Carbonylbis(hydrazine-1-carbothioamide) derivatives as a new class of α-glucosidase inhibitors and their mechanistic insights via molecular docking and dynamic simulations.

In the past, efforts have been made to find a cure for diabetes, mainly evaluating new classes of compounds to explore their potency. In this study, we present the synthesis and evaluation of carbonylbis(hydrazine-1-carbothioamide) derivatives as potential α-glucosidase inhibitors, employing both in vivo and in silico investigations. The in vitro experiments revealed that all tested compounds were significantly potent for α-glucosidase inhibition, with the lead compound 3a displaying approximately 80 times higher activity than acarbose. To delve deeper, in silico induced fit docking, pharmacokinetics, and molecular dynamics studies were conducted. Significantly, compound 3a exhibited a docking score of -7.87 kcal/mol, surpassing acarbose, which had a docking score of -6.59 kcal/mol. The in silico ADMET indicated that most of the synthesized compounds have properties conducive to drug development. Molecular dynamics analysis demonstrated that, when the ligand 3a was coupled with the target 3TOP, Cα-RMSD backbone RMSD values below 2.4 Å and "Lig_fit_Prot" values below 2.7 Å were observed. QSAR analysis demonstrates that the "fOC8A" descriptor positively correlates with α-glucosidase inhibition activity, while "lipoplus_AbSA" positively contributes and "notringC_notringO_8B" negatively contributes to this activity.

Synthesis of 3-hydroxy-2-naphthohydrazide-based hydrazones and their implications in diabetic management via in vitro and in silico approaches.

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 IC50 in a range of 2.80-29.66 µM as compared with the commercially available inhibitor, acarbose (IC50 = 873.34 ± 1.67 M). Compound 3h showed the highest inhibitory potential with an IC50 value of 2.80 ± 0.03 µM, followed by 3i (IC50 = 4.13 ± 0.06 µM), 3f (IC50 = 5.18 ± 0.10 µM), 3c (IC50 = 5.42 ± 0.11 µM), 3g (IC50 = 6.17 ± 0.15 µM), 3d (IC50 = 6.76 ± 0.20 µM), 3a (IC50 = 9.59 ± 0.14 µM), and 3n (IC50 = 10.01 ± 0.42 µM). Kinetics analysis of the most potent compound 3h revealed a concentration-dependent form of inhibition by 3h with Ki 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.

Synthesis of the chromone-thiosemicarbazone scaffold as promising α-glucosidase inhibitors: An in vitro and in silico approach toward antidiabetic drug design.

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 µM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 µM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.

Synthesis, biological evaluation and molecular modelling of 3-Formyl-6-isopropylchromone derived thiosemicarbazones as α-glucosidase inhibitors.

Type-2 Diabetes Mellitus (T2DM) is one of the most common metabolic disorders in the world and over the past three decades its incidence has increased drastically. α-Glucosidase inhibitors are used to control the hyperglycemic affect of T2DM. Herein, we report the synthesis, α-glucosidase inhibition, structure activity relationship, pharmacokinetics and docking analysis of various novel chromone based thiosemicarbazones 3(a-r). The derivatives displayed potent activity against α-glucosidase with IC50 in range of 0.11 ± 0.01-79.37 ± 0.71 µM. Among all the synthesized compounds, 3a (IC50 = 0.17 ± 0.026 µM), 3 g (IC50 = 0.11 ± 0.01 µM), 3n (IC50 = 0.55 ± 0.02 µM), and 3p (IC50 = 0.43 ± 0.025 µM) displayed higher inhibitory activity as compared to the standard, acarbose. Moreover, we have developed a statistically significant 2D-QSAR model (R2tr:0.9693; F: 50.4647 and Q2LOO:0.9190), which can be used in future to further design potent thiosemicarbazones as inhibitors of α-glucosidase.

Synthesis of new phenoxymethylcoumarin clubbed 4-arylthiazolylhydrazines as α-glucosidase inhibitors and their kinetics and molecular docking studies.

