Mallotus nanus, a traditional Vietnamese medicinal plant, was investigated as a potential source of bioactive phenolic exhibiting acetylcholinesterase (AChE) inhibition and antioxidant properties by using combined in vitro and in silico approaches. Ethanolic extracts from the leaf, stem, and root were tested for antioxidant capacity (DPPH, ABTS, and FRAP assays) and AChE inhibition (Ellman's method). Among them, the leaf extract showed the highest activity, with moderate AChE inhibition (IC50 = 409.45 +/- 5.22 & micro;g/mL) and notable antioxidant capacity (DPPH IC50 = 68.23 +/- 0.34 & micro;g/mL; ABTS IC50 = 44.06 +/- 0.34 & micro;g/mL). UHPLC analysis identified eight major phenolic constituents, seven reported for the first time in M. nanus, including gallic acid, catechin, epigallocatechin gallate (EGCG), caffeine, rutin, ellagic acid, and quercetin. Molecular docking suggested favorable binding of rutin and EGCG to AChE, with rutin (A5; CNN affinity: 6.56) showing a higher docking score than the reference inhibitor donepezil (E2020). Molecular dynamics simulation (MD) confirmed stable ligand-AChE interactions. These findings indicate that M. nanus leaf extract contains phenolic components with combined antioxidant activity and moderate AChE inhibition, supporting its potential as a natural source of compounds for further fractionation and biological studies related to neurodegenerative disorders.

Alzheimer’s disease is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction and neuroinflammation. Dual inhibition of acetylcholinesterase and monoacylglycerol lipase has emerged as a promising therapeutic approach. This study employed an integrative in silico workflow to identify potential dual acetylcholinesterase/monoacylglycerol lipase inhibitors from a molecular library derived from known inhibitors (rivastigmine, JZL-184, ABX-1431). A total of 365 compounds were screened via molecular docking, interaction-based filtering, ADME/toxicity prediction, and molecular dynamics simulations. Among them, compound H34 demonstrated a comparatively favorable overall computational profile, supported by MM/GBSA binding-energy estimates (ΔGbind = − 30.96 and − 37.34 kcal/mol) and comparatively favorable structural stability metrics (RMSD, RMSF, Rg, and SASA) in the MD simulations. Further ProLIF interaction mapping and free energy landscape analysis supported the persistent interaction profile and conformational behavior of the H34-protein complexes. Additionally, H34 displayed favorable pharmacokinetic properties and low predicted acute toxicity. These results highlight H34 as a promising dual-target candidate for Alzheimer’s disease therapy and illustrate the effectiveness of integrated computational strategies in early-stage drug discovery.

para-Menthane-3,8-diol (PMD) is a widely used bio-based insect repellent. However, its conventional synthesis is limited by protracted reaction times. Herein, we report an ultrasound-assisted Prins cyclization of citronellal, a monoterpenoid aldehyde, to PMD under 20 kHz irradiation. Using pure citronellal, ultrasound irradiation at 40% amplitude (∼48 µm) afforded PMD with 98% GC-FID purity within 2 h, compared with 87% PMD obtained after 10 h under conventional heating. Even at 100% amplitude (∼120 µm), the reaction proceeded within 10 min while maintaining a high PMD content of approximately 93%. For lemon eucalyptus (Eucalyptus citriodora) oil, ultrasound irradiation at 40-60% amplitude (∼48-72 µm) reduced reaction times from 15 h to 0.5-2.0 h while providing PMD contents comparable to those obtained by conventional heating. Notably, crystallization from the natural oil feedstock increased the cis-isomer content to 90%, compared with 65% obtained from pure citronellal. The observed cis stereoselectivity is proposed to arise from steric effects associated with the 3-methyl substituent of citronellal during intramolecular cyclization. Density functional theory calculations qualitatively support the proposed stereoselective mechanism. These findings provide an efficient approach for the synthesis and purification of PMD while offering mechanistic insights into stereochemical control in Prins cyclization reactions.

Background: Monoacylglycerol lipase (MAGL) is a key enzyme in the endocannabinoid system, involved in multiple physiological and neurological processes. Developing MAGL inhibitors from semi-synthetic flavonoid scaffolds such as apigenin carbamates offers a promising approach. Objectives: To evaluate the MAGL inhibitory activity of semi-synthetic apigenin carbamate derivatives using integrated in vitro and in silico approaches. Materials and Methods: Four apigenin carbamate derivatives synthesized from natural apigenin were tested for MAGL inhibition using a 4-nitrophenyl acetate hydrolysis assay. Binding affinity and complex stability were investigated through molecular docking and molecular dynamics simulations. Results: Compounds A1 and A3 demonstrated improved MAGL inhibitory potency (IC50 33.04 and 40.60 µM, respectively) over apigenin, with favorable predicted binding affinities and stable interactions in the enzyme active site. Molecular dynamics simulations indicated that A1 maintained greater conformational stability, whereas A3 formed more frequent hydrogen bond interactions. Conclusion: Apigenin carbamate derivatives, particularly A1 and A3, are promising semi-synthetic leads for MAGL inhibitor development.

