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Abstract Background Trends in cannabis use suggest a global increase in the past decade. Current evidence associates cannabis use with an increased risk of psychosis. This association has prompted a growing research interest in the association between cannabis use and psychiatric disorders, especially psychotic disorders. This study aims to gain a better understanding of the effect of cannabis on psychosis and its clinical progression. Results We conducted a retrospective chart review of cannabis use in patients hospitalized for a psychosis episode over five years at the American University of Beirut Medical Center (AUBMC). Cannabis users were more likely to be young single males using other substances compared to non-cannabis users. Frequent cannabis use was associated with a higher likelihood of paranoia and legal problems. Other psychotic symptoms did not significantly differ between frequent cannabis users and non-users. The length of hospital stay and the duration of the psychotic episode did not significantly differ between cannabis users and non-users. Family stressors and family history of a psychotic disorder were associated with a higher likelihood of personal history of violence. Conclusions This study is the first in Lebanon to reproduce findings supporting the association between cannabis and psychosis previously highlighted in other populations. Further prospective research is needed to better understand the effect of cannabis use on psychosis and to accordingly revise policies on cannabis legalization to reduce the global burden of psychotic disorders.

The present study aimed to show how the vegetation structure in the southern part of the Gelibolu (Gallipoli) Peninsula (south of the Eceabat-Kabatepe Highway) is formed according to the site characteristics. For this purpose, 100 sample areas each with a size of 400 m2 were taken. Proportions of the trees, bushes and perennial plants in the sample areas were assessed according to the Braun-Blanquet method. In order to determine the general soil characteristics of the study area, topsoil samples were taken at 0–30 cm depth level from 51 sample areas and the bedrock type was determined. Analyses were made on the soil samples for soil reaction (pH), lime, organic carbon, total nitrogen and texture. Additionally, coordinate, elevation, aspect and slope determinations were made in each sample area. For assessments,in consideration of geographical characteristics and especially topographic structure, the study field was divided into 6 different districts, and the vegetation structure was examined at these 6 districts. As a result of study, 61 different plant species were determined, and it was found that especially topographic structure and aspect were very influential on the distribution of these species. The influence of aspect can be explained by the effects of insolation and prevailing wind on field moisture. The study also determined that individuals of the species in wind-exposed areas and especially in areas close to seashore were often shorter and deformed compared to those in areas sheltered from wind. This can be explained by the fact that where the Mediterranean climate is dominant, plants reduce their above-ground parts for avoiding exposure to physiological drought because strong winds trigger transpiration.

Background: Individuals infected with the COVID-19 virus present with different symptoms of varying severity. In addition, not all individuals are infected despite exposure. Risk factors such as age, sex, and comorbidities play a major role in this variability; however, genetics may also be important in driving the differences in the incidence and prognosis of the disease. An Insertion/Deletion (I/D) polymorphism in the ACE1 gene (rs1799752) may explain these genetic differences. The aims of this study were to determine the potential role of ACE1 I/D genetic polymorphism in the risk of contracting COVID-19 as well as predicting the severity of COVID-19 infection.Methods: Three-hundred and eighty-seven non-related Lebanese subjects, 155 controls and 232 cases, who presented to the American University of Beirut Medical Center (AUBMC) for COVID-19 PCR testing were recruited. Clinical data were collected via filling a questionnaire and accessing the medical records. Peripheral blood was withdrawn for DNA isolation, and genotyping performed with standard PCR followed by band visualization on agarose gel.Results: In our study population, previously described risk factors such as gender, age, and comorbidities were associated with increase in disease susceptibility and severity. ACE1 I was the least common allele, and there was a positive association between ACE1 I and the risk of contracting the COVID-19 disease. More specifically, the frequency of II genotype was significantly higher among cases when compared to controls (P = 0.035) with individuals with the II genotype having greater risk for contracting the COVID-19 disease: OR = 2.074, P = 0.048 in the multivariate analysis. As for disease severity, the DD genotype and D allele were associated with increased risk for developing severe symptoms (OR = 2.845, P = 0.026 and OR = 2.359, P = 0.014, respectively), and the DD genotype with necessitating hospitalization (OR = 2.307, P = 0.042). In parallel, D allele carriers showed a significantly increased risk for developing hypoxia: OR = 4.374, P = 0.045.Conclusion: We found a positive association between ACE1 I and the risk of contracting the COVID-19 disease, and between ACE1 D and a worse outcome of the COVID-19 infection. Therefore, genotyping for ACE1 I/D polymorphism could be used to assess risk and predict severity for better prognosis and management of the disease.

Madura foot, relatively easy to diagnose in tropical countries, is very rare and unrecognized in Morocco, causing diagnostic delays. We present the case of a 54-year-old patient with mycetoma for 3 years who initially consulted two general practitioners, then an endocrinologist and finally a dermatologist in order to be diagnosed correctly. The diagnosis of mycetoma based on biological criteria was established at a late stage of irreversible bone lesions; requiring amputation by the orthopedic team. Mycetomas are fungal or bacterial. Delays in diagnosis and care are frequent in Morocco. The diagnosis is based on biology; however, radiological examinations are necessary to assess the extension. The initial treatment is medicinal. Surgery takes place in late stages.

The use of ultrasonography in acute and critical care medicine is becoming increasingly common. However, use of an airway ultrasound as an adjunct to determine the type of intervention needed and assess complications is not common practice. We report a 56-year-old male who presented to the Emergency Department of the Sungai Buloh Hospital, Selangor, Malaysia, in 2015 with hoarseness, stridor and impending respiratory failure. A point-of-care ultrasound performed to assess the neck and vocal cords indicated a heterogeneous echogenic mass in the larynx, thus ruling out a cricothyroidotomy. The patient was therefore referred for an emergency tracheostomy. This case highlights the importance of point-of-care airway ultrasonography in the assessment of patients with stridor. This imaging technique not only helps to detect the cause of the stridor, but also to determine the feasibility of a cricothyroidotomy in emergency cases. Keywords: Emergency Medicine; Stridor; Ultrasonography; Airway Management; Tracheostomy; Case Report; Malaysia.

Stylometry has got a lot of interest during these recent years because it solved many authorship problems and disputes that were difficult to handle. Author discrimination consists in checking whether two texts are written by the same author or not. In this investigation, we try to make an author discrimination between the Quran (The holy words and statements of God in the Islamic religion) and the Hadith (statements said by the prophet Muhammad) in a segmental form. In fact, 14 text segments are extracted from the Quran book and 11 text segments are extracted from the Bukhari Hadith. These segments have more or less the same size in terms of words and the medium size is about 2080 words per text segment. The Quran is taken in its entirety, whereas for the Prophet’s statements, we chose only the certified texts of the Bukhari book. That is, four series of experiments are done and commented. The first series of experiments concerns several experiments of authorship attribution using different state of the art features and classifiers, the second series of experiments analyses the different texts by using a new parameter called COST, the third series of experiments consists in an authorship discrimination using the frequency of a particular word (“الذين ” meaning those/who in English) and the fourth series of experiments performs a hierarchical clustering on the 25 text segments, in order to assess the real number of clusters (author styles) and to see if the hypothesis of a unique author is possible. This investigation, which represents the continuation of a previous research work on the same topic [Sayoud 2012-a], has further clarified an old enigma, which was impossible to solve for fourteen centuries: all the results of this investigation show unanimously that the two books should have two different authors. La stylométrie a montré beaucoup d'intérêts durant ces dernières années car elle a résolu beaucoup de problèmes et disputes qui étaient difficiles à manipuler. La discrimination d'auteur consiste à vérifier si deux textes sont écrits par le même auteur ou non. Dans cette étude, nous essayons d'exécuter une discrimination d'auteur entre le Coran (Les mots saints et déclarations de Dieu dans la religion Islamique) et le Hadith (déclarations prononcées par le Prophète Muhammad) sous une forme segmentale. En fait, 14 segments de texte sont extraits du Coran et 11 segments sont extraits du Hadith de Bukhari. Ces segments ont plus ou moins la même taille en terme de mots et la taille moyenne est d'environ 2080 mots par segment. Le Coran est pris entièrement, tandis que pour les déclarations du Prophète, nous avons choisi seulement les textes certifiés du livre de Bukhari. Ainsi, quatre séries d'expériences sont faites et commentées. La première série d'expériences concerne plusieurs expériences d'identification d'auteur utilisant différents classifieurs et caractéristiques de l'état de l'art ; la seconde série d'expériences analyse les différents textes en utilisant un nouveau paramètre appelé COST; la troisième série d'expériences consiste en une discrimination d'auteurs utilisant la fréquence d'un mot particulier ("الذين " signifiant Ceux/ Qui en Français) et la quatrième série d'expériences exécute un regroupement hiérarchique sur les 25 segments de texte, dans le but d'estimer le nombre réel de clusters (Styles d'auteurs) et de voir si l'hypothèse d'un auteur unique est possible. Cette étude, qui représente la suite d'un travail de recherche précédent sur le même sujet (Sayoud 2012a), a clarifié d'avantages une ancienne énigme, qui était impossible de résoudre durant quatorze siècles : en fait, tous les résultats de cette étude montrent que les deux livres devraient avoir deux auteurs différents.

