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Abstract Background Drug combination treatments have proven to be a realistic technique for treating challenging diseases such as cancer by enhancing efficacy and mitigating side effects. To achieve the therapeutic goals of these combinations, it is essential to employ multi-targeted drug combinations, which maximize effectiveness and synergistic effects. Results This paper proposes ‘MultiComb’, a multi-task deep learning (MTDL) model designed to simultaneously predict the synergy and sensitivity of drug combinations. The model utilizes a graph convolution network to represent the Simplified Molecular-Input Line-Entry (SMILES) of two drugs, generating their respective features. Also, three fully connected subnetworks extract features of the cancer cell line. These drug and cell line features are then concatenated and processed through an attention mechanism, which outputs two optimized feature representations for the target tasks. The cross-stitch model learns the relationship between these tasks. At last, each learned task feature is fed into fully connected subnetworks to predict the synergy and sensitivity scores. The proposed model is validated using the O’Neil benchmark dataset, which includes 38 unique drugs combined to form 17,901 drug combination pairs and tested across 37 unique cancer cells. The model’s performance is tested using some metrics like mean square error ( $$MSE$$ MSE ), mean absolute error ( $$MAE$$ MAE ), coefficient of determination ( $${R}^{2}$$ R 2 ), Spearman, and Pearson scores. The mean synergy scores of the proposed model are 232.37, 9.59, 0.57, 0.76, and 0.73 for the previous metrics, respectively. Also, the values for mean sensitivity scores are 15.59, 2.74, 0.90, 0.95, and 0.95, respectively. Conclusion This paper proposes an MTDL model to predict synergy and sensitivity scores for drug combinations targeting specific cancer cell lines. The MTDL model demonstrates superior performance compared to existing approaches, providing better results.

Abstract This paper proposes a novel multi-view ensemble predictor model that is designed to address the challenge of determining synergistic drug combinations by predicting both the synergy score value values and synergy class label of drug combinations with cancer cell lines. The proposed methodology involves representing drug features through four distinct views: Simplified Molecular-Input Line-Entry System (SMILES) features, molecular graph features, fingerprint features, and drug-target features. On the other hand, cell line features are captured through four views: gene expression features, copy number features, mutation features, and proteomics features. To prevent overfitting of the model, two techniques are employed. First, each view feature of a drug is paired with each corresponding cell line view and input into a multi-task attention deep learning model. This multi-task model is trained to simultaneously predict both the synergy score value and synergy class label. This process results in sixteen input view features being fed into the multi-task model, producing sixteen prediction values. Subsequently, these prediction values are utilized as inputs for an ensemble model, which outputs the final prediction value. The ‘MVME’ model is assessed using the O’Neil dataset, which includes 38 distinct drugs combined across 39 distinct cancer cell lines to output 22,737 drug combination pairs. For the synergy score value, the proposed model scores a mean square error (MSE) of 206.57, a root mean square error (RMSE) of 14.30, and a Pearson score of 0.76. For the synergy class label, the model scores 0.90 for accuracy, 0.96 for precision, 0.57 for kappa, 0.96 for the area under the ROC curve (ROC-AUC), and 0.88 for the area under the precision-recall curve (PR-AUC).

Abstract This research investigates the application of the ordered ranked set sampling (ORSSA) procedure in constant-stress partially accelerated life-testing (CSPALTE). The study adopts the assumption that the lifespan of a specific item under operational stress follows a half-logistic probability distribution. Through Bayesian estimation methods, it concentrates on estimating the parameters, utilizing both asymmetric loss function and symmetric loss function. Estimations are conducted using ORSSAs and simple random samples, incorporating hybrid censoring of type-I. Real-world data sets are utilized to offer practical context and validate the theoretical discoveries, providing concrete insights into the research findings. Furthermore, a rigorous simulation study, supported by precise numerical calculations, is meticulously conducted to gauge the Bayesian estimation performance across the two distinct sampling methodologies. This research ultimately sheds light on the efficacy of Bayesian estimation techniques under varying sampling strategies, contributing to the broader understanding of reliability analysis in CSPALTE scenarios.

Abstract Polyvinyl chloride (PVC) is one of the most important commercial plastics but it is thermally unstable at processing temperatures. Therefore, heat stabilizers are widely used to safeguard by improving resistance of PVC products at high temperature. But most of them are a highly toxic that can cause severe health issues in humans and harmful to the environment. In the present study mixed of calcium/zinc stearate heat stabilizer and green Expandable graphite (EG) is prepared via hydrothermal treatment using additives of nontoxic, environmental protection. The characteristics of the thermal stability of poly vinyl chloride can be investigated by Scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) will be used to examine structure of the heat stabilizers, A universal testing equipment will be used to determine the mechanical properties and thermal gravimetric analysis (TGA). From TGA results the weight loss was 43.49% at 342°C for sample with Ca/Zn‐ stearate, while wt loss is 55.87% at 260°C for sample with EG which increase thermal stability. Differential scanning calorimetry affirmed the enhancement of PVC's thermal stability, showing a shift in the glass transition temperature an increase of 67°C. Mechanical tests indicated that samples with EG exhibited higher tensile strength and elongation at break, emphasizing the positive impact on PVC's mechanical properties. The burning test highlighted thermal stability of EG‐containing samples, retaining color and structure even after exposure to 180°C heat. This innovative approach not only enhances thermal stability but also aligns with eco‐friendly principles, making it a promising solution for improving PVC properties. Highlights Ca/Zn‐ stearate, expandable graphite developed by a safe hydrothermal process. Comprehensive analysis indicates improved thermal stability. Safe stabilization of eco‐friendly calcium/zinc, expandable graphite. Effective solution: Eco‐friendly, improved PVC properties. Expandable graphite improved mechanical properties of PVC.