The current studies mainly demonstrate the coumarin based azomethine-clubbed thiazoles synthesis and their in-vitro evaluation for the first time against α-glucosidase. Due to the catalytic role of α-glucosidase, it has become a precise target for the treatment of type diabetes mellitus (T2DM). The high rate of prevalence of diabetes and its associated health related problems led us to scrutinize the anti-diabetic capability of the synthesized thiazole derivatives (6a-6k). The anticipated structures of prepared compounds were confirmed through FT-IR and NMR spectroscopic methods. All the compounds showed several times potent activity than the standard drug, acarbose (IC50 = 873.34 ± 1.67 µM) against α-glucosidase with IC50 values in range of 0.87 ± 0.02-322.61 ± 1.14 µM. The compound 6k displayed the highest anti-diabetic activity (IC50 = 1.88 ± 0.03 µM). Kinetic study revealed that these are competitive inhibitors for α-glucosidase. The mode of binding of the synthesized molecules were further evaluated by molecular docking, which reflects the importance of azomethine group in protein-ligand interaction. The docking scores are complementary with the IC50 values of compounds while the interaction pattern of the compounds clearly demonstrates their structure-activity relationship. Current study reported medicinal importance of thiazole derivative as future drug candidates for the management of Type 2 Diabetes Mellitus (T2DM).

Synthesis, biological evaluation, and molecular docking study of chromen-linked hydrazine carbothioamides as potent α-glucosidase inhibitors.

Inhibiting α-glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Several novel chromen-linked hydrazine carbothioamide (3a-r) were designed and synthesized by condensation of chromone-3-carbaldehyde with a variety of substituted thiosemicarbazides. The structures of these new analogues were elucidated through various advanced spectroscopic techniques (1 H NMR, 13 C NMR, and ESI-MS). The resulted compounds were screened for α-glucosidase inhibitory potential and all the compounds (3a-r) exhibited potent inhibition of α-glucosidase with IC50 values ranging 0.29-53.70 µM. Among them compounds 3c, 3f, 3h, and 3r displayed the highest α-glucosidase inhibitor capability with IC50 values of 1.50, 1.28, 1.08, and 0.29 µM, respectively. Structure-activity relationship showed that different substituted groups are responsible for the variation in the α-glucosidase inhibition. The kinetics studies of the most active inhibitor (3r) were performed, to investigate the mode of inhibition and dissociation constants (Ki), that indicated a competitive inhibitor with Ki value of 1.47 ± 0.31 µM. Furthermore, molecular docking studies was performed to reveal the possible interactions, such as H-bonding, or π-π stacking, with the key residues of α-glucosidase. Docking analysis revealed the importance of hydrazine carbothioamide moiety of compounds in the attachment of ligands with the crucial residues of α-glucosidase. The estimated pharmacokinetic, physicochemical, and drug likeness properties of compounds 3a-r reflects that these molecules have acceptable range of these properties.

Synthesis of new clioquinol derivatives as potent α-glucosidase inhibitors; molecular docking, kinetic and structure-activity relationship studies.

Diabetes mellitus is a chronic metabolic disorder with increasing prevalence and long-term complications. The aim of this study was to identify α-glucosidase inhibitory compounds with potential anti-hyperglycemic activity. For this purpose, a series of new clioquinol derivatives 2a-11a was synthesized, and characterized by various spectroscopic techniques. The enzyme inhibitory activities of the resulting derivatives were assessed using an in-vitro mechanism-based assay. All the tested compounds 2a-11a of the series showed a significant α-glucosidase inhibition with IC50 values 43.86-325.81 µM, as compared to the standard drug acarbose 1C50: 875.75 ± 2.08 µM. Among them, compounds 4a, 5a, 10a, and 11a showed IC50 values of 105.51 ± 2.41, 119.24 ± 2.37, 99.15 ± 2.06, and 43.86 ± 2.71 µM, respectively. Kinetic study of the active analogues showed competitive, non-competitive, and mixed-type inhibitions. Furthermore, the molecular docking study was performed to elucidate the binding interactions of most active analogues with the various sites of α-glucosidase enzyme. The results indicate that these compounds have the potential to be further studied as new anti-diabetic agents.

Novel Bis-Schiff's base derivatives of 4-nitroacetophenone as potent α-glucosidase agents: Design, synthesis and in silico approach.