This paper aims to introduce the utilization of hazardous sludge with green-lipped mussel shells as concrete mixture components. The hazardous sludge is a side product of wastewater treatment plant operated in NGCC Priok, while green-lipped mussel shells are side product of community activity in Kalibaru, North Jakarta, Indonesia. Utilization is dedicated to preserve the environment, reducing both hazardous sludge generations from wastewater treatment plant and potential waste from social activities in the coastal area. Three different groups of concretes were prepared. The first group contains normal concretes with W/C ratio of 0.5. Subsequently, the second group contains concretes with dry sludge and mussel as a replacement of fine aggregate at different contents, 5% (C1), 10% (C2), and 15% (C3), with W/C ratio of 0.5. Finally, the last group contains concretes with dry sludge as cement replacement and the green-lipped mussel as fine aggregate replacement at different contents of 5% (C4), 10% (C5), and 15% (C6). The results show that dry sludge and green-lipped mussel provide better results when used as a substitute for fine aggregate rather than as cement replacement. In addition, the rate of strength development of concretes containing waste additions are slow compared to normal concretes.

Ihab Abdel Aziz,1 Mohamed Fawzy Alsoda,2 Tarek Mohamed Elmenofy,1 Mohamed Medhat Sakhsoukh,1 Noha Mohamed Abd el Azim,1 Amr Mahmoud Ahmed,1 Sohaila Ali Abd El-Halim,3 Sherine Salaheldin Hassan Baris,3 Yousef Ahmed Fouad,4 Ayman Mohyieldin Elghonemy,1 Heba Metwally,1 Wael Mohamed El Gendy,1 Raghdaa Ali,2 Yehia Mahmoud Basha,5 Eman Abo ElMaaty Mohamed,6 Wafaa Mohamed Amin,6 Maged Adly Naguib,1 Hazem Abdallah Elnashar1 1Department of Ophthalmology, The Memorial Institute for Ophthalmic Research, Giza, Egypt; 2Department of Pediatrics and Neonatology, Ahmed Maher Teaching Hospital, Cairo, Egypt; 3Department of Pediatrics and Neonatology, Mataria Teaching Hospital, Cairo, Egypt; 4Department of Ophthalmology, Ain Shams University Hospitals, Cairo, Egypt; 5Department of Pediatrics and Neonatology, Damanhour Teaching Hospital, Beheira, Egypt; 6Department of Pediatrics and Neonatology, El-Galaa Teaching Hospital, Cairo, EgyptCorrespondence: Hazem Abdallah Elnashar, Department of Ophthalmology, The Memorial Institute for Ophthalmic Research, Giza, 23314, Egypt, Tel +201227011043, Email Dr.hazemelnashar@gmail.comBackground: Retinopathy of prematurity (ROP) is increasing in incidence in developing nations, including Egypt. Secondary prevention requires timely detection through the development of regional screening guidelines, which should be preceded by large-scale studies to characterize the population at risk.Methods: A prospective, multicentric exploratory study that included five large tertiary institutions in an urban Egyptian setting. All infants born with gestational age (GA) < 37 weeks and/or birth weight (BW) ≤ 2000 grams were screened. More mature and heavier infants with unstable clinical course were also included. The primary outcome measure was the rate of ROP and high-risk disease occurrence in relation to underlying risk factors.Results: Of the 768 eyes (384 screened infants), 347 eyes (45.2%) had stage 1 or higher disease, and 43 eyes (5.6%) had high-risk disease. Eyes with stage 1 or higher ROP and treatment-requiring ROP had a mean (± SD) GA of 33.4 (± 2.6) weeks and 32.8 (± 3.2) weeks, and BW of 1842.3 (± 570.1) grams and 1747.6 ± (676.2) grams, respectively. Treatment-requiring eyes belonged to infants that had significantly lower GA and significantly higher prevalence of co-morbidities than non-treatment-requiring eyes.Conclusion: The incidence of ROP and high-risk disease in an urban Egyptian setting are similar to those in comparable settings elsewhere and locally. This exploratory study supports tailoring local screening criteria for ROP, and may aid the future development of national guidelines.Keywords: retinopathy of prematurity, ROP, screening, plus disease, preterm

Diabetes is a multifactorial global health disorder marked by unusually high plasma glucose levels, which can lead to serious consequences including diabetic neuropathy, kidney damage, retinopathy, and cardiovascular disease. One effective therapy approach for reducing hyperglycemia associated with type 2 diabetes is to target α-glucosidase, enzymes that catalyze starch breakdown in the intestine. In the current study, two new (1, 2) and nine known (3-11) compounds were isolated from the rutaceous plant Haplophyllum tuberculatum and characterized by extensive nuclear magnetic resonance spectroscopic techniques and high-resolution electrospray ionization mass spectrometry. After structural elucidation, nine compounds were evaluated for their ability to inhibit α-glucosidase, a target for the treatment of type-2 diabetes. Among them, three compounds (7, 5, and 2) exhibited notable inhibition with half-maximal inhibitory concentration (IC 50 ) values of 3.42 ± 0.12, 5.79 ± 0.28, and 6.75 ± 1.18 µM, respectively, while the remaining six compounds (1, 3, 4, 6, 8, and 9) had a moderate activity with IC 50 values ranging from 12.14 ± 0.35 to 24.60 ± 0.57 µM, compared to the standard drug acarbose (IC 50 = 875.75 ± 1.24 µM). A kinetic study of compounds 5 and 7 exhibited the competitive type of inhibition with K i values of 4.82 ± 0.0036 and 3.92 ± 0.0062 µM, respectively. Furthermore, a structure-based prediction of the compounds' binding mode suggested that these inhibitors fitted exceptionally well within the active site of the target enzyme, α-glucosidase, forming multiple hydrogen and hydrophobic interactions with its active site residues. In conclusion, compounds with potent α-glucosidase inhibitory activity are abundant in nature and can be explored and further developed for treating diabetes mellitus., (© 2024 Wiley‐VHCA AG, Zurich, Switzerland.)

Carbonic anhydrase II (CA II) is crucial for maintaining homeostasis in several processes, including respiration, lipogenesis, gluconeogenesis, calcification, bone resorption, and electrolyte balance. It is a pivotal druggable target which is implicated in glaucoma, renal, gastric, and pancreatic carcinomas, as well as in malignant brain tumours. Therefore, to identify new CA II (bovine) inhibitors, the current study was designed to synthesize a library of 20 new triazole-linked hydrazones (6a-t). All compounds were characterized by using spectroscopic techniques such as NMR and mass spectrometry. The in-vitro evaluation resulted in impressive inhibitory capability against CA II with IC 50 values ranging from 9.10 ± 0.26-48.26 ± 1.30 µM. Among all derivatives, compounds 6a, 6b, 6d, 6k-6m, 6q, 6s and 6t exhibited potent inhibitory potential with 6t deemed as the most active inhibitor. Additionally, kinetic study of the hybrid 6t revealed concentration dependent type of inhibition with K i value 7.24 ± 0.0086 µM. Furthermore, molecular docking of 6t correlates well with the kinetic analysis. The in-silico ADMET indicated that most of the synthesized compounds have properties conducive to drug development., 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.)

