Using pollen DNA metabarcoding to trace the geographical and botanical origin of honey from Karangasem, Indonesia.

The unique floral fingerprint embedded within honey holds valuable clues to its geographical and botanical origin, playing a crucial role in ensuring authenticity and detecting adulteration. Honey from native Apis cerana and Heterotrigona itama bees in Karangasem, Indonesia, was examined utilizing pollen DNA metabarcoding for honey source identification. In this study, we used ITS2 amplicon sequencing to identify floral DNA in honey samples. The finding reveals distinct pollen signatures for each bee species. Results analysis showed A. cerana honey generated 179,267 sequence reads, assembled into Amplicon Sequence Variants (ASVs) with a total size of 485,932 bp and an average GC content of 59 %. H. itama honey generated 177,864 sequence reads, assembled into ASVs with a total size of 350,604 bp and an average GC content of 57 %. A. cerana honey exhibited a rich tapestry of pollen from eleven diverse genera, with Schleichera genus dominating at an impressive relative read abundance of 72.8 %. In contrast, H. itama honey displayed a remarkable mono-dominance of the Syzygium genus, accounting for a staggering 99.95 % of its pollen composition or relative read abundance, highlighting their distinct foraging preferences and floral resource utilization. Notably, all identified pollen taxa were indigenous to Karangasem, solidifying the geographical link between honey and its origin. This study demonstrates pollen DNA metabarcoding may identify honey floral sources. By using pollen profiles from different bee species and their foraging patterns, we may protect consumers against honey adulteration and promote sustainable beekeeping in Karangasem district. Future research could explore expanding the database of reference pollen sequences and investigating the influence of environmental factors on pollen composition in honey. Investigating this technology's economic and social effects on beekeepers and consumers may help promote fair trade and sustainable beekeeping worldwide.

The first ITS1 profiling of honey samples from the Southeast Asian region Lombok, Bali and Banggi Island.

Southern Asian flowers offer honeybees a diversity of nectar. Based on its geographical origin, honey quality varies. Traditional methods are less authentic than DNA-based identification. The origin of honey is determined by pollen, polyphenolic, and macro-microorganisms. In this study, amplicon sequencing targets macro-microorganisms in eDNA using the ITS1 region to explore honey's geographical location and authentication. The variety of honey samples was investigated using ITS1 with Illumina sequencing. For all four honey samples, raw sequence reads showed 979,380 raw ITS1 amplicon reads and 375 ASVs up to the phylum level. The highest total number of 202 ASVs up to phylum level identified Bali honey with 211,189 reads, followed by Banggi honey with 309,207 a total number of 111 ASVs, and Lombok represents only 63 ASVs up to phylum level with several read 458,984. Based on Shannon and Chao1, honey samples from Bali (B2) and (B3) exhibited higher diversity than honey from Lombok (B1) and green honey from Sabah (B4), while the Simpson index showed that Banggi honey (B4) had higher diversity. Honey samples had significant variance in mycobiome taxonomic composition and abundance. Zygosaccharomyces and Aspergillus were the main genera found in Lombok honey, with percentages of 68.81% and 29.76% respectively. Bali honey samples (B2 and B3) were identified as having a significant amount of the genus Aureobasidium, accounting for 40.81% and 25% of the readings, respectively. The microbiome composition of Banggi honey (B4) showed a high presence of Zygosaccharomyces 45.17% and Aureobasidium 35.24%. The ITS1 analysis effectively distinguishes between honey samples of different origins and its potential as a discriminatory tool for honey origin and authentication purposes.

Design, synthesis, molecular docking study, and α-glucosidase inhibitory evaluation of novel hydrazide-hydrazone derivatives of 3,4-dihydroxyphenylacetic acid.

A series of novel Schiff base derivatives (1-28) of 3,4-dihydroxyphenylacetic acid were synthesized in a multi-step reaction. All the synthesized Schiff bases were obtained in high yields and their structures were determined by 1HNMR, 13CNMR, and HR-ESI-MS spectroscopy. Except for compounds 22, 26, 27, and 28, all derivatives show excellent to moderate α-glucosidase inhibition. Compounds 5 (IC50 = 12.84 ± 0.52 µM), 4 (IC50 = 13.64 ± 0.58 µM), 12 (IC50 = 15.73 ± 0.71 µM), 13 (IC50 = 16.62 ± 0.47 µM), 15 (IC50 = 17.40 ± 0.74 µM), 3 (IC50 = 18.45 ± 1.21 µM), 7 (IC50 = 19.68 ± 0.82 µM), and 2 (IC50 = 20.35 ± 1.27 µM) shows outstanding inhibition as compared to standard acarbose (IC50 = 873.34 ± 1.67 µM). Furthermore, a docking study was performed to find out the interaction between the enzyme and the most active compounds. With this research work, 3,4-dihydroxyphenylacetic acid Schiff base derivatives have been introduced as a potential class of α-glucosidase inhibitors that have remained elusive till now.