Abstract This paper proposes a multi-task deep learning model for determining drug combination synergistic by simultaneously output synergy scores and synergy class labels. Initially, the two drugs are represented using a Simplified Molecular-Input Line-Entry (SMILE) system. Chemical structural features of the drugs are extracted from the SMILE using the RedKit package. Additionally, an improved Multi-view representation is proposed to extract graph-based drug features. Furthermore, the cancer cell line is represented by gene expression. Then, a three fully connected layers are learned to extract cancer cell line features. To investigate the impact of drug interactions on cell lines, the drug interaction features are extracted from a pretrained drugs interaction network and fed into an attention mechanism along with the cancer cell line features, resulting in the output of affected cancer cell line features. Subsequently, the drug and cell line features are concatenated and fed into an attention mechanism, which produces a two-feature representation for the two predicted tasks. The relationship between the two tasks is learned using the cross-stitch algorithm. Finally, each task feature is inputted into a fully connected subnetwork to predict the synergy score and synergy label. The proposed model ‘MutliSyn’ is evaluated using the O'Neil cancer dataset, comprising 38 unique drugs combined to form 22,737 drug combination pairs, tested on 39 cancer cell lines. For the synergy score, the model achieves a mean square error (MSE) of 219.14, a root mean square error (RMSE) of 14.75, and a Pearson score of 0.76. Regarding the synergy class label, the model achieves an area under the ROC curve (ROC-AUC) of 0.95, an area under the precision-recall curve (PR-AUC) of 0.85, precision of 0.93, kappa of 0.61, and accuracy of 0.90.

Abstract Triple modular redundancy (TMR) is a robust technique utilized in safety-critical applications to enhance fault-tolerance and reliability. This article focuses on estimating the distribution parameters of a TMR system under step-stress partially accelerated life tests, where each component included in the system follows a Lomax distribution. The study aims to analyze the system’s reliability and mean residual lifetime based on the estimated parameters. Various estimation techniques, including maximum likelihood, percentile, least squares, and maximum product of spacings, are explored. Additionally, the optimal stress change time is determined using two criteria. An illustrative example supported by two actual data sets is presented to showcase the methodology’s application. By conducting Monte Carlo simulations, the assessment of the estimation methods’ effectiveness reveals that the maximum likelihood method outperforms the other three methods in terms of both accuracy and performance, as indicated by the numerical outcomes. This research contributes to the understanding and practical implementation of TMR systems in safety-critical industries, potentially saving lives and preventing catastrophic events.

In this article, we introduce and study the truncated inverse power Lindley distribution. The aim is to transpose the remarkable flexibility of the two-parameter inverse power Lindley distribution to the interval [0,1]. The corresponding probability density function has the potential to be unimodal, decreasing, right-skewed, and heavy-tailed. On the other hand, the hazard rate function can be increasing, N-shaped, or U-shaped. These shapes’ versatility enables accurate representation and analysis of proportional or percentage data across a wide range of applications, such as survival analysis, reliability, and uncertainty modeling. Several statistical features, such as the mode, quantiles, Bowley’s skewness, Moor’s kurtosis, MacGillivray’s skewness, moments, inverse moments, incomplete moments, and probability-weighted moments, are computed. In practice, for the estimation of the model parameters from truncated data under the progressively type-II censoring scheme, the maximum likelihood, maximum product spacing, and Bayesian approaches are used. The Tierney–Kadane approximation and Markov chain Monte Carlo techniques are employed to produce the Bayesian estimates under the squared error loss function. We present some simulation results to evaluate these approaches. Four applications based on real-world datasets—one of them is on times of infection, the second is on failure times, and the other two are on the rate of inflation in Asia and Africa—explain the significance of the new truncated model in comparison to some reputed comparable models, such as the inverse power Lindley, Kumaraswamy, truncated power Lomax, beta, truncated Weibull, unit-Weibull, Kumaraswamy Kumaraswamy, and exponentiated Kumaraswamy models.

Background and Aim: Given the rise in stray and imported dogs in Egypt over the past 5 years, it is surprising that no report of Brucella canis infection in dogs or humans has been documented in Egypt's published papers. This study aimed to detect the presence of antibodies against the rough (B. canis) and smooth Brucellae among dogs in Egypt and to characterize the Brucella species circulating in dogs. Materials and Methods: Blood samples (n = 449) were collected from owned and stray dogs in the Greater Cairo region (n = 309) and Damietta governorate (n = 140). The apparent, true, and total seroprevalence of canine brucellosis caused by B. canis infection were calculated using the 2-mercaptoethanol tube agglutination test (2-ME TAT) and rapid slide agglutination test (RSAT). We used the rose Bengal test (RBT) and the buffered acidified plate antigen test (BAPAT) to check the serum samples from dogs for the presence of antibodies against smooth Brucellae. Three polymerase chain reaction (PCR) assays - Bruce-ladder PCR, B. canis species-specific PCR (BcSS-PCR), and Abortus Melitensis Ovis Suis (AMOS)-PCR - were used to determine the Brucella species in the buffy coats of the serologically positive dogs. Results: The overall apparent and true prevalence of B. canis infection in dogs were estimated to be 3.8% and 13.2%. The estimated true prevalence in stray dogs (15%) was higher than in owned dogs (12.5%). The BAPAT and the RBT using smooth antigens revealed that 11 (2.4%) and 9 (2%) were positive. Bruce-ladder PCR targeting eryC, ABC, and Polysaccharide deacetylase genes was able to identify B. canis in nine out of 17 buffy coat samples. AMOS-PCR identified the eight undetermined Brucella species by Bruce-ladder PCR as Brucella abortus (n = 4) and Brucella melitensis (n = 4). To exclude the presence of Brucella suis, a one-step species-specific BcSS-PCR was performed and specifically amplified all B. canis DNA (n = 9) the same as did the Bruce-ladder PCR. Conclusion: To the best of our knowledge, this is the first report of B. canis detection in dogs in Egypt. Molecular identification of B. abortus and B. melitensis in the Egyptian canines highlights the role of stray dogs in brucellosis remerging in Brucellosis-free dairy farms. Brucella canis infection can be diagnosed specifically with the one-step BcSS-PCR. The obtained results set-an-alarm to the veterinary authorities to launch plans to control this disease in dogs.