A profound grasp of anatomy is indispensable for shaping competent and safe medical practitioners. This knowledge acquisition is pivotal in the early stages of medical education and remains crucial throughout clinical training. However, the evolving landscape of medical education has ushered in changes to the anatomy curriculum, marked by a reduction in contact hours and a streamlined content structure to accommodate novel subjects and teaching methodologies. This transformation has precipitated a quandary in defining the essential scope and depth of anatomical knowledge to be imparted. Traditionally, surgeons assumed the role of anatomy instructors until Flexner's recommendations catalyzed the integration of trained anatomists. Nevertheless, the varied backgrounds of anatomists and the heterogeneity in anatomy curricula across institutions have introduced potential disparities in the quality of graduates. Addressing these challenges mandates the identification of key anatomy competencies tailored for undergraduate medical students. The imperative lies in ensuring that these competencies span cognitive, psychomotor, and affective domains, offering not only comprehensiveness but also direct applicability to clinical practice. Hence, this viewpoint highlights the necessity of adopting a systematic approach that includes gathering input from various stakeholders in developing and implementing a universal anatomy core competency framework, ensuring graduates are equipped for the multifaceted demands of clinical practice. Overall, the manuscript provides a comprehensive overview of the challenges and opportunities in anatomy education, with a clear call to action for a transformative approach to meet the evolving needs of medical practice., (© 2024 American Association for Anatomy.)

Food insecurity, pollution, and malnutrition are some critical issues tackled by the modern world in the recent era. However, edible mushrooms are nutritionally, economically, and biotechnologically valuable groups of macro fungi. Besides being an essential source of edible food, it is also exploited in pharmacological industries as a potential source of anticancer, antioxidant and immunomodulating agents. Mushrooms are not only a rich nutritional source of functional food all over the world, but also have highly significant bioactive compounds that are considered nutraceuticals, cosmeceuticals, and mycotherapeutics across the globe. However, their cultivation is very low compared to their demand. Its cultivation consents the sustainable management of agro-industrial waste and generates decent income using low inputs. Additionally, the mushroom could also be used for the recirculation of forest waste by acting as a natural decomposer that in turn creates great opportunities for the development of economically miserable developing countries, like Pakistan. Mushroom farming is one of the promising approaches to explore such unwanted agro-waste materials from the environment and ensure food security. Mushroom farming is one of the cheapest sources to overcome the deficiency caused by malnutrition. Interestingly, it supports the local economy by offering more and more livelihood opportunities and significant income sources for local and national trade. The current review article emphasizes the prompt mushroom farming industries in Pakistan that can save lives by providing cheaper nutritional food and rich income sources., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:No reports was provided by NO. No reports a relationship with No that includes:. No has patent NA pending to NA. The authors declare that they have no conflict of interest. Authors Ajmal Khan and Sobia Ahsan Halim are working as associate editor in section “Pharmaceutical Sciences” of this journal. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In this present work, we describe the syntheses of a new series of 32 1H-indole-based-meldrum linked 1H-1,2,3-triazole derivatives (2-13, 15a-15f, 16a-16f, 17a-17f and 19a, 19b, 20a), which constitute a new class of 1H-1,2,3-triazoles. Compounds 15a-15f, 16a-16f, 17a-17f have been prepared by employing "click" reactions between substituted 1H-indole-based meldrum alkynes (11, 12 and 13) and substituted aromatic azides (14a-14f) in the presence of copper iodide (CuI) and Hünig's base. Then, the synthesis of compounds 19, 20 through decomposition of meldrum moiety. The resulting compounds have been screened for their dihydrofolate reductase (DHFR) inhibition activity. All the newly synthesized compounds were characterized by 1 H NMR, 13 C NMR, 19 F NMR (spectroscopy when applicable), and HR-ESI-MS spectroscopy techniques. The X-ray crystallography studies have unambiguously confirmed the structure of compounds 6, 11 and 13. Furthermore, their DHFR-inhibitory activity was evaluated in-vitro. The results obtained from the DHFR-inhibitory assay revealed that all the synthesized 1H-indole-based-meldrum linked 1H-1,2,3-triazole derivatives were highly potent inhibitors, with IC 50 values in the range 3.48 ± 0.16-30.37 ± 1.20 μM. Ten compounds (15c-15f, 16c-16f, 17e and 17f) among the 32 synthesized 1H-indole-based-meldrum linked 1H-1,2,3-triazole compounds were found to exhibit exceptional inhibitory while the rest of the derivatives showed moderate activities. Additionally, molecular docking analysis of the most active (16f), moderate (15c) and least active (16a) inhibitors reflect excellent binding of 16f with the binding residues of DHFR with higher docking score (-9.13 kcal/mol) than that of 15c and 16a. The docking analysis correlates well with the inhibitory potential of these synthesized molecules. Overall, this study may pave the way to medicinal analogues of 1H-indole-based-meldrum linked 1H-1,2,3-triazoles as potent DHFR inhibition activity., 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 Masson SAS. All rights reserved.)

In the quest for novel therapeutic agents against SARS-CoV-2, the proposed study explores the potential of traditional Omani medicinal plants, focusing on the efficacy of natural ligands against the virus's Spike protein. Among 437 identified medicinal plants across Oman, 47 species that are documented for their traditional use in treating respiratory infections, with 30 species' ligands available were chosen for analysis. Molecular docking was performed using Autodock Vina on these ligands, yielding 406 unique ligands post-duplication removal. The binding affinities of target-ligand complexes were precisely determined, ranking them by interaction strength. This process identified Corilagin, a phytochemical from the Acalypha indica plant (locally known as Aeyan Al Aqrada), as the most promising inhibitor. Subsequent analyses using GROMACS for molecular dynamics simulation confirmed its binding stability and interaction dynamics of the Corilagin-protein complex. The in-vitro studies further validated Corilagin's inhibitory effect on SARS-CoV-2, demonstrating a remarkable 92 % inhibition at 0.5 mM concentration. Dilution studies to ascertain the IC 50 value revealed Corilagin's high potency at a micromolar level (IC 50  = 2.15 ± 0.13 μM), underscoring its potential as a drug candidate for SARS-CoV-2 treatment. These findings highlight the significance of ethnomedicine and in-silico methodologies in drug discovery, offering promising directions for future antiviral research., Competing Interests: All the listed authors have read and approved the submitted manuscript. This manuscript/data, or parts thereof, has not been submitted for possible publication to another journal or that the work has previously been published elsewhere. The present study was performed according to international, national and institutional rules considering animal experiments, clinical studies and biodiversity rights., (© 2024 The Authors.)