Structural, dynamic behaviour, in-vitro and computational investigations of Schiff's bases of 1,3-diphenyl urea derivatives against SARS-CoV-2 spike protein.

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.

Synthesis of hydrazone-based polyhydroquinoline derivatives - antibacterial activities, α-glucosidase inhibitory capability, and DFT study.

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 (1H-NMR, 13C 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 (IC50 = 5.31 ± 0.25 µM) in vitro, followed by compounds 10 (IC50 = 6.70 ± 0.38 µM), and 12 (IC50 = 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.

Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study.

A serine protease called prolyl endopeptidase (PEP) hydrolyses the peptide bonds on the carboxy side of the proline ring. The excessive PEP expression in brain results in neurodegenerative illnesses like dementia, Alzheimer's disease, and Parkinson's disease. Results of the prior studies on antioxidant activity, and the non-cytotoxic effect of bi-carbazole-linked triazoles, encouraged us to extend our studies towards its anti-diabetic potential. Hence, for this purpose all compounds 1-9 were evaluated to reveal their anti-prolyl endo peptidase activity. Fortunately, seven compounds resulted into significant inhibitory capability ranging from 26 to 63 µM. Among them six compounds 4-9 exhibited more potent inhibitory activity with IC50 values 46.10 ± 1.16, 42.30 ± 1.18, 37.14 ± 1.21, 26.29 ± 0.76, 28.31 ± 0.64 and 31.11 ± 0.84 µM respectively, while compound 3 was the least active compound in the series with IC50 value 63.10 ± 1.58 µM comparing with standard PEP inhibitor bacitracin (IC50 = 125 ± 1.50 µM). Moreover, mechanistic study was performed for the most active compounds 7 and 8 with Ki values 24.10 ± 0.0076 and 23.67 ± 0.0084 µM respectively. Further, the in silico studies suggested that the compounds exhibited potential interactions and significant molecular conformations, thereby elucidating the structural basis for their inhibitory effects.

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

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

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.

Discovery of Novel Natural Inhibitors Against SARS-CoV-2 Main Protease: A Rational Approach to Antiviral Therapeutics.

BACKGROUND/AIM: The global pandemic caused by the novel SARS-CoV-2 virus underscores the urgent need for therapeutic interventions. Targeting the virus's main protease (Mpro), crucial for viral replication, is a promising strategy. OBJECTIVE: The current study aims to discover novel inhibitors of Mpro. METHODS: The current study identified five natural compounds (myrrhanol B (C1), myrrhanone B (C2), catechin (C3), quercetin (C4), and feralolide (C5) with strong inhibitory potential against Mpro through virtual screening and computational methods, predicting their binding efficiencies and validated it using the in-vitro inhibition activity. The selected compound's toxicity was examined using the MTT assay on a human BJ cell line. RESULTS: Compound C1 exhibited the highest binding affinity, with a docking score of -9.82 kcal/mol and strong hydrogen bond interactions within Mpro's active site. A microscale molecular dynamics simulation confirmed the stability and tight fit of the compounds in the protein's active pocket, showing superior binding interactions. in vitro assays validated their inhibitory effects, with C1 having the most significant potency (IC50 = 2.85 µM). The non-toxic nature of these compounds in human BJ cell lines was also confirmed, advocating their safety profile. CONCLUSION: These findings highlight the effectiveness of combining computational and experimental approaches to identify potential lead compounds for SARS-CoV-2, with C1-C5 emerging as promising candidates for further drug development against this virus.

Physicochemical and antioxidant properties of Apis cerana honey from Lombok and Bali Islands.