Bis-Schiff's base derivatives of 4-nitroacetophenone (1-18) were synthesized in good yields by reacting hydrazone of 4-nitroacetophenone with substituted aldehydes and ketones with catalytic amount of acetic acid. The structures of synthesized products (1-18) were deduced with the help of spectroscopic techniques like 1H NMR, 13C NMR and HR-ESIMS. The synthesized bis-Schiff's bases were assessed for their α-glucosidase inhibitory activity where compound 4 (IC50 = 2.79 ± 0.04 µM), 1 (IC50 = 9.76 ± 0.31 µM), 6 (IC50 = 11.37 ± 0.20 µM), 17 (IC50 = 14.10 ± 0.12 µM), 14 (IC50 = 17.21 ± 0.28 µM), and 8 (IC50 = 20.73 ± 0.53 µM), showed a very high potential for inhibition of α-glucosidase. Compounds 11, 15, 16, 2, 18, 7, and 5 showed significant inhibition against alpha-glucosidase with IC50 values 22.98 ± 0.34, 24.45 ± 0.53, 27.31 ± 0.29, 40.56 ± 0.60, 41.58 ± 0.47, 46.53 ± 0.76, and 47.46 ± 0.89 µM, respectively. Furthermore, compound 10 (IC50 = 52.63 ± 0.74 µM), 12 (IC50 = 70.80 ± 3.59 µM), 3 (IC50 = 82.68 ± 0.69 µM), 13 (IC50 = 88.89 ± 4.25 µM), and 9 (IC50 = 94.58 ± 0.86 µM) showed moderate activity towards the inhibition of α-glucosidase enzyme. All these compounds were compared with acarbose (IC50 = 875.75 ± 1.24 µM) as a standard α-glucosidase inhibitor. Molecular docking was used to know the molecular bases of such high activities against α-glucosidase. High docking scores were recorded implying significant interactions between the active compounds and amino acid residues of the active site of α-glucosidase.

Synthesis of 1,2,3,triazole modified analogues of hydrochlorothiazide via click chemistry approach and in-vitro α-glucosidase enzyme inhibition studies.

The current study was aimed to discover potent inhibitors of α-glucosidase enzyme. A 25 membered library of new 1,2,3-triazole derivatives of hydrochlorothiazide (1) (HCTZ, a diuretic drug also being used for the treatment of high blood pressure) was synthesized through click chemistry approach. The structures of all derivatives 2-26 were deduced by MS, IR, 1H-NMR, and 13C-NMR spectroscopic techniques. All the compounds were found to be new. Compounds 1-26 were evaluated for α-glucosidase enzyme inhibition activity. Among them, 18 compounds showed potent inhibitory activity against α-glucosidase with IC50 values between 24 and 379 µM. α-Glucosidase inhibitor drug acarbose (IC50 = 875.75 ± 2.08 µM) was used as the standard. Kinetics studies of compounds 6, 9, 11, 12, 15, 20, 23, and 24 revealed that only compound 15 as a mixed-type of inhibitor, while others were non-competitive inhibitors of α-glucosidase enzyme. All the compounds were found to be non-cytotoxic when checked against mouse fibroblast 3T3 cell line.

Identification of α-Glucosidase Inhibitors from Scutellaria edelbergii: ESI-LC-MS and Computational Approach.

The recent study investigated the in vitro anti-diabetic impact of the crude extract (MeOH) and subfractions ethyl acetate (EtOAc); chloroform; n-butanol; n-hexane; and aqueous fraction of S. edelbergii and processed the active EtOAc fraction for the identification of chemical constituents for the first time via ESI-LC-MS analysis through positive ionization mode (PIM) and negative ionization mode (NIM); the identified compounds were further validated through computational analysis via standard approaches. The crude extract and subfractions presented appreciable activity against the α-glucosidase inhibitory assay. However, the EtOAc fraction with IC50 = 0.14 ± 0.06 µg/mL revealed the maximum potential among the fractions used, followed by the MeOH and n-hexane extract with IC50 = 1.47 ± 0.14 and 2.18 ± 0.30 µg/mL, respectively. Moreover, the acarbose showed an IC50 = 377.26 ± 1.20 µg/ mL whereas the least inhibition was observed for the chloroform fraction, with an IC50 = 23.97 ± 0.14 µg/mL. Due to the significance of the EtOAc fraction, when profiled for its chemical constituents, it presented 16 compounds among which the flavonoid class was dominant, and offered eight compounds, of which six were identified in NIM, and two compounds in PIM. Moreover, five terpenoids were identified-three and two in NIM and PIM, respectively-as well as two alkaloids, both of which were detected in PIM. The EtOAc fraction also contained one phenol that was noticed in PIM. The detected flavonoids, terpenoids, alkaloids, and phenols are well-known for their diverse biomedical applications. The potent EtOAc fraction was submitted to computational analysis for further validation of α-glucosidase significance to profile the responsible compounds. The pharmacokinetic estimations and protein-ligand molecular docking results with the support of molecular dynamic simulation trajectories at 100 ns suggested that two bioactive compounds-dihydrocatalpol and leucosceptoside A-from the EtOAc fraction presented excellent drug-like properties and stable conformations; hence, these bioactive compounds could be potential inhibitors of alpha-glucosidase enzyme based on intermolecular interactions with significant residues, docking score, and binding free energy estimation. The stated findings reflect that S. edelbergii is a rich source of bioactive compounds offering potential cures for diabetes mellitus; in particular, dihydrocatalpol and leucosceptoside A could be excellent therapeutic options for the progress of novel drugs to overcome diabetes mellitus.