Introduction: Prolyl-specific oligopeptidase (POP), one of the brain's highly expressed enzymes, is an important target for the therapy of central nervous system disorders, notably autism spectrum disorder, schizophrenia, Parkinson's, Alzheimer's disease, and dementia., Method: The current study was designed to investigate 2,4-bis(trifluoromethyl) benzaldehyde- based thiosemicarbazones as POP inhibitors to treat the above-mentioned disorders. A variety of techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier-transform infrared spectroscopy (FTIR), were used for the structural confirmation of synthesized compounds. After in-vitro evaluation, all of these compounds were found to be prominent inhibitors of the POP enzyme (IC50= 10.14 - 41.73 μM)., Result: Compound 3a emerged as the most active compound (IC50 10.14 ± 0.72 μM) of the series. The kinetic study of the most active 3a (Ki =13.66 0.0012 μM) indicated competitive inhibition of the aforementioned enzyme., Conclusion: Moreover, molecular docking depicted a noticeable role of thiosemicarbazide moiety in the binding of these molecules within the active site of the POP enzyme., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Prolyl specific oligopeptidase (POP), is one of the highly expressed enzymes in the brain and is a prime target to treat disorders related to the central nervous system. Here, we describe the structure-based design of the tacrine derivatives, selective, and brain-permeable POP inhibitors. These compounds inactivate POP in-vitro specifically and sustainably at very low concentrations (nano molar). Among this series, compound 6b (IC 50 = 0.81 ± 0.04 µM) exhibited most potent inhibition. Furthermore, kinetic study revealed that these molecules target active site of POP which is further confirmed by in-silico molecular interaction analysis. The computational docking results indicates that the compounds are well fitted in the active site with high binding score (i.e., > -7 to > -4 kcal/mol) where Trp595, Arg643, Tyr473, and Ser554 plays important role in binding with the active compounds. The molecular dynamic simulation of most active compounds ( 6a , 6b , 6d , and 6f ) displayed higher free energy binding, when compared to the standard drug in MM-PBSA based binding free energy calculation. In addition, the predicted pharmacokinetic profile suggests that these compounds can serve as excellent inhibitors upon additional optimization which makes them prime choice for further investigation.Communicated by Ramaswamy H. Sarma.

The single-stranded RNA genome of SARS-CoV-2 encodes several structural and non-structural proteins, among which the papain-like protease (PLpro) is crucial for viral replication and immune evasion and has emerged as a promising therapeutic target. The current study aims to discover new inhibitors of PLpro that can simultaneously disrupt its protease and deubiquitinase activities. Using multiple computational approaches, six compounds (CP1-CP6) were selected from our in-house compounds database, with higher docking scores (-7.97 kcal/mol to -8.14 kcal/mol) and fitted well in the active pocket of PLpro. Furthermore, utilizing microscale molecular dynamics simulations (MD), the dynamic behavior of selected compounds was studied. Those molecules strongly binds at the PLpro active site and forms stable complexes. The dynamic motions suggest that the binding of CP1-CP6 brought the protein to a closed conformational state, thereby altering its normal function. In an in vitro evaluation, CP2 showed the most significant inhibitory potential for PLpro (protease activity = 2.71 ± 0.33 μM and deubiquitinase activity = 3.11 ± 0.75 μM), followed by CP1, CP5, CP4 and CP6. Additionally, CP1-CP6 showed no cytotoxicity at a concentration of 30 μM in the human BJ cell line., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Aims: The aim of the current study was to explore the anti-diabetic potential of Ochradenus aucheri Boiss (O. aucheri)., Method: All the fractions of O. aucheri were evaluated for α-glucosidase inhibition, followed by bioassay-guided isolation which resulted in a new sesquiterpenoid, as a potential α-glucosidase inhibitor., Results: The preliminary screening showed that all the fractions including n-hexane (38.0 ± 1.38 μg/mL), dichloromethane (92.6 ± 6.18 μg/mL), ethyl acetate (29.2 ± 0.51 μg/mL) and n-butanol (361.8 ± 5.80 μg/mL) displayed significant α-glucosidase inhibitory activity. The activity-directed fractionation and purification of ethyl acetate fraction led to the isolation of one new sesquiterpenoid, Jardenol (1), and two known metabolites: β-stitosterol-3-O-β-D-glucopyranoside (2) and β-Sitosterol (3). To the best of our knowledge, these metabolites have not been isolated from this plant previously. The structure of the new metabolite 1 was confirmed through 1D and 2D NMR spectroscopy, and MS analysis. Compound 1 showed significant α-glucosidase inhibition with an IC50 value of 138.2 ± 2.43 μg/mL as compared to positive control acarbose (IC50 = 942.0 ± 0.60 μg/mL). Additionally, in-silico docking was employed to predict the binding mechanism of compound 1 in the active site of the target enzyme, α-glucosidase. The docking results suggested that the compound forms strong interactions at the catalytic site of α-glucosidase., Conclusion: The results of the present study indicated that the newly purified secondary metabolite, Jardenol, can be a promising anti-diabetic compound., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: The pandemic caused by SARS-CoV-2 significantly impacted human life around the globe. Numerous unexpected modifications of the SARS-CoV-2 genome have resulted in the emergence of new types and have caused great concern globally., Method: Inhibitory effects of bioactive phytochemicals derived from natural and synthetic sources are promising for pathogenic viruses. in vitro and in silico techniques were used in the current study to identify novel inhibitors of coumarin clubbed thiazolo[3,2-b][1,2,4]triazoles against the SARS-CoV-2 spike protein., Result: Interestingly, all the tested molecules demonstrated substantial inhibition of spike protein with 91.81-57.90% inhibition. The spike protein was remarkably inhibited by compounds 6k (91.83%), 6j (89.75%), 6m (87.69%),6i (86.60%), 6l (85.40%), 6h (84.70%), 6l (84.70%), 6g (83.40%), 6b (82.60%), 6f (81.90%), while compounds 6d 6a, 6c, and 6e exhibited significant activity against spike protein with 79.60%, 77.10%, 75.30%, and 57.90% inhibition, respectively. The binding mechanism of these novel inhibitors with spike protein was deduced in silico, which reflects that the active molecules firmly bind with the receptor binding domain (RBD) of spike protein, thereby inhibiting its function., Conclusion: The combined in vitro and in silico investigations unfold the therapeutic potential of coumarin-thiazolotriazole scaffolds in the treatment of SARS-CoV-2 infection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Prolyl oligopeptidase (POP) is a pivotal druggable target implicated in diverse biological processes and linked to the development of various ailments, including neurodegenerative disorders. While conventional peptide-based inhibitors have been a centerpiece, their limitations, such as restricted bioavailability, necessitate exploration of non-peptidic inhibitors for their therapeutic potential., Method: This study focuses on designing, synthesizing, and assessing morpholine-based hydrazones targeting the catalytic serine residue of POP. The hydrazones (5a-o), reported as moderately potent analogs compared to the renowned Z-Pro-Prolinal, demonstrated in vitro POP inhibition with IC50 values ranging from 13.60 ± 2.51 to 36.51 ± 1.82 μM. The derivative 5h, with an IC50 of 13.60 ± 2.51 μM, emerged as the most potent inhibitor., Results: Moreover, the in vitro kinetic study of compound 5h indicated that it exhibited concentration-dependent type of inhibition. in silico docking studies of 5h revealed robust interactions in the POP enzyme's active site, yielding a docking score of -6.30 Kcal/- mol, consistent with experimental results., Conclusion: All findings underscored the potential of synthesized derivatives for drug development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Diabetes mellitus has become a major global health burden because of several related consequences, including heart disease, retinopathy, cataracts, metabolic syndrome, collapsed renal function, and blindness. In the recent study, thirty Schiff base derivatives of 1,3-diphenylurea were synthesized and their anti-diabetic activity was evaluated by targeting α-glucosidase. The compounds exhibited an overwhelming inhibitory potential for α-glucosidase with higher potency ranging from 2.49-37.16 μM. The most effective compound, 5h, showed competitive inhibition of α-glucosidase ( K i = 3.96 ± 0.0048 μM) in the kinetic analysis and strong binding interactions with key residues α-glucosidase in docking analysis, indicating its potential for better glycemic control in diabetes patients., Competing Interests: The authors have declared no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Myocardial infarction (MI) is considered one of the most common cardiac diseases and major cause of death worldwide. The prevalence of MI and MI-associated mortality have been increasing in recent years due to poor lifestyle habits viz. residency, obesity, stress, and pollution. Synthetic drugs for the treatment of MI provide good chance of survival; however, the demand to search more safe, effective, and natural drugs is increasing. Plants provide fruitful sources for powerful antioxidant and anti-inflammatory agents for prevention and/or treatment of MI. However, many plant extracts lack exact information about their possible dosage, toxicity and drug interactions which may hinder their usefulness as potential treatment options. Phytoconstituents play cardioprotective role by either acting as a prophylactic or adjuvant therapy to the concurrently used synthetic drugs to decrease the dosage or relief the side effects of such drugs. This review highlights the role of different herbal formulations, examples of plant extracts and types of several isolated phytoconstituents (phenolic acids, flavonoids, stilbenes, alkaloids, phenyl propanoids) in the prevention of MI with reported activities. Moreover, their possible mechanisms of action are also discussed to guide future research for the development of safer substitutes to manage MI., (© 2024 John Wiley & Sons Ltd.)