Limited honey production worldwide leads to higher market prices, thus making it prone to adulteration. Therefore, regular physicochemical analysis is imperative for ensuring authenticity and safety. This study describes the physicochemical and antioxidant properties of Apis cerana honey sourced from the islands of Lombok and Bali, showing their unique regional traits. A comparative analysis was conducted on honey samples from Lombok and Bali as well as honey variety from Malaysia. Moisture content was found slightly above 20% in raw honey samples from Lombok and Bali, adhering to the national standard (SNI 8664:2018) of not exceeding 22%. Both honey types displayed pH values within the acceptable range (3.40-6.10), ensuring favorable conditions for long-term storage. However, Lombok honey exhibited higher free acidity (78.5±2.14 meq/kg) than Bali honey (76.0±1.14 meq/kg), surpassing Codex Alimentarius recommendations (≤50 meq/kg). The ash content, reflective of inorganic mineral composition, was notably lower in Lombok (0.21±0.02 g/100) and Bali honey (0.14±0.01 g/100) compared to Tualang honey (1.3±0.02 g/100). Electric conductivity, indicative of mineral content, revealed Lombok and Bali honey with lower but comparable values than Tualang honey. Hydroxymethylfurfural (HMF) concentrations in Lombok (14.4±0.11 mg/kg) and Bali (17.6±0.25 mg/kg) were slightly elevated compared to Tualang honey (6.4±0.11 mg/kg), suggesting potential processing-related changes. Sugar analysis revealed Lombok honey with the highest sucrose content (2.39±0.01g/100g) and Bali honey with the highest total sugar content (75.21±0.11 g/100g). Both honeys exhibited lower glucose than fructose content, aligning with Codex Alimentarius guidelines. The phenolic content, flavonoids, and antioxidant activity were significantly higher in Lombok and Bali honey compared to Tualang honey, suggesting potential health benefits. Further analysis by LC-MS/MS-QTOF targeted analysis identified various flavonoids/flavanols and polyphenolic/phenolic acid compounds in Lombok and Bali honey. The study marks the importance of characterizing the unique composition of honey from different regions, ensuring quality and authenticity in the honey industry.

Synthesis of novel hydrazide Schiff bases with anti-diabetic and anti-hyperlipidemic effects: in-vitro, in-vivo and in-silico approaches.

The increasing global incidence of non-insulin-dependent diabetes mellitus (NIDDM) necessitates innovative therapeutic solutions. This study focuses on the design, synthesis and biological evaluation of Schiff base derivatives from 2-bromo-2-(2-chlorophenyl) acetic acid, particularly hydrazone compounds 4a and 4b. Both in-vitro and in-vivo assays demonstrate these derivatives' strong antidiabetic and anti-hyperlipidemic properties. In a 15-d experiment, we administered 4a and 4b at doses of 2.5 and 5 mg/kg body weight, which effectively improved symptoms of alloxan-induced diabetes in mice. These symptoms included weight loss, increased water consumption and high blood glucose levels. The compounds also normalized abnormal levels of total cholesterol (TC), triacylglycerol (TG) and low-density lipoprotein cholesterol (LDL-C), while raising the levels of high-density lipoprotein cholesterol (HDLC). Computational analysis showed that these compounds effectively inhibited the α-glucosidase enzyme by interacting with key catalytic residues, specifically Asp214 and Asp349. These computational results were confirmed through in-vitro tests, where 4a and 4b showed strong α-glucosidase inhibitory activity, with IC50 values of 0.70 ± 0.11 and 10.29 ± 0.30 µM, respectively. These compounds were more effective than the standard drug, acarbose, which had an IC50 value of 873.34 ± 1.67 µM. Mechanistic studies further indicated competitive inhibition, reinforcing the therapeutic potential of 4a and 4b for NIDDM treatment.Communicated by Ramaswamy H. Sarma.

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.

Identification of new pharmacophore against SARS-CoV-2 spike protein by multi-fold computational and biochemical techniques.

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 ΔGTOTAL 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.

Baseline amplicon sequencing data for the ITS2 region in the green honey of Banggi Island, Sabah.

Green honey, was discovered on Banggi Island, Sabah, showing high in essential amino acids and chlorophyll derivatives. Despite its lucrative market potential owing to its distinctive color, uncertainties persist regarding its nature. This study leverages amplicon sequencing by targeting micro- and macro-organisms present in honey environmental DNA (eDNA) using Internal Transcribed Spacer 2 (ITS2) region, enabling the identification of floral and microorganism sources that represent the honey's composition. The investigation into green honey from Banggi Island concerns the prevalence of honey adulteration and authenticity for economic gain. Adulteration methods, such as the addition of sugar syrups, compromise honey purity. Using a sequencing approach would help in determining the geographic origin and verifying the authenticity of the honey. The study aims to identify plant species or microorganisms in honey's eDNA. To authenticate honey, we utilized ITS2 with Illumina sequencing, exploring the diversity of green honey samples. Raw sequence reads obtained for the green honey sample revealed 1,438,627 raw reads, with a GC average of 49.22 %. A total of 44 amplicon sequence variances (ASVs) were identified, including three genera: Zygosaccharomyces with two species, Fraxinus with three species, and the genus Ficaria with only one species. Their respective relative abundances were 98.55%, 0.94%, and 0.51%. Zygosaccharomyces rouxii and Zygosaccharomyces mellis were identified as the pre-dominant yeast species in honey, while the Fraxinus and Ficaria genus represent common plant species in Sabah, particularly in Banggi Island. The dominance of Zygosaccharomyces species aligns with their known prevalence in honey, affirming the reliability of our findings. The presence of Fraxinus and Ficaria in the honey sample correlates with its abundance in the local environment. This amplicon sequencing approach not only contributes to our understanding of green honey composition but also serves as a valuable resource for authenticating honey origin in Malaysia, particularly for green honey from Banggi Island, Sabah. Our study pioneers the application of ITS2 amplicon sequencing for green honey amplicon sequencing, providing valuable insights into its composition and origin. This methodology, with a focus on eDNA, contributes to the authentication and quality determination of honey in Malaysia, addressing the pressing concerns of adulteration and variability in production practices.