Aroma Profile and Biological Effects of Ochradenus arabicus Essential Oils: A Comparative Study of Stem, Flowers, and Leaves.

The present analysis explores the chemical constituents and determines the in vitro antimicrobial, antidiabetic, and antioxidant significance of the essential oils (EOs) of the stem, leaves, and flowers of Ochradenus arabicus for the first time. The EOs of the flowers presented seventy-four constituents contributing to 81.46% of the total EOs, with the major compounds being 24-norursa-3,12-diene (13.06%), 24-norursa-3,12-dien-11-one (6.61%), and 24-noroleana-3,12-diene (6.25%). The stem EOs with sixty-one compounds contributed 95.95% of the total oil, whose main bioactive compounds were (+)-camphene (21.50%), eremophilene (5.87%), and δ-selinene (5.03%), while a minimum of fifty-one compounds in the leaves' EOs (98.75%) were found, with the main constituents being n-hexadecanoic acid (12.32%), octacosane (8.62%), tetradecanoic acid (8.54%), and prehydro fersenyl acetone (7.27%). The antimicrobial activity of the EOs of O. arabicus stem, leaves, and flowers was assessed against two bacterial strains (Escherichia coli and Streptococcus aureus) and two fungal strains (Penicillium simplicissimum and Rhizoctonia solani) via the disc diffusion assay. However, the EOs extracted from the stem were found effective against one bacterial strain, E. coli, and one fungal strain, R. Solani, among the examined microbes in comparison to the standard and negative control. The tested EOs samples of the O. arabicus stem displayed a maximum potential to cure diabetes with an IC50 = 0.40 ± 0.10 µg/mL, followed by leaves and flowers with an IC50 = 0.71 ± 0.11 µg/mL and IC50 = 10.57 ± 0.18 µg/mL, respectively, as compared to the standard acarbose (IC50 = 377.26 ± 1.20 µg/mL). In addition, the EOs of O. arabicus flowers had the highest antioxidant activity (IC50 = 106.40 ± 0.19 µg/mL) as compared to the standard ascorbic acid (IC50 = 73.20 ± 0.17 µg/mL) using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. In the ABTS assay, the EOs of the same sample (flower) depicted the utmost potential to scavenge the free radicals with an IC50 = 178.0 ± 0.14 µg/mL as compared with the ascorbic acid, having an IC50 of 87.34 ± 0.10 µg/mL the using 2,2-Azino-Bis-3-Ethylbenzothiazoline-6-Sulfonic acid (ABTS) assay. The EOs of all parts of O. arabicus have useful bioactive components due to which they present antidiabetic and antioxidant significance. Furthermore, additional investigations are considered necessary to expose the responsible components of the examined biological capabilities, which would be effective in the production of innovative drugs.

Dibenzazepine-linked isoxazoles: New and potent class of α-glucosidase inhibitors.

α-Glucosidase inhibition is a valid approach for controlling hyperglycemia in diabetes. In the current study, new molecules as a hybrid of isoxazole and dibenzazepine scaffolds were designed, based on their literature as antidiabetic agents. For this, a series of dibenzazepine-linked isoxazoles (33-54) was prepared using Nitrile oxide-Alkyne cycloaddition (NOAC) reaction, and evaluated for their α-glucosidase inhibitory activities to explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against α-glucosidase (EC 3.2.1.20) enzyme (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 µM) using acarbose as a reference drug (IC50 = 875.75 ± 2.08 µM). Structure-activity relationship, kinetics and molecular docking studies of active isoxazoles were also determined to study enzyme-inhibitor interactions. Compounds 33, 40, 41, 46, 48-50, and 54 showed binding interactions with critical amino acid residues of α-glucosidase enzyme, such as Lys156, Ser157, Asp242, and Gln353.

Synthesis, crystal structure and Hirshfeld Surface analysis of benzamide derivatives of thiourea as potent inhibitors of α-glucosidase in-vitro.