INTRODUCTION:Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development. This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone derivatives with varied ring B substituents on mushroom tyrosinase. METHODS:A set of 4,6-dihydroxyaurone derivatives, each with varied substituent patterns on ring B, were designed and subjected to computational studies to predict their binding affinity, binding modes with tyrosinase, and drug-likeness properties. These aurone derivatives were subsequently synthesized and evaluated in vitro for their tyrosinase inhibitory activity. Enzyme kinetics studies were conducted to determine the mode of tyrosinase inhibition. RESULTS:Computational studies of the twenty designed aurone derivatives indicated their strong binding within the active site and exhibited favorable drug-likeness properties. In vitro UV-Vis spectrophotometric assays of the synthesized compounds revealed that compound 5h, featuring a 3,4-dichlorophenyl substituent on ring B, showed the most potent tyrosinase inhibitory activity (IC50 = 6.3 ± 0.3 μM) compared to kojic acid (IC50 = 136.5 ± 11.5 μM). Kinetic studies and molecular docking simulations indicated that compound 5h inhibits tyrosinase through a mixedtype inhibition mechanism, with competitive and uncompetitive inhibition constants of 21 μM and 68 μM, respectively. CONCLUSION:These findings highlight the promising potential of 4,6-dihydroxyaurone derivatives as potent tyrosinase inhibitors for applications in pharmaceuticals, cosmetics, and agriculture.

Molecular hybridization of flavonoids with carbamate moieties led to novel compounds with potent AChE and MAGL inhibition, providing a promising multi-target strategy for Alzheimer's disease treatment.

INTRODUCTION:Chalcone compounds exhibit diverse bioactivities, attracting significant interest. Morpholine is a heterocycle commonly used in medicinal chemistry. It could enhance the potency, pharmacokinetics, and bioactivities of its compounds. METHODS:Adding morpholine into the chalcone scaffold could help create new compounds with favorable bioactivities. In this study, a new parallel synthesis procedure has been developed. Using this procedure, 18 novel morpholinoalkoxychalcones have been successfully synthesized. They had chains with morpholine appended on ring A or ring B. All the synthesized compounds were evaluated for the antibacterial and antifungal activities by agar diffusion method on 5 bacteria and 2 fungi strains. RESULTS:The compounds with good inhibition were determined with respect to the MIC values by the agar dilution method. Among the tested compounds, B.21 was found to be the best against E. faecalis, with an MIC value of 0.6 mM. B.43 with an MIC value of 2.04 mM has displayed its potential in inhibiting A. niger and C. albicans the best among other compounds. CONCLUSION:The in silico study has revealed two targets to align with the in vitro results. Longer alkyl chains have enhanced the activity, along with the presence of OH, NH2, and halogen groups on both rings A and B.

The COVID-19 pandemic posed a threat to global society. Delta and Omicron are concerning variants due to the risk of increasing human-to-human transmissibility and immune evasion. This study aims to evaluate the binding ability of these variants toward the angiotensin-converting enzyme 2 receptor and antibodies using a computational approach. The receptor-binding domain (RBD) of the two variants was created by CHARMM-GUI and then docked to the hACE2 receptor and two antibodies (REGN10933 and REGN10987). These complexes were also subjected to molecular dynamics simulation within 100 ns. As a result, the two variants, Omicron and Delta, exhibited stronger interaction with the hACE2 receptor than the wild type. The mutations in the RBD region also facilitated the virus's escape from antibody neutralization.

Alzheimer’s disease is a complex neurodegenerative disorder characterized by cognitive decline and memory loss, with acetylcholinesterase and monoacylglycerol lipase being two key enzymes involved in its pathogenesis. In this study, a series of carbamoyl flavonoid derivatives were synthesized and evaluated as potential dual inhibitors of acetylcholinesterase and monoacylglycerol lipase. Among them, compound B3 (a baicalein derivative) exhibited the most potent dual inhibition, with IC50 values of 67.95 µM for acetylcholinesterase and 61.28 µM for monoacylglycerol lipase. Molecular docking and molecular dynamics simulations confirmed the strong binding affinity and stability of B3 within the active sites of both enzymes. The MM-GBSA binding free energy analysis revealed ΔGbind values of –31.58 ± 2.24 kcal/mol for acetylcholinesterase and –41.24 ± 2.42 kcal/mol for monoacylglycerol lipase, indicating favorable interactions through hydrogen bonding, π-stacking interactions, and hydrophobic contacts. These findings suggest that carbamoyl flavonoid derivatives, particularly B3, hold promise as multifunctional inhibitors, providing a novel and effective strategy for the treatment of Alzheimer’s disease.