Green honey of Banggi Island: A preliminary anti-diabetic study on zebrafish model.

Zebrafish is a developing vertebrate model with several advantages, including its small size, and high experimental efficiency. Malaysia exhibit one of the highest diabetes rates in the Western Pacific and incurring an annual cost of 600 million US dollars. The objective of the study is to determine the antidiabetic properties of green honey (GH) using a zebrafish model. Adult zebrafish, aged 3-4 months, were subjected to overfeeding and treated with streptozotocin (STZ) through intraperitoneal injection (IP) on days 7 and 9. The study assessed the oral sucrose tolerance test (OSTT) and the anti-diabetic effects of green honey. The evaluation was conducted at three time points: 30, 60, and 120 min after treatment and sucrose administration. The study utilised a model with a sample size of 5. The study was performed in six groups. These groups are (1) Normal control (non-diabetic, no intervention), (2) Normal control + GH (non-diabetic, supplemented with GH 3 µl), (3) DM control (diabetic, no intervention), (4) DM Gp1 (diabetic, 3 µL GH), (5) DM Gp2 (diabetic, 6 µ L GH), (6) DM Acarbose (diabetic, treated with acarbose). Fasting blood glucose levels for non-diabetic (non-DM) and diabetic (DM) groups were evaluated before and after the 10 days of diabetic induction. DM groups (excess of food and two injections of STZ) have caused a significant increment in the fasting blood glucose to 11.55 mmol/l (p < 0.0001). Both GH treatments effectively decreased postprandial blood glucose levels and the area under the curve in the oral glucose tolerance test (OSTT). Based on these results, it is concluded that green honey could play a role in hyperglycemia management and show potential as a natural alternative to conventional diabetes therapy. The underlying mechanisms need to be clarified, and their potential use in human diabetes therapy needs to be investigated.

Novel hydrazone schiff's base derivatives of polyhydroquinoline: synthesis, in vitro prolyl oligopeptidase inhibitory activity and their Molecular docking study.

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,1H- and 13C-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 IC50 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.

Synthesis of new bis(dimethylamino)benzophenone hydrazone for diabetic management: In-vitro and in-silico approach.

Inhibiting α-glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Bis(dimethylamino)benzophenone derivatives 1-27 were synthesized from bis(dimethylamino)benzophenone via two-step reaction. Different spectroscopic techniques, including EI-MS and 1H NMR, were employed to characterize all synthetic derivatives. The elemental composition of synthetic compounds was confirmed by elemental analysis and results were found in agreement with the calculated values. The synthetic compounds 1-27 were evaluated for α-glucosidase inhibitory activity, except five compounds all derivatives showed good to moderate inhibitory potential in the range of IC50 = 0.28 ± 2.65 - 0.94 ± 2.20 µM. Among them, the most active compounds were 5, 8, 9, and 12 with IC50 values of 0.29 ± 4.63, 0.29 ± 0.93, 0.28 ± 3.65, and 0.28 ± 2.65, respectively. Furthermore, all these compounds were found to be non-toxic on human fibroblast cell lines (BJ cell lines). Kinetics study of compounds 8 and 9 revealed competitive type of inhibition with Ki values 2.79 ± 0.011 and 3.64 ± 0.012 µM, respectively. The binding interactions of synthetic compounds were also confirmed through molecular docking studies that indicated that compounds fit well in the active site of enzyme. Furthermore, a total of 30ns MD simulation was carried out for the most potent complexes of the series. The molecular dynamics study revealed that compound-8 and compound-12 were stable during the MD simulation.

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.

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.

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.