Benzamide based structural analogues 1-15 were synthesized, and evaluated for α-glucosidase inhibition activity in vitro for the first time. Compounds 1-9 were found to be known, while compounds 10-15 were found to be new. However, to the best of our knowledge we are reporting α-glucosidase inhibitory activity of these bezamide derivatives of thiourea for the first time. Compounds 1, 3, 6-8, 10-14 were found to be potent inhibitors of α-glucosidase within IC50 range of 20.44-333.41 µM, in comparison to the standard inhibitor, acarbose (IC50 = 875.75 ± 2.08 µM). Mode of the enzyme inhibition was determined on the basis of kinetic studies which demonstrated that compounds 8, and 10 were non-competitive and competitive inhibitors of α-glucosidase enzyme, respectively. These compounds were also evaluated for their DPPH radical scavenging activity, and cytotoxicity against 3T3 mouse fibroblast cell lines. All synthesized compounds showed a significant to moderate DPPH radical scavenging activity and appeared to be non-cytotoxic except compound 9 which showed cytotoxicity against 3T3 normal mouse fibroblast cell lines. A single crystal X-ray and Hirshfeld Surface analysis of a representative compound is also presented.

Celebrex derivatives: Synthesis, α-glucosidase inhibition, crystal structures and molecular docking studies.

Celebrex (1), commonly used as an anti-inflammatory drug, was functionalized (compounds 2-9) to identify new α-glucosidase inhibitors. Initially, all the synthesized derivatives were evaluated for anti-inflammatory activity but none was found to be active. Subsequently a random biological screening was carried out. Interestingly many of them were found to be potent α-glucosidase inhibitors in vitro. All the structures of synthesized derivatives were deduced through 1H NMR, FAB-MS, HR-MS, FT-IR analysis. The single-crystal X-ray structures of compounds 1, and 5 further confirmed the assigned structures. Compounds exhibited a potent α-glucosidase inhibitory activity (IC50 = 92.32 ± 1.530-445.20 ± 1.04 µM) against tested standard acarbose (IC50 = 875.75 ± 2.08 µM), except compounds 2 and 4, which appeared as inactive. Among them, compound 9 (IC50 = 92.32 ± 1.530 µM) was the most potent inhibitor of α-glucosidase enzyme. Molecular docking studies revealed that compounds 6, and 9 interacted with the key amino acid residues of α-glucosidase via H-bonding, and π-π stacking interactions. α-Glucosidase is a key target for the anti-diabetic drug development, and its inhibitors are known to exert anti hyperglycemic effect and help in lowering of post-prandial blood glucose levels.

GC-MS Analysis and Biomedical Therapy of Oil from n-Hexane Fraction of Scutellaria edelbergii Rech. f.: In Vitro, In Vivo, and In Silico Approach.

The current study aimed to explore the crude oils obtained from the n-hexane fraction of Scutellaria edelbergii and further analyzed, for the first time, for their chemical composition, in vitro antibacterial, antifungal, antioxidant, antidiabetic, and in vivo anti-inflammatory, and analgesic activities. For the phytochemical composition, the oils proceeded to gas chromatography-mass spectrometry (GC-MS) analysis and from the resultant chromatogram, 42 bioactive constituents were identified. Among them, the major components were linoleic acid ethyl ester (19.67%) followed by ethyl oleate (18.45%), linolenic acid methyl ester (11.67%), and palmitic acid ethyl ester (11.01%). Tetrazolium 96-well plate MTT assay and agar-well diffusion methods were used to evaluate the isolated oil for its minimum inhibitory concentrations (MIC), minimum bactericidal concentration (MBC), half-maximal inhibitory concentrations (IC50), and zone of inhibitions that could determine the potential antimicrobial efficacy's. Substantial antibacterial activities were observed against the clinical isolates comprising of three Gram-negative bacteria, viz., Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, and one Gram-positive bacterial strain, Enterococcus faecalis. The oils were also effective against Candida albicans and Fusarium oxysporum when evaluated for their antifungal potential. Moreover, significant antioxidant potential with IC50 values of 136.4 and 161.5 µg/mL for extracted oil was evaluated through DPPH (1,1-Diphenyl-2-picryl-hydrazyl) and ABTS assays compared with standard ascorbic acid where the IC50 values were 44.49 and 67.78 µg/mL, respectively, against the tested free radicals. The oils was also potent, inhibiting the α-glucosidase (IC50 5.45 ± 0.42 µg/mL) enzyme compared to the standard. Anti-glucosidase potential was visualized through molecular docking simulations where ten compounds of the oil were found to be the leading inhibitors of the selected enzyme based on interactions, binding energy, and binding affinity. The oil was found to be an effective anti-inflammatory (61%) agent compared with diclofenac sodium (70.92%) via the carrageenan-induced assay. An appreciable (48.28%) analgesic activity in correlation with the standard aspirin was observed through the acetic acid-induced writhing bioassay. The oil from the n-hexane fraction of S. edelbergii contained valuable bioactive constituents that can act as in vitro biological and in vivo pharmacological agents. However, further studies are needed to uncover individual responsible compounds of the observed biological potentials which would be helpful in devising novel drugs.