Abstract The researchers, engineers, and physical experimenters may face difficulty to get a distribution that fits the failure data arising from certain systems. So, in this paper, a new distribution is introduced, named Poisson–logarithmic half-logistic distribution, based on a parallel–series system’s failure times. Specific statistical properties are investigated for the introduced distribution. Also, two real data sets are considered to compare the introduced distribution with some other distributions. The progressive-stress accelerated life test is applied using an increasing exponential function of time to units whose lifetimes are expected to follow the new distribution at normal stress conditions. Different estimation methods, such as maximum likelihood, percentile, least squares, and weighted least square methods, are considered on the basis of adaptive type-II progressive hybrid censoring. To assess the efficiency of the estimation methods, a simulation study is conducted, as well as numerical calculations.

Abstract Background Brucella suis is a zoonotic pathogen with a serious impact on public health and the pig industry worldwide. Information regarding B. suis in pigs in Egypt is scarce. This study aimed to investigate the prevalence of B. suis in slaughtered domestic pigs at El-Basatin abattoir in Cairo, Egypt. A total of 1,116 domestic pigs slaughtered in 2020 were sampled for Brucella isolation and identification. Identified Brucella isolates were molecularly confirmed at species, and biovar levels using Bruce ladder PCR and Suis ladder multiplex PCR. Additionally, high-risk practices of 16 abattoir workers (4 veterinarians, 10 butchering and evisceration workers, and 2 scalding workers) were investigated using a pre-piloted structured questionnaire. Results Brucella isolates were recovered from 1.3% of examined pigs (n = 14) at consistently low rates (1.1—2.9%) across the year of sampling from February to December 2020. All isolates were confirmed as B. suis biovar (bv) 2. Remarkably, 92.9% (13/14) of isolates showed atypical ability to produce H2S and hence were considered as B. suis bv2 atypical phenotype. The prevalence was higher in males (1.8%) than in females (0.9). However, this difference was not significant (Odds ratio = 1.9; CI 95% 0.7 – 5.7; P = 0.2). No detectable pathological lesions were associated with B. suis bv2 infection in examined pigs. All strains were isolated from cervical lymph nodes, highlighting a potential oral transmission. High-risk practices were recorded among swine abattoir workers in this study: 75% do not wear gloves or disinfect their knives daily, and 18.8% were willing to work with open wound injuries. Conclusions To the best of our knowledge, this is the first isolation of B. suis bv2 in Egypt. Detection of H2S producing B. suis bv2 atypical phenotype is alarming as it may result in misinterpretation of these isolates as highly human pathogenic B. suis bv1 in Egypt and possibly elsewhere. Further epidemiological tracing studies are crucial for the detection of the origin of this biovar. Including pigs in the national surveillance program of brucellosis, and an education program for swine abattoir workers about occupational risk of B. suis is a need in Egypt.

Pork production is a niche economy in Egypt, and pigs are typically raised as backyard animals with no sanitary control, potentially exposing them to various pathogens. Commercially available ELISAs were used to detect specific antibodies to the food-borne zoonotic parasites Toxoplasma gondii and Trichinella spp., as well as to Neospora caninum, in serum samples of pigs slaughtered at Egypt’s only licensed pig abattoir, the El-Bassatin abattoir in Cairo. Among the tested sera (n = 332), seroreactivity for T. gondii was 45.8% (95% confidence interval: 40.4–51.3), N. caninum was 28.0% (95% CI: 23.3–33.2), and Trichinella spp. was 1.2% (95% CI: 0.4–3.3). Mixed infection was only detected for T. gondii and N. caninum (18.7%; 95% CI: 14.7–23.4). The seroprevalence of T. gondii was significantly higher (p = 0.0003) in animals collected from southern Cairo (15 May city slum) than in eastern Cairo (Ezbet El Nakhl slum). Seroprevalence for N. caninum was higher in western (Manshiyat Naser slum; p = 0.0003) and southern Cairo (15 May city slum; p = 0.0003) than in that of eastern Cairo (Ezbet El Nakhl slum; p = 0.0003). Moreover, female pigs exhibited a higher rate of N. caninum antibodies than male ones (p < 0.0001). This study provides the first seroprevalence data for N. caninum in pigs in Egypt, and updates the prevalence of the zoonotic parasites Trichinella spp. and T. gondii.

It is of great importance for physicists and engineers to assess a lifetime distribution of a series-parallel system when its components' lifetimes are subject to a finite mixture of distributions. The present article addresses this problem by introducing a new distribution called "Poisson-geometric-Lomax distribution". Important properties of the proposed distribution are discussed. When the stress is an increasing nonlinear function of time, the progressive-stress model is considered and the inverse power-law model has suggested a relationship between the stress and the scale parameter of the proposed distribution. Based on the progressive type-II censoring with binomial removals, estimation of the included parameters is discussed using maximum likelihood and Bayes methods. An example, based on two real data sets, demonstrates the superiority of the proposed distribution over some other known distributions. To compare the performance of the implemented estimation methods, a simulation study is carried out. Finally, some concluding remarks followed by certain features and motivations to the proposed distribution are presented.

The objective of ranked set sampling is to gather observations from a population that is more likely to cover the population’s full range of values. In this paper, the ordered ranked set sample is obtained using the idea of order statistics from independent and nonidentically distributed random variables under progressive-stress accelerated life tests. The lifetime of the item tested under normal conditions is suggested to be subject to the Rayleigh distribution with a scale parameter satisfying the inverse power law such that the applied stress is a nonlinear increasing function of time. Considering the type-II censoring scheme, one-sample prediction for censored lifetimes is discussed. Numerous point predictors including the Bayes point predictor, conditional median predictor, and best unbiased predictor for future order statistics are discussed. Additionally, conditional prediction intervals for future order statistics are also studied. The theoretical findings reported in this work are shown by illustrative examples based on simulated data as well as real data sets. The effectiveness of the prediction methods is then evaluated by a Monte Carlo simulation study.