According to the most recent edition of the DSM V, neurocognitive disorder (NCD), formerly referred to as dementia, is a debilitating condition that progressively diminishes quality of life. It impacts both physical and cognitive domains, including memory and aberrant behavior. If usual presentation is uncertain, perfusion, functional, and molecular imaging are useful. Gold standard marker for the diagnosis of Alzheimer's disease (AD) is FDG PET imaging. Recent studies have shown promising results, whereby the cerebral blood flow in arterial spin labeling (ASL) of MRI and the hypometabolism FDG PET both show a consistent regional abnormality. Therefore, ASL MRI imaging carries a potential role in assisting diagnosis of neurocognitive disorder., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

α-Amylase play important role in hydrolyses of α-bonds of large α-linked polysaccharides; thus, it is a potential drug target in diabetes mellites (DM) and its inhibition is one of the therapeutic strategies in DM. With the aim to discover novel and safer therapeutic molecules to combat diabetes, a huge dataset of ∼0.69 billion compounds from ZINC20 database were screened against α-amylase using multi-fold structure-based virtual screening protocol. Based on receptor-based pharmacophore model, docking results, pharmacokinetic profile, molecular interactions with α-amylase, several compounds were retrieved as lead candidates to be further scrutinized in the in vitro assay and in vivo animal testing. Among the selected hits, CP26 exhibited the highest binding free energy in MMGB-SA analysis, followed by CP7 and CP9, which is higher than the binding free energy of acarbose. While CP20 and CP21 showed comparative binding free energy to acarbose. All the selected ligands showed acceptable binding energy range, therefore, several molecules with enhanced efficacy can be designed by derivatizing these molecules. The in-silico results indicates that the selected molecules could serve as potential selective α-amylase inhibitors and can be used for the treatment of diabetes.Communicated by Ramaswamy H. Sarma.

The COVID-19 has had a significant influence on people's lives across the world. The viral genome has undergone numerous unanticipated changes that have given rise to new varieties, raising alarm on a global scale. Bioactive phytochemicals derived from nature and synthetic sources possess lot of potential as pathogenic virus inhibitors. The goal of the recent study is to report new inhibitors of Schiff bases of 1,3-dipheny urea derivatives against SARS COV-2 spike protein through in-vitro and in-silico approach. Total 14 compounds were evaluated, surprisingly, all the compounds showed strong inhibition with inhibitory values between 79.60% and 96.00% inhibition. Here, compounds 3a (96.00%), 3d (89.60%), 3e (84.30%), 3f (86.20%), 3g (88.30%), 3h (86.80%), 3k (82.10%), 3l (90.10%), 3m (93.49%), 3n (85.64%), and 3o (81.79%) exhibited high inhibitory potential against SARS COV-2 spike protein. While 3c also showed significant inhibitory potential with 79.60% inhibition. The molecular docking of these compounds revealed excellent fitting of molecules in the spike protein receptor binding domain (RBD) with good interactions with the key residues of RBD and docking scores ranging from - 4.73 to - 5.60 kcal/mol. Furthermore, molecular dynamics simulation for 150 ns indicated a strong stability of a complex 3a:6MOJ. These findings obtained from the in-vitro and in-silico study reflect higher potency of the Schiff bases of 1,3-diphenyl urea derivatives. Furthermore, also highlight their medicinal importance for the treatment of SARS COV-2 infection. Therefore, these small molecules could be a possible drug candidate., (© 2024. The Author(s).)

Sirtuin 3 (SIRT3) belongs to the Sirtuin protein family, which consists of NAD + -dependent lysine deacylase, involved in the regulation of various cellular activities. Dysregulation of SIRT3 activity has been linked to several types of cancer, including breast cancer. Because of its ability to stimulate adaptive metabolic pathways, it can aid in the survival and proliferation of breast cancer cells. Finding new chemical compounds targeted towards SIRT3 was the primary goal of the current investigation. Virtual screening of ~ 800 compounds using molecular docking techniques yielded 8 active hits with favorable binding affinities and poses. Docking studies verified that the final eight compounds formed stable contacts with the catalytic domain of SIRT3. Those compounds have good pharmacokinetic/dynamic properties and gastrointestinal absorption. Based on excellent pharmacokinetic and pharmacodynamic properties, two compounds (MI-44 and MI-217) were subjected to MD simulation. Upon drug interaction, molecular dynamics simulations demonstrate mild alterations in the structure of proteins and stability. Binding free energy calculations revealed that compounds MI-44 (- 45.61 ± 0.064 kcal/mol) and MI-217 (- 41.65 ± 0.089 kcal/mol) showed the maximum energy, suggesting an intense preference for the SIRT3 catalytic site for attachment. The in-vitro MTT assay on breast cancer cell line (MDA-MB-231) and an apoptotic assay for these potential compounds (MI-44/MI-217) was also performed, with flow cytometry to determine the compound's ability to cause apoptosis in breast cancer cells. The percentage of apoptotic cells (including early and late apoptotic cells) increased from 1.94% in control to 79.37% for MI-44 and 85.37% for MI-217 at 15 μM. Apoptotic cell death was effectively induced by these two compounds in a flow cytometry assay indicating them as a good inhibitor of human SIRT3. Based on our findings, MI-44 and MI-217 merit additional investigation as possible breast cancer therapeutics., (© 2024. The Author(s).)

The study examined the antimicrobial and antioxidant potential of pure Acetyl-11-keto-β-boswellic acid (AKBA), boswellic acid (70%) and AKBA loaded nanoparticles as topical polymeric films. The optimized concentration (0.05 % w/v) of pure AKBA, boswellic acid (BA), and AKBA loaded silver nanoparticles were used to study its impact on film characteristics. Carboxymethyl cellulose (CMC), sodium alginate (SA), and gelatin (Ge) composite films were prepared in this study. The polymeric films were evaluated for their biological (antioxidant and antimicrobial activities) and mechanical characteristics such as tensile strength (TS) and elongation (%). Moreover, other parameters including water barrier properties and color attributes of the film were also evaluated. Furthermore, assessments were conducted using analytical techniques like FTIR, XRD, and SEM. Surface analysis revealed that AgNP precipitation led to a few particles in the film structure. Overall, the results indicate a relatively consistent microstructure. Moreover, due to the addition of AKBA, BA, and AgNPs, a significant decrease in TS, moisture content, water solubility, and water vapor permeation was observed. The films transparency also showed a decreasing trend, and the color analysis revealed decreasing yellowness (b*) of the films. Importantly, a significant increase in antioxidant activity against DPPH free radicals and ABTS cations was observed in the CSG films. Additionally, the AgNP-AKBA loaded films displayed significant antifungal activity against C. albicans . Moreover, the molecular docking analysis revealed the inter-molecular interactions between the AKBA, AgNPs, and composite films. The docking results indicate good binding of AKBA and silver nanoparticles with gelatin and carboxymethyl cellulosemolecules. In conclusion, these polymeric films have potential as novel materials with significant antioxidant and antifungal activities., Competing Interests: 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., (© 2024 The Authors.)