Nondestructive Inspection of Reinforced Concrete Utility Poles with ISOMAP and Random Forest.

Reinforced concrete poles are very popular in transmission lines due to their economic efficiency. However, these poles have structural safety issues in their service terms that are caused by cracks, corrosion, deterioration, and short-circuiting of internal reinforcing steel wires. Therefore, they must be periodically inspected to evaluate their structural safety. There are many methods of performing external inspection after installation at an actual site. However, on-site nondestructive safety inspection of steel reinforcement wires inside poles is very difficult. In this study, we developed an application that classifies the magnetic field signals of multiple channels, as measured from the actual poles. Initially, the signal data were gathered by inserting sensors into the poles, and these data were then used to learn the patterns of safe and damaged features. These features were then processed with the isometric feature mapping (ISOMAP) dimensionality reduction algorithm. Subsequently, the resulting reduced data were processed with a random forest classification algorithm. The proposed method could elucidate whether the internal wires of the poles were broken or not according to actual sensor data. This method can be applied for evaluating the structural integrity of concrete poles in combination with portable devices for signal measurement (under development).

Comparison of permeatal medial placement of graft without raising the tympano-meatal flaps to conventional methods of myringoplasty: An experience at tertiary care hospital in Pakistan.

OBJECTIVE: To compare the results of permeatal approach without raising the tympano-meatal flap to end-aural or post-aural approach in myringoplasty. METHODS: This Quasi-experimental study was carried out in CMH (Combined Military Hospital) Peshawar, from August 2006 to July 2013. Three hundred fifty patients of chronic suppurative otitis media (CSOM) with dry central; small, medium and large perforations were selected. They were divided into two groups depending upon the type of approach. In Group-A (n-200); permeatal approach without raising tympano-meatal flap was used; while in Group-B (n-150) end-aural or post-aural approach was used. Subjects were followed up for two years; graft take was checked regularly by examinations of ear under microscope. Data was collected on structured Performa and analysed by SPSS-17. RESULTS: Male and female were 74% and 26% respectively; Age ranged from 15 to 46 Years. There was no significant difference in the graft success at the end of two years in Group-A(80%) and Group-B(85%) (p-0.261). Type of approach had a significant impact on duration of surgery(p<0.001) and post-operative recovery time(p<0.001). CONCLUSION: The permeatal approach and end-aural/post-aural approach had almost equal graft success rates, but former is more useful as it causes lesser morbidity, decreased post-operative hospital stay and reduced operative time. It is under-utilized and should be employed more frequently.

Novel benzimidazole derivatives as effective inhibitors of prolyl oligopeptidase: synthesis, in vitro and in silico analysis.

Background: This research aims to discover novel derivatives having potential therapeutic applications in treating conditions related to prolyl oligopeptidase (POP) dysfunction. Method: Novel benzimidazole derivatives have been synthesized, characterized and screened for their in vitro POP inhibition. Results: All these derivatives showed excellent-to-good inhibitory activities in the range of IC50 values of 3.61 ± 0.15 to 43.72 ± 1.18 µM, when compared with standard Z-prolyl-prolinal. The docking analysis revealed the strong interactions between our compounds and the target enzyme, providing critical insights into their binding affinities and potential implications for drug development. Conclusion: The significance of these compounds in targeting POP enzyme offers promising prospects for future research in the field of neuropharmacology.

Targeting papain-like protease by natural products as novel therapeutic potential SARS-CoV-2.

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.

Biochemical and computational inhibition of α-glucosidase by novel metronidazole-linked 1H-1,2,3-triazole and carboxylate moieties: kinetics and dynamic investigations.

In the current study, metronidazole derivatives containing 1H-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 IC50 values in range of 9.73-56.39 µM, as compared to marketed drug acarbose (IC50 = 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.