In this article, a new modified asymmetric Topp–Leone distribution is created and developed from a theoretical and inferential point of view. It has the feature of extending the remarkable flexibility of a special one-shape-parameter lifetime distribution, known as the inverse Topp–Leone distribution, to the bounded interval [0, 1]. The probability density function of the proposed truncated distribution has the potential to be unimodal and right-skewed, with different levels of asymmetry. On the other hand, its hazard rate function can be increasingly shaped. Some important statistical properties are examined, including several different measures. In practice, the estimation of the model parameters under progressive type-II censoring is considered. To achieve this aim, the maximum likelihood, maximum product of spacings, and Bayesian approaches are used. The Markov chain Monte Carlo approach is employed to produce the Bayesian estimates under the squared error and linear exponential loss functions. Some simulation studies to evaluate these approaches are discussed. Two applications based on real-world datasets—one on the times of infection, and the second dataset is on trading economics credit rating—are considered. Thanks to its flexible asymmetric features, the new model is preferable to some known comparable models.

Proline is water soluble amino acid extensively used in drug delivery systems. Compounds of cobalt (Co) transition metal have potent antimicrobial and anticancer activities. However, a drug delivery system combining proline cobalt is not reported yet. For the first time, new hybrid semi-organic single crystals of proline cobalt chloride (PCC) are prepared. The novelty of the article is also that single crystal proline cobalt chloride showed potent antimicrobial and antitumor activity. Doping of PCC by Ag0NPs significantly increased these biological activities. The anisotropic magnetic properties of single crystals can mitigate the cytotoxicity of Ag0NPs on normal cells. Silver nanoparticles (Ag0NPs) improved the crystal habits and physicochemical properties. Ag0NPs showed the best performance, paramagnetic materials n-type semiconductors due to delocalized excess electrons of Ag0NPs incorporated in the crystal lattice interstitially. Crystals have high absorptivity for UV-radiation electromagnetic radiation. Ag0NPs enhanced AC electrical conductivity up to 2.3 × 104 Ω cm−1 due to high electron density. Proline doped crystals are obtained in good purity as triclinic unit cell with having anisotropic magnetism. PCCAg0NPs crystal exhibited: high antimicrobial activities to various bacterial and fungal species, inhibition zone (mm): 21, 25, 24, 26, 30, 28, 12, and 46 for S. aureus, E. faecalis, S. typhi, E. coli, P. aerugino, K. pneumoniae, A. braselienses, and C. albicans, respectively, in comparison to ciprofloxacin antibiotic (23, 0, 26, 26, 25, 0, 0, 0) for the same tested species, respectively; higher cytotoxicity against breast cancer cells (IC50 22.1 μM) than the reference drug cisplatin (IC50 11.7 μM); and lower cytotoxicity to normal healthy lung cells MRC-5, (IC50 145.5 μM) than cisplatin (IC50 30.2 μM). Hence, this crystal is a candidate for chemotherapy of breast cancer.

Brucellosis is a highly contagious and incapacitating disease of humans, livestock and wildlife species globally. Treatment of brucellosis in animals is not recommended, and in humans, combinations of antibiotics recommended by the World Health Organization are used. However, sporadic antimicrobial-resistant (AMR) isolates and relapse cases have been reported from different endemic regions. In the current study, molecular characterization and antibiotic susceptibility testing using the microdilution method for 35 B. abortus and B. melitensis strains isolated from humans, milk and animal were carried out. Additionally, Next-Generation-Sequencing (NGS) technology was applied to confirm Brucella at the species level and investigate AMR and pathogenicity-associated determinants. MALDI-TOF seemed to be a rapid and reliable tool for routine identification of brucellae to the genus level; however, DNA-based identification is indispensable for accurate species identification. Brucella abortus strains were isolated from two human cases and a sheep. Such infections are uncommon in Egypt. Egyptian Brucella strains are still in-vitro susceptible to doxycycline, tetracyclines, gentamicin, ciprofloxacin, levofloxacin, chloramphenicol, streptomycin, trimethoprim/sulfamethoxazole and tigecycline. Probable (no CLSI/EUCAST breakpoints have been defined yet) in-vitro resistance to rifampicin and azithromycin was observed. WGS failed to determine classical AMR genes, and no difference in the distribution of virulence-associated genes in all isolates was found. Isolates of human and non-human origins were still susceptible to the majority of antibiotics used for treatment in humans. The absence of classical AMR genes in genomes of “resistant” Brucella strains may reflect a lack of information in databases, or resistance might not be encoded by single resistance genes. The One Health approach is necessary for tackling brucellosis. Continuous susceptibility testing, updating of breakpoints, assessing mutations that lead to resistance are needed.

Brucellosis is a zoonosis that has a devastating impact on the economy and public health, particularly in the Middle East, including Egypt. This study aimed to define risk factors associated with brucellosis in humans and in their cattle in Fayoum governorate - Upper Egypt. Also, molecular genotyping of recovered Brucella isolates from human cases and their cattle to assess the potential cross-species transmission in the study region. Data were obtained via double matched case–control studies for brucellosis in humans (106 cases and 160 controls) and in their cattle (78 cattle cases and 105 cattle controls). The results of multivariate regression analysis revealed that predictors of human brucellosis were animal-related occupations (OR 2.1, P 0.02), previous infection in other household members (OR 3.2, P 0.007), eating home-made soft cheese (OR 2.3, P 0.03), and exposure to cattle abortions (OR 6.9, P

The progressive-stress accelerated life test is discussed under the ordered ranked set sampling procedure. It is assumed that the lifetime of an item under use stress is exponentially distributed and the law of inverse power is considered as the relationship between the scale parameter and the applied stress. The involved parameters are estimated using the Bayesian technique, under symmetric and asymmetric loss functions, based on ordered ranked set samples and simple random samples subject to type-II censoring. Real and simulated data sets are used to illustrate the theoretical results presented in this paper. Finally, a simulation study followed by numerical calculations is performed to evaluate the Bayesian estimation performance based on the two sampling types.