The present article describes the muscle relaxant and antipyretic effects of pentacyclic triterpenes, oleanolic acid ( OA ), ursolic acid ( UA ) and betulinic acid ( BA ) isolated from roots of Diospyros lotus in animal models. The muscle relaxant effects of isolated pentacyclic triterpenes were determined by chimney and inclined plane tests. In the chimney test, pretreatment of pentacyclic triterpenes evoked significant dose dependent influence on muscle coordination. When administered intraperitoneally (i.p.) to mice at 10 mg/kg for 90 min, OA , UA , and BA exhibited muscle relaxant effects of 66.72 %, 60.21 %, and 50.77 %, respectively. Similarly, OA , UA, and BA (at 10 mg/kg) illustrated 65.74 %, 59.84 % and 51.40 % muscle relaxant effects in the inclined plane test. In the antipyretic test, significant amelioration was caused by pretreatment of all compounds in dose dependent manner. OA , UA, and BA (at 5 mg/kg) showed 39.32 %, 34.32 % and 29.99 % anti-hyperthermic effects, respectively 4 h post-treatment, while at 10 mg/kg, OA , UA, and BA exhibited 71.59 %, 60.99 % and 52.44 % impact, respectively. The muscle relaxant effect of benzodiazepines is well known for enhancement of GABA receptors. There may exist a similar mechanism for muscle relaxant effect of pentacyclic triterpenes. The in-silico predicted binding pattern of all the compounds reflects good affinity of compounds with GABA A receptor and COX-2. These results indicate that the muscle relaxant and antipyretic activities of these molecules can be further improved by structural optimization., Competing Interests: 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. Authors Ajmal Khan and Sobia Ahsan Halim are working as associate editor in section “Pharmaceutical Sciences” of this journal., (© 2024 The Authors.)

The synthesis of a new series of thiadiazine thiones including 5-(2-hydroxyethyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones ( 1 - 5 ), 5-(2-hydroxypropyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones ( 6 - 8 ), 3,5-dipropyl-1, 3, 5-thiadiazine-2-thione ( 9 ) and (2-(5-alkyl/aryl-6-thioxo-1, 3, 5-thiadiazine-3-yl) alkyl acetate/benzoate) ( 10 - 17 ) was accomplished via one pot reaction. The structures of the synthesized compounds were characterized through NMR and Mass spectrometry. The anti-nociceptive activity of compounds was performed on BALB/C mice by hot plate method, where compounds 3 , 5 (50  μ g/kg), and 8 (50, 100  μ g/kg) exhibited significant effect (P < 0.01, P < 0.05) in latency time of 15, 30, and 60 min, while compounds 6 and 16 (100  μ g/kg) exhibited significant effect (P < 0.01, P < 0.05) in latency time interval of 15 and 30 min. Compounds 1 , 12-13 , and 15 showed moderate activity. Among the tested hits, compounds 5 (17.3 ± 2.2), 11 (16.2 ± 2.1), and 8 (16.1 ± 2.1) showed significant anti-nociceptive potential. Molecular docking studies on the most active anti-nociceptive hits indicated that the activity might be attributed to the ability of the compounds to target μ-opioid receptor (μOR) effectively. Furthermore, compounds 14 and 11 showed anti-bacterial activity against Pseudomonas aeruginosa and MSRA with MIC of 40.97 and 54.77  μ g/mL, respectively. In addition, the predicted ADMET profile of 5 , 9 , and 11 indicates that these molecules follow the drug-likeness criteria, and their activity can be enhanced through structural optimization., Competing Interests: 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. Author Ajmal Khan working as a associate editor in section “Pharmaceutical Sciences” of this journal., (© 2024 The Authors.)

In recent years, polyhydroquinolines have gained much attention due to their widespread applications in medicine, agriculture, industry, etc. Here, we synthesized a series of novel hydrazone-based polyhydroquinoline derivatives via multi-step reactions. These molecules were characterized by modern spectroscopic techniques ( 1 H-NMR, 13 C NMR, and LC-HRMS) and their antibacterial and in vitro α-glucosidase inhibitory activities were assessed. Compound 8 was found to be the most active inhibitor against Listeria monocytogenes NCTC 5348, Bacillus subtilis IM 622, Brevibacillus brevis , and Bacillus subtilis ATCC 6337 with a zone of inhibition of 15.3 ± 0.01, 13.2 ± 0.2, 13.1 ± 0.1, and 12.6 ± 0.3 mm, respectively. Likewise, compound 8 also exhibited the most potent inhibitory potential for α-glucosidase (IC 50 = 5.31 ± 0.25 μM) in vitro , followed by compounds 10 (IC 50 = 6.70 ± 0.38 μM), and 12 (IC 50 = 6.51 ± 0.37 μM). Furthermore, molecular docking and DFT analysis of these compounds showed good agreement with experimental work and the nonlinear optical properties calculated here indicate that these compounds are good candidates for nonlinear optics., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Diabetic neuropathic pain is one of the most devasting disorders of peripheral nervous system. The loss of GABAergic inhibition is associated with the development of painful diabetic neuropathy. The current study evaluated the potential of 3-Hydroxy-2-methoxy-6-methyl flavone (3-OH-2'MeO6MF), to ameliorate peripheral neuropathic pain using an STZ-induced hyperglycemia rat model. The pain threshold was assessed by tail flick, cold, mechanical allodynia, and formalin test on days 0, 14, 21, and 28 after STZ administration accompanied by evaluation of several biochemical parameters. Administration of 3-OH-2'-MeO6MF (1,10, 30, and 100 mg/kg, i.p) significantly enhanced the tail withdrawal threshold in tail-flick and tail cold allodynia tests. 3-OH-2'-MeO6MF also increased the paw withdrawal threshold in mechanical allodynia and decreased paw licking time in the formalin test. Additionally, 3-OH-2'-MeO6MF also attenuated the increase in concentrations of myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), nitrite, TNF-α, and IL 6 along with increases in glutathione (GSH). Pretreatment of pentylenetetrazole (PTZ) (40 mg/kg, i.p.) abolished the antinociceptive effect of 3-OH-2'-MeO6MF in mechanical allodynia. Besides, the STZ-induced alterations in the GABA concentration and GABA transaminase activity attenuated by 3-OH-2'-MeO6MF treatment suggest GABAergic mechanisms. Molecular docking also authenticates the involvement of α2β2γ2L GABA-A receptors and GABA-T enzyme in the antinociceptive activities of 3-OH-2'-MeO6MF., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the current study, metronidazole derivatives containing 1 H -1,2,3-triazole and carboxylate moieties were evaluated in vitro and by computational methods for their anti-diabetic potential to insight into their medicinal use for the management of type II diabetes mellitus. Interestingly all 14 compounds displayed high to significant inhibitory capability against the key carbohydrate's digestive enzyme α-glucosidase with IC 50 values in range of 9.73-56.39 μM, as compared to marketed drug acarbose (IC 50 = 873.34 ± 1.67 μM). Compounds 5i and 7c exhibited the highest inhibition, therefore, these two compounds were further evaluated for their mechanistic studies to explore its type of inhibition. Compounds 5i and 7c both displayed a concentration-dependent (competitive type of inhibition) with Ki values 7.14 ± 0.01, 6.15 ± 0.02 μM, respectively, which conclude their favourable interactions with the active site residues of the α-glucosidase. Interestingly all compounds are non-cytotoxic against BJ cell line. To further validate our findings, in-silico approaches like molecular docking, and molecular dynamic simulations were applied to investigate the mode of bindings of compounds with the enzyme and identifies their inhibition mechanism, which strongly complements our experimental findings.Communicated by Ramaswamy H. Sarma.

