) members, both in field applications and experimental settings, often deviates from the estimation based on existing code provisions. This discrepancy can be attributed to the limitations of code provisions in fully capturing the nature of FRP-strengthened RC members. Accordingly, machine learning methods, including gene expression programming (GEP) and multi-expression programming (MEP), were utilized in this study to predict the flexural capacity of the FRP-strengthened RC beam. To develop data-driven estimation models, an extensive collection of experimental data on FRP-strengthened RC beams was compiled from the experimental studies. For the assessment of the accuracy of developed models, various statistical indicators were utilized. The machine learning (ML) based models were compared with empirical and conventional linear regression models to substantiate their superiority, providing evidence of enhanced performance. The GEP model demonstrated outstanding predictive performance with a correlation coefficient (R) of 0.98 for both the training and validation phases, accompanied by minimal mean absolute errors (MAE) of 4.08 and 5.39, respectively. In contrast, the MEP model achieved a slightly lower accuracy, with an R of 0.96 in both the training and validation phases. Moreover, the ML-based models exhibited notably superior performances compared to the empirical models. Hence, the ML-based models presented in this study demonstrated promising prospects for practical implementation in engineering applications. Moreover, the SHapley Additive exPlanation (SHAP) method was used to interpret the feature's importance and influence on the flexural capacity. It was observed that beam width, section effective depth, and the tensile longitudinal bars reinforcement ratio significantly contribute to the prediction of the flexural capacity of the FRP-strengthened reinforced concrete beam.

Review of real-world evidence of dual inhibition of VEGF-A and ANG-2 with faricimab in NAMD and DME.

Management of vitreoretinal disorders (e.g., neovascular age-related macular degeneration [nAMD] and diabetic macular edema [DME]) have assumed the standard therapy of lifelong anti-VEGF injections with drugs like aflibercept, brolucizumab, ranibizumab and bevacizumab. However, the burden imposed on patients is a major deterrent for continual therapy and recovery. Faricimab, a bispecific antibody, blocking both VEGF-A and Ang-2 molecules, produces a comparable functional and anatomical results, with less injections, significantly reducing patient burden. Visual acuity, safety, adverse effects, and anatomical outcomes are discussed in the pivotal clinical trials (YOSEMITE/RHINE and TENAYA/LUCERNE), and early data from real-world studies (TRUCKEE, TAHOE, FARWIDE-DME, FARETINA and others). In YOSEMITE and RHINE, faricimab demonstrated non-inferior vision gains, better anatomical outcomes compared to aflibercept every 8 weeks. Faricimab in the personalized treatment interval (PTI), after week 96, achieved 12-week interval in 78.1% of the patients and 16-week interval in 62.3%. TENAYA and LUCERNE reported comparable best corrected visual acuity (BCVA) improvement and better anatomic outcomes during head-to-head phase, parallel to aflibercept, at its 8-week treatment schedule. Faricimab in the PTI regimen, after week 96 achieved 12-week interval in 77.8% of the patients and 16-week interval in 63.1%. Safety of faricimab has been comparable to aflibercept in these pivotal trials. Real-world data supports the data from the pivotal studies regarding the efficacy and safety profile of faricimab in heterogenous real world patient population. Moreover, in previously treated patients, it also demonstrated a faster fluid resolution, good safety profile. Considering faricimab has demonstrated anatomic and durability benefit in the treatment of nAMD and DME, additional data from ongoing extension clinical trials, AVONELLE-X and RHONE-X will help understand longer term outcomes for patients treated with faricimab as well as patients switching from aflibercept to faricimab after finishing the pivotal trials. Longer term data from the real-world studies will also continue to contribute to our understanding of long-term efficacy, safety and durability in the real world patient population.

Oncologic and Functional Outcomes After Stereotactic Body Radiation Therapy for High-Grade Malignant Spinal Cord Compression.