A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC 50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC 50  = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC 50 values in the range of 16.64-70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC 50  = 5.88 µM). Moreover, oxadiazole derivative 2c (IC 50  = 463.85 µM) was more potent antioxidant than quercetin (IC 50  = 491.23 µM). Compounds 3b (IC 50  = 536.83 µM) and 3c (IC 50  = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC 50  = 140.02 µM) and 4c (IC 50  = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC 50  = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC 50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC 50  = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives' significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development., (© 2024. The Author(s).)

A library of 16 3-benzyl- N 1 -substituted quinoxalin-2-ones was synthesized as N 1 -substituted quinoxalines and quinoxaline-triazole hybrids via click reaction. These compounds were tested for their anticancer activity via MTT assay on HCT-116 and normal colonocyte cell lines to assess their cytotoxic potentials and safety profiles. Overall, compounds 6 , 9 , 14 , and 20 were found to be promising anticolorectal cancer agents; they exhibited remarkable cytotoxicity (IC 50 0.05-0.07 μM) against HCT-116 cells within their safe doses (EC100) on normal colon cells. Their pronounced anticancer activities were observed as severe morphological alterations and shrinkage of the treated cancer cells. Besides, qRT-PCR analysis was conducted showing the potential of the promising hits to downregulate HIF-1a, VEGF, and BCL-2 as well as their ability to enhance the expression of proapoptotic genes p21, p53, and BAX in HCT-116 cells. In silico prediction revealed that most of our compounds agree with Lipinski and Veber parameters of rules, in addition to remarkable medicinal chemistry and drug-likeness parameters with no CNS side effects. Interestingly, docking studies of the compounds in the VEGFR-2' active site showed significant affinity toward the essential amino acids, which supported the biological results., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The EGFR/PI3K/Akt/mTOR pathway is important for metastasis, medication resistance, apoptosis prevention, and malignant transformation. Mutations in lung and colon cancer typically change this pathway's expression. As a result, a novel class of 1,2,4-oxdiazoles that are attached to 1,2,3-triazoles, 5-11, were created as possible anticancer drugs. The produced compounds are all examined by spectroscopic and micro-analytical techniques. MTT assay results on lung (A549) colon (Caco-2) and normal lung fibroblast (WI38) revealed that compounds 6a, 6b, 8a, and 11b demonstrated strong and selective antiproliferative activities against lung (A549) and colon (Caco-2) cancer cell lines while the remaining derivatives showed moderate to low activity. qPCR data revealed that the potential hits had large fold changes in the downregulation of EGFR, mTOR, and PI3K; they upregulate the amount of p53 to support their mode of action even more. Interestingly, docking investigations validated the biological outcomes by demonstrating a strong affinity of our compounds against EGFR active regions. Computational predictions of all the synthesized compounds' pharmacokinetic profiles, physicochemical characteristics, and drug-likeness data indicated that the promising hits might be taken into consideration as drug-like prospects., Competing Interests: The authors declare that none of their relationships or conflicting financial interests could have influenced the findings of this study., (This journal is © The Royal Society of Chemistry.)

A series of novel 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their potential anti-Alzheimer disease activity. The results revealed that compounds 2b, 2c, 2d, 3a, 4a, 6, 9a, 9b, and 13b showed excellent inhibitory activity against acetylcholinesterase (AChE) with IC 50 values in the range of 0.0158 to 0.121 μM. They were 1.01 to 7.78 times more potent than donepezil (IC 50 = 0.123 μM). The newly synthesized compounds exhibited lower activity towards butyrylcholinesterase (BuChE) when compared to rivastigmine. Compounds 4b and 13b showed the most prominent inhibitory potential against BuChE with IC 50 values of 11.50 and 15 μM, respectively. Moreover, 4b, and 9b were found to be more potent antioxidant agents (IC 50 values of 59.25, and 56.69 μM, respectively) in comparison with ascorbic acid (IC 50 = 74.55 μM). Compounds 2b and 2c exhibited monoamine oxidase-B (MAO-B) inhibitory activity with IC 50 values of 74.68 and 225.48 μM, respectively. They were 3.55 and 1.17 times more potent than biperiden (IC 50 = 265.85 μM). The prominent interactions of the compounds with the AChE active site can be used to computationally explain the high AChE inhibitory activity. The results unveiled 1,2,4-oxadiazole derivatives 2c and 3a as multitarget anti-AD agents. The predicted ADME properties for compounds 2b and 4a were satisfactory, and 4a had the highest likelihood of crossing the blood-brain barrier (BBB), making it the optimum compound for future optimization., Competing Interests: “The authors declare that none of their relationships or conflicting financial interests could have influenced the findings of this study”., (This journal is © The Royal Society of Chemistry.)