A series of twenty-seven bis(acylhydrazones) were successfully synthesized with high yields through a multistep process, which entailed the esterification of hydroxyl groups, hydrazination with an excess of hydrazine hydrate, and subsequent reactions with various carbonyl moieties (aldehydes). In the final stage of synthesis, different chemical species including aromatic, heterocyclic, and aliphatic compounds were integrated into the framework. The resulting compounds were characterized using several spectroscopic techniques ( 1 H NMR, 13 C NMR, and mass spectrometry). Their anticholinesterase activities were assessed in vitro by examining their interactions with two cholinesterase enzymes: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the synthesized hits, compounds 3, 5, 6, 9-12, and 14 exhibited good to moderate inhibition of AChE. Specifically, 10 (IC 50  = 26.3 ± 0.4 μM) and 11 (IC 50  = 28.4 ± 0.5 μM) showed good inhibitory activity against AChE, while 9, 12, 3, and 6 exhibited significant inhibition potential against AChE with IC 50 values ranging from 35.2 ± 1.1 μM to 64.4 ± 0.3 μM. On the other hand, 5 (IC 50  = 22.0 ± 1.1 μM) and 27 (IC 50  = 31.3 ± 1.3 μM) displayed significant, and 19 (IC 50  = 92.6 ± 0.4 μM) showed moderate inhibitory potential for BChE. Notably, 5 and 27 exhibited dual inhibition of AChE and BChE, with greater potency than the standard drug galantamine. The binding patterns of these molecules within the binding cavities of AChE and BChE were anticipated by molecular docking which showed good correlation with our in vitro findings. Further structural optimization of these molecules may yield more potent AChE and BChE inhibitors., 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.)

This research work reports the synthesis of new derivatives of the hydrazone Schiff bases ( 1-17 ) based on polyhydroquinoline nucleus through multistep reactions. HR-ESIMS, 1 H- and 13 C-NMR spectroscopy were used to structurally infer all of the synthesized compounds and lastly evaluated for prolyl oligopeptidase inhibitory activity. All the prepared products displayed good to excellent inhibitory activity when compared with standard z-prolyl-prolinal. Three derivatives 3 , 15 and 14 showed excellent inhibition with IC 50 values 3.21 ± 0.15 to 5.67 ± 0.18 µM, while the remaining 12 compounds showed significant activity. Docking studies indicated a good correlation with the biochemical potency of compounds estimated in the in-vitro test and showed the potency of compounds 3, 15 and 14 . The MD simulation results confirmed the stability of the most potent inhibitors 3, 15 and 14 at 250 ns using the parameters RMSD, RMSF, Rg and number of hydrogen bonds. The RMSD values indicate the stability of the protein backbone in complex with the inhibitors over the simulation time. The RMSF values of the binding site residues indicate that the potent inhibitors contributed to stabilizing these regions of the protein, through formed stable interactions with the protein. The Rg. analysis assesses the overall size and compactness of the complexes. The maintenance of stable hydrogen bonds suggests the existence of favorable binding interactions. SASA analysis suggests that they maintained stable conformations without large-scale exposure to the solvent. These results indicate that the ligand-protein interactions are stable and could be exploited to design new drugs for disease treatment.Communicated by Ramaswamy H. Sarma.

COVID-19 appeared as a highly contagious disease after its outbreak in December 2019 by the virus, named SARS-CoV-2. The threat, which originated in Wuhan, China, swiftly became an international emergency. Among different genomic products, spike protein of virus plays a crucial role in the initiation of the infection by binding to the human lung cells, therefore, SARS-CoV-2's spike protein is a promising therapeutic target. Using a combination of a structure-based virtual screening and biochemical assay, this study seeks possible therapeutic candidates that specifically target the viral spike protein. A database of ~ 850 naturally derived compounds was screened against SARS-CoV-2 spike protein to find natural inhibitors. Using virtual screening and inhibitory experiments, we identified acetyl 11-keto-boswellic acid (AKBA) as a promising molecule for spike protein, which encouraged us to scan the rest of AKBA derivatives in our in-house database via 2D-similarity searching. Later 19 compounds with > 85% similarity with AKBA were selected and docked with receptor binding domain (RBD) of spike protein. Those hits declared significant interactions at the RBD interface, best possess and excellent drug-likeness and pharmacokinetics properties with high gastrointestinal absorption (GIA) without toxicity and allergenicity. Our in-silico observations were eventually validated by in vitro bioassay, interestingly, 10 compounds (A3, A4, C3, C6A, C6B, C6C, C6E, C6H, C6I, and C6J) displayed significant inhibitory ability with good percent inhibition (range: > 72-90). The compounds C3 (90.00%), C6E (91.00%), C6C (87.20%), and C6D (86.23%) demonstrated excellent anti-SARS CoV-2 spike protein activities. The docking interaction of high percent inhibition of inhibitor compounds C3 and C6E was confirmed by MD Simulation. In the molecular dynamics simulation, we observed the stable dynamics of spike protein inhibitor complexes and the influence of inhibitor binding on the protein's conformational arrangements. The binding free energy ΔG TOTAL of C3 (-38.0 ± 0.08 kcal/mol) and C6E (-41.98 ± 0.08 kcal/mol) respectively indicate a strong binding affinity to Spike protein active pocket. These findings demonstrate that these molecules particularly inhibit the function of spike protein and, therefore have the potential to be evaluated as drug candidates against SARS-CoV-2., (© 2024. The Author(s).)

The highly infectious respiratory illness 'COVID-19' was caused by SARS-CoV-2 and is responsible for millions of deaths. SARS-single-stranded viral RNA genome encodes several structural and nonstructural proteins, including papain-like protease (PLpro), which is essential for viral replication and immune evasion and serve as a potential therapeutic target. Multiple computational techniques were used to search the natural compounds that may block the protease and deubiquitinase activities of PLpro. Five compounds showed strong interactions and binding energy (ranges between -8.18 to -8.69 Kcal/mol) in our in-silico studies. Interestingly, those molecules strongly bind in the PLpro active site and form a stable complex, as shown by microscale molecular dynamic simulations (MD). The dynamic movements indicate that PLpro acquires closed conformation by the attachment of these molecules, thereby changing its normal function. In the in-vitro evaluation, compound COMP4 showed the most potent inhibitory potential for PLpro (protease activity: 2.24 ± 0.17 μM and deubiquitinase activity: 1.43 ± 0.14 μM), followed by COMP1, 2, 3, and 5. Furthermore, the cytotoxic effect of COMP1-COMP5 on a human BJ cell line revealed that these compounds demonstrate negligible cytotoxicity at a dosage of 30 μM. The results suggest that these entities bear therapeutic efficacy for SARS-CoV-2 PLpro., 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 B.V. All rights reserved.)

The lumbar plexus provides innervation to the lower limbs and is essential in enabling motor movement and sensation in the lower limbs. Some of its branches also innervate the muscles in the pelvic girdle. Compared to the brachial plexus in the upper limbs, the lumbar plexus appears to garner less recognition among physicians and surgeons. However, it is important to understand the anatomy of the lumbar plexus and its branches along with the innervation they enable, as injury to them can cause plexopathies and pathologies that should be recognised by any treating clinician. Lumbar disc herniation, trauma and entrapment by muscles or hypertrophic ligaments are common causes of lumbar plexus or nerve injuries. A video was produced to demonstrate the examination techniques explained in this article. To provide comprehensive examination of the lower limbs, the sciatic nerve and its branches are also included in the examination video., Competing Interests: Conflict of Interest: None., (© Penerbit Universiti Sains Malaysia, 2024.)