Purpose: Although surgical decompression is the gold standard for metastatic epidural spinal cord compression (MESCC) from solid tumors, not all patients are candidates or undergo successful surgical Bilsky downgrading. We report oncologic and functional outcomes for patients treated with stereotactic body radiation therapy (SBRT) to high-grade MESCC. Methods and Materials: Patients with Bilsky grade 2 to 3 MESCC from solid tumor metastases treated with SBRT at a single institution from 2009 to 2020 were retrospectively reviewed. Patients who received upfront surgery before SBRT were included only if postsurgical Bilsky grade remained ≥2. Neurologic examinations, magnetic resonance imaging, pain assessments, and analgesic usage were assessed every 3 to 4 months post-SBRT. Cumulative incidence of local recurrence was calculated with death as a competing risk, and overall survival was estimated by Kaplan-Meier. Results: One hundred forty-three patients were included. The cumulative incidence of local recurrence was 5.1%, 7.5%, and 14.1% at 6, 12, and 24 months, respectively. At first post-SBRT imaging, 16.2% of patients with initial Bilsky grade 2 improved to grade 1, and 53.8% of patients were stable. Five of 13 patients (38.4%) with initial Bilsky grade 3 improved to grade 1 to 2. Pain response at 3 and 6 months post-SBRT was complete in 45.4% and 55.7%, partial in 26.9% and 13.1%, stable in 24.1% and 27.9%, and worse in 3.7% and 3.3% of patients, respectively. At 3 and 6 months after SBRT, 17.8% and 25.0% of patients had improved ambulatory status and 79.7% and 72.4% had stable status. Conclusions: We report the largest series to date of patients with high-grade MESCC treated with SBRT. The excellent local control and functional outcomes suggest SBRT is a reasonable approach in inoperable patients or cases unable to be successfully surgically downgraded.

Umbrella review and network meta-analysis of diagnostic imaging test accuracy studies in Differentiating between brain tumor progression versus pseudoprogression and radionecrosis.

PURPOSE: In this study we gathered and analyzed the available evidence regarding 17 different imaging modalities and performed network meta-analysis to find the most effective modality for the differentiation between brain tumor recurrence and post-treatment radiation effects. METHODS: We conducted a comprehensive systematic search on PubMed and Embase. The quality of eligible studies was assessed using the Assessment of Multiple Systematic Reviews-2 (AMSTAR-2) instrument. For each meta-analysis, we recalculated the effect size, sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio from the individual study data provided in the original meta-analysis using a random-effects model. Imaging technique comparisons were then assessed using NMA. Ranking was assessed using the multidimensional scaling approach and by visually assessing surface under the cumulative ranking curves. RESULTS: We identified 32 eligible studies. High confidence in the results was found in only one of them, with a substantial heterogeneity and small study effect in 21% and 9% of included meta-analysis respectively. Comparisons between MRS Cho/NAA, Cho/Cr, DWI, and DSC were most studied. Our analysis showed MRS (Cho/NAA) and 18F-DOPA PET displayed the highest sensitivity and negative likelihood ratios. 18-FET PET was ranked highest among the 17 studied techniques with statistical significance. APT MRI was the only non-nuclear imaging modality to rank higher than DSC, with statistical insignificance, however. CONCLUSION: The evidence regarding which imaging modality is best for the differentiation between radiation necrosis and post-treatment radiation effects is still inconclusive. Using NMA, our analysis ranked FET PET to be the best for such a task based on the available evidence. APT MRI showed promising results as a non-nuclear alternative.

Utilizing the drug repurposing strategy on current drugs: new leads for peptic ulcers via biochemical and biomolecular dynamics studies.

The hyperactivity of urease enzymes plays a crucial role in the development of hepatic coma, hepatic encephalopathy, urolithiasis, gastric and peptic ulcers. Additionally, these enzymes adversely impact the soil's nitrogen efficiency for crop production. In the current study 100 known drugs were tested against Jack Bean urease and Proteus mirabilis urease and identified three inhibitors i.e. terbutaline (compound 1), Ketoprofen (compound 2) and norepinephrine bitartrate (compound 3). As a result, these compounds showed excellent inhibition against Jack Bean urease i.e. (IC50 = 2.1-11.3 µM), and Proteus mirabilis urease (4.8-11.9 µM). Moreover, in silico studies demonstrate maximum interactions of compounds in the enzyme's active site. Furthermore, intermolecular interactions between compounds and enzyme atoms were examined using STD-NMR spectrophotometry. In parallel, molecular dynamics simulation was carried out to study compounds dynamic behavior within the urease binding region. Urease remained stable during most of the simulation time and ligands were bound in the protein active pocket as observed from the Root mean square deviation (RMSD) and ligand RMSD analyses. Furthermore, these compounds display interactions with the crucial residues, including His492 and Asp633, in 100 ns simulations. In the binding energy analysis, norepinephrine bitartrate exhibited the highest binding energy (-76.32 kcal/mol) followed by Ketoprofen (-65.56 kcal/mol) and terbutaline (-62.15 kcal/mol), as compared to acetohydroxamic acid (-52.86 kcal/mol). The current findings highlight the potential of drug repurposing as an effective approach for identifying novel anti-urease compounds.Communicated by Ramaswamy H. Sarma.

SPECT/CT and PET/CT for the Evaluation of Persistent or Recurrent Pain After Spine Surgery: A Systematic Review and Case Series.