A series of new sulfonamide derivatives connected through an imine linker to five or seven membered heterocycles were designed and synthesized. All synthesized derivatives were characterized using a variety of spectroscopic methods, including IR, 1 HNMR, and 13 CNMR. In vitro α-glucosidase and α-amylase inhibition activities, as well as glucose uptake were assessed for each of the synthesized compounds. Four sulfonamide derivatives namely 3a, 3b, 3h and 6 showed excellent inhibitory potential against α-glucosidase with IC 50 values of 19.39, 25.12, 25.57 and 22.02 μM, respectively. They were 1.05- to 1.39-fold more potent than acarbose. Sulfonamide derivatives 3g, 3i and 7 (EC 50 values of 1.29, 21.38 and 19.03 μM, respectively) exhibited significant glucose uptake activity that were 1.62- to 27-fold more potent than berberine. Both α-glucosidase protein (PDB: 2QMJ) and α-amylase (PDB: 1XCW) complexed with acarbose were adopted for docking investigations for the most active synthesized compounds. The docked compounds were able to inhabit the same space as the acarviosin ring of acarbose. The docking of the most active compounds showed an analogous binding with the active site of α-glucosidase as acarbose. The superior activity of the synthesized compounds against α-glucosidase enzyme than α-amylase enzyme can be rationalized by the weak interaction with the α-amylase. The physiochemical parameters of all synthesized compounds were aligned with Lipinski's rule of five., Competing Interests: The authors have no conflict of interest concerning this work., (This journal is © The Royal Society of Chemistry.)

Monoamine oxidases (MAOs) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promoters of colorectal cancer (CRC) and central signaling nodes in epithelial-mesenchymal transition (EMT) induced by activating hypoxia-inducible factors (HIFs). Herein, a novel series of rationally designed triazole-tethered quinoxalines were synthesized and evaluated against HCT-116 CRC cells. The tailored scaffolds combine the pharmacophoric themes of both VEGFR-2 inhibitors and MAO inhibitors. All the synthesized derivatives were screened utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay for their possible cytotoxic effects on normal human colonocytes, then evaluated for their anticancer activities against HCT-116 cells overexpressing MAOs. The hit derivatives 11 and 14 exhibited IC 50  = 18.04 and 7.850 µM, respectively, against HCT-116cells within their EC 100 doses on normal human colonocytes. Wound healing assay revealed their efficient CRC antimetastatic activities recording HCT-116 cell migration inhibition exceeding 75 %. In vitro enzymatic assays demonstrated that both 11 and 14 efficiently inhibited VEGFR-2 (IC 50  = 88.79 and 9.910 nM), MAO-A (IC 50  = 0.763 and 629.1 nM) and MAO-B (IC 50  = 0.488 and 209.6 nM) with observed MAO-B over MAO-A selectivity (SI = 1.546 and 3.001), respectively. Enzyme kinetics studies were performed for both compounds to identify their mode of MAO-B inhibition. Furthermore, qRT-PCR analysis showed that the hits efficiently downregulated HIF-1α in HCT-116cells by 3.420 and 16.96 folds relative to untreated cells. Docking studies simulated their possible binding modes within the active sites of VEGFR-2 and MAO-B to highlight their essential structural determinants of activities. Finally, they recorded in silico drug-like absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as ligand efficiency metrics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Selective induction of breast cancer apoptosis is viewed as the mainstay of various ongoing oncology drug discovery programs. Passerini scaffolds have been recently exploited as selective apoptosis inducers via a caspase 3/7 dependent pathway. Herein, the optimized Passerini caspase activators were manipulated to synergistically induce P53-dependent apoptosis via modulating the closely related P53-MDM2 signaling axis. The adopted design rationale and synthetic routes relied on mimicking the general thematic features of lead MDM2 inhibitors incorporating multiple aromatic rings. Accordingly, the cyclization of representative Passerini derivatives and related Ugi compounds into the corresponding diphenylimidazolidine and spiro derivative was performed, resembling the nutlin-based and spiro MDM-2 inhibitors, respectively. The study was also extended to explore the apoptotic induction capacity of the scaffold after simplification and modifications. MTT assay on MCF-7 and MDA-MB231 breast cancer cells compared to normal fibroblasts (WI-38) revealed their promising cytotoxic activities. The flexible Ugi derivatives 3 and 4, cyclic analog 8, Passerini adduct 12, and the thiosemicarbazide derivative 17 were identified as the study hits regarding cytotoxic potency and selectivity, being over 10-folds more potent (IC 50 = 0.065-0.096 μM) and safer (SI = 4.4-18.7) than doxorubicin (IC 50 = 0.478 μM, SI = 0.569) on MCF-7 cells. They promoted apoptosis induction via caspase 3/7 activation (3.1-4.1 folds) and P53 induction (up to 4 folds). Further apoptosis studies revealed that these compounds enhanced gene expression of BAX by 2 folds and suppressed Bcl-2 expression by 4.29-7.75 folds in the treated MCF-7 cells. Docking simulations displayed their plausible binding modes with the molecular targets and highlighted their structural determinants of activities for further optimization studies. Finally, in silico prediction of the entire library was computationally performed, showing that most of them could be envisioned as drug-like candidates., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Although vaccines are obviously mitigating the COVID-19 pandemic diffusion, efficient complementary antiviral agents are urgently needed to combat SARS-CoV-2. The viral papain-like protease (PLpro) is a promising therapeutic target being one of only two essential proteases crucial for viral replication. Nevertheless, it dysregulates the host immune sensing response. Here we report repositioning of the privileged 1,2,4-oxadiazole scaffold as promising SARS-CoV-2 PLpro inhibitor with potential viral entry inhibition profile. The design strategy relied on mimicking the general structural features of the lead benzamide PLpro inhibitor GRL0617 with isosteric replacement of its pharmacophoric amide backbone by 1,2,4-oxadiazole core. Inspired by the multitarget antiviral agents, the substitution pattern was rationalized to tune the scaffold's potency against other additional viral targets, especially the spike receptor binding domain (RBD) that is responsible for the viral invasion . The Adopted facial synthetic protocol allowed easy access to various rationally substituted derivatives. Among the evaluated series, the 2-[5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl]aniline (5) displayed the most balanced dual inhibitory potential against SARS-CoV-2 PLpro (IC 50= 7.197 μM) and spike protein RBD (IC 50  = 8.673 μM), with acceptable ligand efficiency metrics, practical LogP (3.8) and safety profile on Wi-38 (CC 50  = 51.78 μM) and LT-A549 (CC 50  = 45.77 μM) lung cells. Docking simulations declared the possible structural determinants of activities and enriched the SAR data for further optimization studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Proline is water soluble amino acid extensively used in drug delivery systems. Compounds of cobalt (Co) transition metal have potent antimicrobial and anticancer activities. However, a drug delivery system combining proline cobalt is not reported yet. For the first time, new hybrid semi-organic single crystals of proline cobalt chloride (PCC) are prepared. The novelty of the article is also that single crystal proline cobalt chloride showed potent antimicrobial and antitumor activity. Doping of PCC by Ag 0 NPs significantly increased these biological activities. The anisotropic magnetic properties of single crystals can mitigate the cytotoxicity of Ag 0 NPs on normal cells. Silver nanoparticles (Ag 0 NPs) improved the crystal habits and physicochemical properties. Ag 0 NPs showed the best performance, paramagnetic materials n-type semiconductors due to delocalized excess electrons of Ag 0 NPs incorporated in the crystal lattice interstitially. Crystals have high absorptivity for UV-radiation electromagnetic radiation. Ag 0 NPs enhanced AC electrical conductivity up to 2.3 × 10 4 Ω cm -1 due to high electron density. Proline doped crystals are obtained in good purity as triclinic unit cell with having anisotropic magnetism. PCCAg 0 NPs crystal exhibited: high antimicrobial activities to various bacterial and fungal species, inhibition zone (mm): 21, 25, 24, 26, 30, 28, 12, and 46 for S. aureus , E. faecalis , S. typhi , E. coli , P. aerugino , K. pneumoniae , A. braselienses , and C. albicans , respectively, in comparison to ciprofloxacin antibiotic (23, 0, 26, 26, 25, 0, 0, 0) for the same tested species, respectively; higher cytotoxicity against breast cancer cells (IC 50 22.1 μM) than the reference drug cisplatin (IC 50 11.7 μM); and lower cytotoxicity to normal healthy lung cells MRC-5, (IC 50 145.5 μM) than cisplatin (IC 50 30.2 μM). Hence, this crystal is a candidate for chemotherapy of breast cancer., Competing Interests: The authors declare no conflict of interest.