The rise of Plasmodium falciparum resistance to Artemisinin-based combination therapies (ACTs) is a significant concern in the fight against malaria. This situation calls for the search for novel anti-malarial candidates. 1-deoxy-D-xylulose 5-phosphate reductoisomerase (IspC) is a potential target involved in various cellular processes in P. falciparum (Pf). We screened ∼0.69 billion novel compounds from the ZINC20 library and repurposed ∼1400 FDA drugs using computational drug discovery methods against PfIspC. Following our computational pipeline, we found five novel ZINC20 compounds (Z-2, Z-3, Z-10, Z-13, and Z-14) and three FDA drugs (Aliskiren, Ceftolozane, and Ombitasvir) that showed striking docking energy (ranging from -8.405 to -10.834 kcal/mol), and strong interactions with key binding site residues (Ser269, Ser270, Ser306, Asn311, Lys312, and Met360) of PfIspC. The novel anti-malarial compounds also exhibited favorable pharmacokinetics and physicochemical properties. Furthermore, through molecular dynamics simulation, we observed the stable dynamics of PfIspC-inhibitor complexes and the influence of inhibitor binding on the protein's conformational arrangements. Notably, the binding free energy estimation confirmed high binding affinity (varied from -11.68 to -33.16 kcal/mol) of these compounds for PfIspC. Our findings could contribute to the ongoing efforts in combating malaria and invite experimental-lab researchers for validation., 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 B.V. All rights reserved.)

Diabetes mellitus (DM) has prevailed as a chronic health condition and has become a serious global health issue due to its numerous consequences and high prevalence. We have synthesized a series of hydrazone derivatives and tested their antidiabetic potential by inhibiting the essential carbohydrate catabolic enzyme, "α-glucosidase." Several approaches including fourier transform infrared, 1 H NMR, and 13 C NMR were utilized to confirm the structures of all the synthesized derivatives. In vitro analysis of compounds 3a-3p displayed more effective inhibitory activities against α-glucosidase with IC 50 in a range of 2.80-29.66 µM as compared with the commercially available inhibitor, acarbose (IC 50  = 873.34 ± 1.67 M). Compound 3h showed the highest inhibitory potential with an IC 50 value of 2.80 ± 0.03 µM, followed by 3i (IC 50  = 4.13 ± 0.06 µM), 3f (IC 50  = 5.18 ± 0.10 µM), 3c (IC 50  = 5.42 ± 0.11 µM), 3g (IC 50  = 6.17 ± 0.15 µM), 3d (IC 50  = 6.76 ± 0.20 µM), 3a (IC 50  = 9.59 ± 0.14 µM), and 3n (IC 50  = 10.01 ± 0.42 µM). Kinetics analysis of the most potent compound 3h revealed a concentration-dependent form of inhibition by 3h with K i value = 4.76 ± 0.0068 µM. Additionally, an in silico docking approach was applied to predict the binding patterns of all the compounds, which indicates that the hydrazide and the naphthalene-ol groups play a vital role in the binding of the compounds with the essential residues (i.e., Glu277 and Gln279) of the α-glucosidase enzyme., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Present research was designed to synthesize and characterize the flurbiprofen derivatives and to evaluate their analgesic, anti-inflammatory and gastro-protective activities in post-operative and chronic inflammatory pain models. Flurbiprofen derivatives were produced by using three-step processes involving esterification, hydrazide production, and schiff base, each of which modified a different carboxyl group. All the newly synthesized flurbiprofen derivatives ( NS5-NS8 ) were characterized by 1 H NMR, 13 C NMR, 19 F NMR and HR-ESI-MS, and the post-operative, inflammatory pain and ulcerogenic activities were determined in well-established in-vivo animal models. To evaluate post-operative and inflammatory pain, various doses of compounds [1, 3, 10, and 30 mg/kg (bwt)] were used, while their ulcerogenic potential was assessed at doses of 100 and 150 mg/kg (bwt). The incisional damage linked pain was significantly ( p  < 0.001) reduced by derivatives at different doses in both the acute and repeated tests with decreased response of phologistic agent-induced inflammation. The stomach histology and biochemical features demonstrate that the synthesized derivatives have no potential to cause ulcerogenicity as compared to aspirin and flurbiprofen. Furthermore, docking shows that the hydrazide moiety of these compounds is crucial in interacting within COX-2 binding site. Therefore, the synthesized compounds exhibit strong analgesic and anti-inflammatory effects and a low risk of causing ulcers. These attributes render them potentially valuable therapeutic agents for the treatment of pathological disorders associated with inflammation and pain.Communicated by Ramaswamy H. Sarma.

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. (IC 50 = 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.

Plasticizers are employed to stabilize films by safeguarding their physical stability and avoiding the degradation of the loaded therapeutic drug during processing and storage. In the present study, the plasticizer effect (glycerol) was studied on bioadhesive films based on sodium alginate (SA), carboxymethyl cellulose (CMC) and gelatin (GE) polymers loaded with amphotericin B (AmB). The main objective of the current study was to assess the morphological, mechanical, thermal, optical, and barrier properties of the films as a function of glycerol (Gly) concentration (0.5-1.5 %) using different techniques such as Scanning Electron Microscope (SEM), Texture analyzer (TA), Differential Scanning Calorimeter (DSC), X-Ray Diffraction (XRD), and Fourier Transforms Infrared Spectroscopy (FTIR). The concentration increase of glycerol resulted in an increase in Water Vapor Permeability (WVP) (0.187-0.334), elongation at break (EAB) (0.88-35.48 %), thickness (0.032-0.065 mm) and moisture level (17.5-41.76 %) whereas opacity, tensile strength (TS) (16.81-0.86 MPa), and young's modulus (YM) (0.194-0.002 MPa) values decreased. Glycerol incorporation in the film-Forming solution decreased the brittleness and fragility of the films. Fourier Transform Infrared (FTIR) spectra showed that intermolecular hydrogen bonding occurred between glycerol and polymers in plasticized films compared to control films. Furthermore, molecular docking was applied to predict the binding interactions betweem AmB, CMC, gelatin, SA and glycerol, which further endorsed the stabilizing effects of glycerol in the complex formation between AmB, CMC, SA, and gelatin. The Findings of the current study demonstrated that this polymeric blend could be used to successfully prepare bioadhesive films with glycerol as a plasticizer., Competing Interests: The authors declare no financial interests/personal relationships which may be considered as potential competing interests., (© 2024 The Authors.)

Theoretical research on the keto-enol tautomerization of 2-(2-Hydroxyphenyl)-1-aza azulene (2HPhAZ) and its thiol-thione (2MPhAZ) analouge has been performed using the density functional B3LYP method with the 6-311 +  + G(2d,2p) basis set in gas and ethanol phases. The findings of the MO computation on the energy scale and the prediction of the frontier molecular orbital (FMO) energies demonstrate that the tautomeric structures exist in a static mixture in the ground state, with the enol and thiol structure being more stable than the keto and thione structures in gas phase. The ethanol solvent causes some reordering of the relative stability of 2HPhAZ and 2MPhAZ conformers. The geometries created at the B3LYP/6-311 +  + G(2d,2p) level of theory were used for NBO analysis. In the tautomerization of 2HPhAZ and its mercapto analogue 2-(2-Mercaptophenyl)-1-azaazulene (2MPhAZ), it has been found that the O(S)-C sigma bond is weak due to n O(S) -> σ* C25-O26(S26) and n O(S) -> σ* C15-N16 delocalization. It is also noted that the resulting p character of the corresponding oxygen (sulfur) natural hybrid orbital (NHO) of σ O(S)-C bond orbital is related to the decreased occupancy of the localized σ O(S)-C orbital in the idealized Lewis structure or the increased occupancy of σ* O(S)-C of the non-Lewis orbital and their subsequent impact on molecular stability and geometry (bond lengths) in gas phase and ethanol. Additionally, the energy of charge transfer decreases as the potential rotamers' Hammett constants (R1-R3 for O(S) atoms) increase. The partial charge distribution on the skeleton atoms demonstrates that the intra- and intermolecular interactions can be significantly influenced by the electrostatic attraction or repulsion between atoms. Lastly, the currently applied NBO-based HB strength indicator enables a fair prediction of the frequency of the proton donor NH stretching mode, but this simple picture is hidden by abundant hype conjugative effects., (© 2024. The Author(s).)

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, 1 HNMR, 13 CNMR, 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 (IC 50 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" (IC 50  = 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., 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. Published by Elsevier B.V.)

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., Methods: 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, and QTME-12 exhibited significant anti-proliferative capability with IC 50 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 (IC 50 = 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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)