OBJECTIVE: The differential diagnosis for postoperative back pain is broad, and conventional imaging modalities are not always conclusive. Therefore, we performed a systematic review of the literature and present case studies describing the use of single-photon emission CT (SPECT)/CT or positron emission tomography (PET)/CT in the diagnosis of back pain following spine surgery. METHODS: A systematic review was conducted according to PRISMA guidelines across 5 databases. Relevant keywords included PET/CT, bone SPECT/CT, and pseudarthrosis. The studies were assessed for diagnostic accuracy of the imaging technologies. RESULTS: A total of 2,444 studies were screened, 91 were selected for full-text review, and 21 were ultimately included. Six retrospective studies investigated the use of SPECT/CT with a total sample size of 309 patients. Two of these studies used SPECT/CT to predict screw loosening in over 50% of patients. Eight studies examined the use of 18-fluoride sodium fluoride (18F-NaF) PET/CT. Among these studies, measures of diagnostic accuracy varied but overall demonstrated the ability of 18F-NaF PET/CT to detect screw loosening and pseudarthrosis. Seven studies examined 18F-fluorodeoxyglucose (FDG) PET/CT and supported its utility in the diagnosis of postoperative infections in the spine. CONCLUSIONS: PET/CT and SPECT/CT are useful in the evaluation of postoperative pain of the spine, especially in patients for whom conventional imaging modalities yield inconclusive results. More diagnostic accuracy studies with strong reference standards are needed to compare hybrid imaging to conventional imaging.

Synthesis of new class of non-sulfonamide bis-benzimidazoles as antitumor agents by inhibiting carbonic anhydrase-IX enzyme.

In several types of cancers, the expression of carbonic anhydrase-IX (CA-IX) enzyme is elevated than its normal level which ultimately plays a key role in the tumor growth of epithelial cells in breast and lung cancer by acidifying tumor microenvironment, therefore, inhibition of this target is important in antitumor therapy. We have synthesized bis-benzimidazole derivatives (1-25) by using 3,3'-diaminobenzidine and various aromatic aldehydes and characterized by various spectroscopic methods (UV/Visible, 1HNMR, 13CNMR, and mass spectrometry). Their inhibitory potential for human CA-IX (hCA-IX) was evaluated in-vitro, where several synthesized derivatives showed potent inhibition of hCA-IX (IC50 values in range of 5.23 ± 1.05 to 40.10 ± 1.78 µM) and compounds 3-5, 7-8, 13-16, 21 and 23 showed superior activity than the standard drug "acetazolamide" (IC50 = 18.24 ± 1.43 µM). Furthermore, all these compounds showed no toxicity on human fibroblast cell lines (BJ cell lines). Moreover, molecular docking was carried out to predict their binding modes in the active site of CA-IX and revealed a significant role of imidazole ring of synthesized entities in their effective binding with the specific residues of CA-IX. The obtained results paved the way for further in vivo and other pharmacological studies for the optimization of these molecules as possible anti-cancer agents.

Isoxazole analogues of dibenzazepine as possible leads against ulcers and skin disease: In vitro and in silico exploration.

Utilizing multi-target drugs shows great promise as an effective strategy against polygenic diseases characterized by intricate patho-mechanisms, such as ulcers, skin dermatitis, and cancers. The current research centers around the creation of hybrid compounds, connecting dibenzazepine and isoxazole, with the aim of exploring their potential as inhibitors for urease and tyrosinase enzymes. Analogs 6a, 6b, 6d, 6 h-6j, and 6 l demonstrated strong inhibitory potential against tyrosinase enzyme with IC50 values of 4.32 ± 0.31-12.36 ± 0.48. Whereas analogs 6a, 6c, 6e, 6f, 6h-6m, and 6r exhibited potent inhibitory activities against urease enzyme with IC50 values of 3.67 ± 0.91-15.60 ± 0.18 µM. Furthermore, compounds 6i, 6n, and 6r showed weak toxic effect in BJ-cell line, whereas the remaining compounds were found non-toxic to normal cell line. The mechanistic studies of potent inhibitors of both the enzymes showed competitive mode of inhibition. Molecular docking was employed to establish the relationship between structure and activity and to elucidate the interaction mechanism. This analysis revealed that the active analogs exhibited crucial interactions with the active site residues of urease and tyrosinase, thus corroborating our experimental results. Hence, the generated derivatives of dibenzazepine-linked isoxazoles present intriguing starting points for further investigations into their potential as inhibitors of urease and tyrosinase, with the potential for future modification and enhancement.