We explored a new isonitrile, namely 4-( N -phthalimido)phenyl isonitrile, with extraordinary features. The novel isocyanide has a pharmacophore, the phthalimido (Pht) group, that possesses promising pharmaceutical activities. We found that the novel isonitrile is unexpectedly odorless as an extra bonus which makes its handling easy in organic synthesis to serve as a scaffold for building several new amide derivatives through multicomponent reactions, overcoming the stink of common aromatic isonitriles such as phenyl isonitrile, benzyl isonitrile, p -nitrophenyl isonitrile, and ethyl 4-isocyano benzoate. The novel isonitrile 9 serves as a source of N -protected isonitrile with a Pht group, where the Pht group can be easily removed via hydrazinolysis, affording the corresponding primary amine/alcohol scaffold which could be used as a precursor to synthesize Passerini products via acylation directly to afford Passerini adducts 14 and 15 without carrying out the traditional Passerini three-component reaction; this new isonitrile is considered as a novel convertible isocyanide analogue., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The development of novel therapeutics promoting selective tumor elimination is the mainstay of clinical oncology. Emerging insights into tumor targeting reveal caspases activation, especially caspase-3, as a personalized anticancer strategy. Our on-going cancer research has exploited Passerini α-acyloxy carboxamides as caspase-3/7-dependent apoptotic inducers. Herein, we adopted scaffold hopping design to introduce new series of isoindole-based Passerini adducts as caspase-3/7 activators inspired by natural alkaloids from Lion's Mane mushroom promoting caspase-3-mediated apoptosis. Additional pharmacophoric motifs of lead caspase activators were merged into the tailored Passerini skeleton. The rationally designed adducts were synthesized utilizing one-pot reaction of the novel 4-(2'-phthalimido)phenylisonitrile 5, cyclohexanone and miscellaneous carboxylic acids under Passerini conditions. All derivatives were screened for their antiproliferative activities against lung A549, colorectal Caco-2 and breast MDA-MB 231 cancer cells compared to normal fibroblasts utilizing MTT assay. Most of the evaluated derivatives were superior to 5-fluorouracil. The 2-(1H-indol-3-yl)acetate derivative (8a) recorded the highest anticancer potency (IC 50  = 0.04-0.11 μM) and selectivity (SI = 42.59-125.53), followed by the 3-(4-(trifluoromethyl)phenyl)acrylate (8m), the 2-(phenylsulfonyl)glycinate (8q), and the 2-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetate (8c) derivatives, respectively. The four hits induced cancer cells apoptosis (up to 57.99%) via caspase-3/7 activation (up to 5.47 folds). Apoptosis-inducing factor1 (AIF1) quantification assay excluded their caspase-independent apoptosis induction potential via AIF1 signaling pathway. Docking simulations clarified the possible binding modes of the hit compounds with XIAP BIR2 domain; the specific receptor of caspase-3/7 activators, and aided identifying their structural determinants of activity. Finally, their practical LogP, efficiency metrics, in silico ADMET profiling were drug-like., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Selective elimination of tumors has always been the mainstay of oncology research. The on-going research underlying the cellular apoptotic mechanisms reveal caspases activation, especially the key effector caspase-3, as a personalized tumor-selective therapeutic strategy. Our continued research protocol has exploited new optimized Passerini α-acyloxy carboxamides as efficient apoptotic inducers via caspase-3/7 dependent mechanism with highly selective anticancer profiles. The adopted design rationale relied on excluding structural alerts of previous leads, while merging various pharmacophoric motifs of natural and synthetic caspase activators via optimized one-pot Passerini reaction conditions. The prepared compounds resulting from Passerini reaction were screened for their cytotoxic activities against colorectal Caco-2 and liver HepG-2 cancer cells compared to normal fibroblasts utilizing MTT assay. Notably, all compounds exhibited promising low-range submicromolar IC 50 against the studied cancer cell lines, with outstanding tumor selectivity (SI values up to 266). Hence, they were superior to 5-fluorouracil. Notably, 7a, 7g, and 7j conferred the highest potencies against Caco-2 and HepG-2 cells and were selected for further mechanistic studies. Caspas-3/7 activation assay of the hit compounds and flow cytometric analysis of the treated apoptotic cancer cells demonstrated their significant caspase activation potential (up to 4.2 folds) and apoptotic induction capacities (up to 58.7%). Further assessment of Bcl2 expression was performed being a physiological caspase-3 substrate. Herein, the three studied Passerini adducts were able to downregulate Bcl2 in the treated Caco-2 cells. Importantly, the mechanistic studies results of the three hits echoed their preliminary MTT antiproliferative potencies data highlighting their caspase-3 dependent apoptotic induction. Finally, the in silico predicted physicochemical and pharmacokinetic profiles, as well as ligand efficiency metrics were drug-like., (© 2022. The Author(s).)

In this study, a novel magnetic organic-inorganic composite was fabricated. Chitosan, sulfacetamide and ethylacetoacetae were used to prepare a new Sulfacetamide-Ethylacetoacetate hydrazone-chitosan Schiff-base (SEH-CSB) with a variety of active sites that capable of forming coordinate covalent bonds with Cr(VI). This was followed by modification of the formed SHE-CSB with NiFe 2 O 4 to obtain the magnetic Chitosan-Schiff-base composite (NiFe 2 O 4 @SEH-CSB). NiFe 2 O 4 @SEH-CSB was characterized using FTIR, zeta potential, SEM, VSM and XPS. Results clarified that SHE played a crucial role in the removal of Cr(VI). The removal of Cr(VI) on NiFe 2 O 4 @SEH-CSB was found to be more fitted to pseudo-second order kinetics model and Freundlich isotherm. Besides, the maximum adsorption capacity of NiFe 2 O 4 @SEH-CSB towards Cr(VI) was found to be 373.61 mg/g. The plausible mechanism for the removal of Cr(VI) by NiFe 2 O 4 @SEH-CSB composite suggested the domination of coulombic interaction, outer-sphere complexation, ion-exchange, surface complexation and coordinate-covalent bond pathways. The magnetic property enabled easy recycling of NiFe 2 O 4 @SEH-CSB composite for seven sequential cycles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Pancreatic cystic lesions (PCLs) are common in clinical practice. The accurate classification and diagnosis of these lesions are crucial to avoid unnecessary treatment of benign lesions and missed opportunities for early treatment of potentially malignant lesions., Aim: To evaluate the role of cyst fluid analysis of different tumor markers such as cancer antigens [ e.g. , cancer antigen (CA)19-9, CA72-4], carcinoembryonic antigen (CEA), serine protease inhibitor Kazal-type 1 (SPINK1), interleukin 1 beta (IL1-β), vascular endothelial growth factor A (VEGF-A), and prostaglandin E2 (PGE2)], amylase, and mucin stain in diagnosing pancreatic cysts and differentiating malignant from benign lesions., Methods: This study included 76 patients diagnosed with PCLs using different imaging modalities. All patients underwent endoscopic ultrasound (EUS) and EUS-fine needle aspiration (EUS-FNA) for characterization and sampling of different PCLs., Results: The mean age of studied patients was 47.4 ± 11.4 years, with a slight female predominance (59.2%). Mucin stain showed high statistical significance in predicting malignancy with a sensitivity of 87.1% and specificity of 95.56%. It also showed a positive predictive value and negative predictive value of 93.1% and 91.49%, respectively ( P < 0.001). We found that positive mucin stain, cyst fluid glucose, SPINK1, amylase, and CEA levels had high statistical significance ( P < 0.0001). In contrast, IL-1β, CA 72-4, VEGF-A, VEGFR2, and PGE2 did not show any statistical significance. Univariate regression analysis for prediction of malignancy in PCLs showed a statistically significant positive correlation with mural nodules, lymph nodes, cyst diameter, mucin stain, and cyst fluid CEA. Meanwhile, logistic multivariable regression analysis proved that mural nodules, mucin stain, and SPINK1 were independent predictors of malignancy in cystic pancreatic lesions., Conclusion: EUS examination of cyst morphology with cytopathological analysis and cyst fluid analysis could improve the differentiation between malignant and benign pancreatic cysts. Also, CEA, glucose, and SPINK1 could be used as promising markers to predict malignant pancreatic cysts., Competing Interests: Conflict-of-interest statement: No conflict of interest exists., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Facile synthesis of molecular hybrids containing a 2,4-dinitrophenyl moiety was achieved via nucleophilic aromatic substitution of the fluoride anion of Sanger's reagent (2,4-dinitrofluorobenzene) with various N , S , and O nucleophiles, considered as bioactive moieties. Antimicrobial evaluation of the new hybrids was carried out using amoxicillin and nystatin as antibacterial and antifungal reference standards, respectively. MIC test results identified the compounds 3, 4 , and 7 as the most active hybrids against standard strains and multidrug-resistant strains (MDR) of Staphylococcus aureus , Escherichia coli , and Pseudomonas aurginosa . Most of the hybrids displayed two times the antibacterial activity of AMOX against MDR Pseudomonas aeruginosa , E. coli , and a standard strain of P. aeruginosa (ATCC 29853), while demonstrating a weak antifungal profile against Candida albicans . Selectivity profiles of the promising compounds 3, 4, 6, 7, 8 , and 11 on WI-38 human cells were characterized, which indicated that compound 3 is the safest one (CC 50 343.72 μM). The preferential anti-Gram-negative activity of our compounds led us to do docking studies on DNA gyrase B. Docking revealed that the potential antimicrobial compounds fit well into the active site of DNA gyrase B. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) predictions revealed that most of the new compounds have high gastrointestinal absorption and a good oral bioavailability with no BBB permeability., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)