Alzheimer's disease is one of the most common neurodegenerative disorders, where acetylcholinesterase (AChE) and monoacylglycerol lipase (MAGL) play critical roles in its pathophysiology. In this study, six carbamoyl luteolin derivatives were synthesized from luteolin via reactions with carbamoyl chloride reagents, achieving yields ranging from 41% to 64%. The structures of these derivatives were characterized using UV, HRMS, 1 H‐NMR, and 13 C‐NMR spectroscopy. Biological evaluation demonstrated that derivatives L1 (IC 50 = 42.0 μM for AChE, 58.0 μM for MAGL) and L3 (IC 50 = 114.2 μM for AChE, 34.9 μM for MAGL) exhibited significantly enhanced inhibitory activities compared with luteolin. Computational studies, including molecular docking and molecular dynamics simulations, validated the strong binding affinities and stable interactions of L1 and L3 with the enzymes' active sites. These findings suggest that modifying luteolin with carbamate groups can improve enzymatic inhibitory activity, providing a foundation for developing flavone‐based derivatives as potential therapeutic candidates for Alzheimer's disease.

WHO declared the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as a global pandemic (coronavirus disease 2019 (COVID-19)) in March 2020. Molnupiravir (MPV) is an oral antiviral drug that received use authorization for mild to moderate COVID-19 treatment in adults. However, the global and national drug testing and research of MPV is still difficult due to lack of standards and validated procedures. Therefore, this work aims to synthesize the standard substance of two main molnupiravir impurities, N-hydroxycytidine (NHC) and dimethyl dioxol (DMDO), followed by development of a HPLC-photo diode array (PDA) for their simultaneous analysis. The procedure was validated in compliance with the international pharmaceutical analysis guideline (ICH), and employed to test these compounds in molnupiravir on the market. As a result, NHC and DMDO were successfully synthesized by a hydrolysis in an alkaline environment, and acetalization in an acid environment with very high yields of 83.76 and 73.51%, respectively, along with the purities of over 99%. NHC was detected below the allowable threshold whereas DMDO could not be detected in our samples. The findings show the high applicability of our synthesis and determination procedures in the large-scale production and quality control of impurities of commercial molnupiravir medicines.

Diabetes mellitus remains a major global health burden and great attention is directed at natural therapeutics. This systematic review aimed to evaluate the potential of flavonoids as antidiabetic agents through their ability to inhibit α-amylase and α-glucosidase, two key starch digestive enzymes. Six scientific databases were queried up until August 21, 2022, for in vitro studies reporting the IC50 results of purified flavonoids on α-amylase or α-glucosidase, along with the respective data of acarbose control. A total of 339 articles were assessed as eligible and subjected to the data extraction process, resulting in 1643 retrieved flavonoid structures. Chemical structures were then rigorously standardized and curated to 974 unique compounds, in which 177 flavonoids showed both inhibitions against α-amylase and α-glucosidase. Quality assessment was conducted following a modified CONSORT checklist. The structure-activity relationships revealed that a double bond C2=C3 and a keto group C4=O is essential for simultaneous inhibition. The hydroxyl group at C3 is favourable for α-glucosidase inhibition but detrimental to the effect against α-amylase. Further notable features which affect α-glucosidase and α-amylase inhibition were also discussed. Several limitations were considered, including the inconsistency among included studies, language restriction, and the contemporaneity of the review. In conclusion, the systematic review has summarized some crucial findings in the investigation of flavonoids as dual-target inhibitors against α-glucosidase and α-amylase and proposed several orientations for future research.

Aurones are a minor subgroup of flavonoids. Unlike other subgroups such as chalcones, flavones, and isoflavones, aurones have not been extensively explored as pancreatic lipase inhibitors. In this work, we studied the pancreatic lipase inhibitory potency of synthetic aurone derivatives. Thirty-six compounds belonging to four series (4,6-dihydroxyaurone, 6-hydroxyaurone, 4,6-dialkoxyaurone, and 6-alkoxyaurone) were designed and synthesized. Their in vitro inhibitory activities were determined by spectrophotometric assay in comparison with quercetin and orlistat. Alkoxyaurone derivatives with long-chain (6-10 carbons) alkoxy substituents showed greater potency. Of them, 4,6-dialkoxyaurone 8 displayed the highest activity against pancreatic lipase (IC50 of 1.945 +/- 0.520 mu M) relative to quercetin (IC50 of 86.98 +/- 3.859 mu M) and orlistat (IC50 of 0.0334 +/- 0.0015 mu M). Fluorescence quenching measurement confirmed the affinity of alkoxyaurone derivatives to pancreatic lipase. Kinetic study showed that 8 inhibited lipase through a competitive mechanism (Ki of 1.288 +/- 0.282 mu M). Mo-lecular docking results clarified the role of long-chain substituents on ring A in interacting with the hydrophobic pockets and pushing the inhibitor molecule closer to the catalytic triad. The findings in this study may contribute to the development of better pancreatic lipase inhibitors with aurone structure.

The IL-6/IL-6R or IL-6/GP130 protein-protein interactions play a significant role in controlling the development of chronic inflammatory diseases, such as rheumatoid arthritis, Castleman disease, psoriasis, and, most recently, COVID-19. Modulating or antagonizing protein-protein interactions of IL6 binding to its receptors by oral drugs promises similar efficacy to biological therapy in patients, namely monoclonal antibodies. In this study, we used a crystal structure of the Fab part of olokizumab in a complex with IL-6 (PDB ID: 4CNI) to uncover starting points for small molecule IL-6 antagonist discovery. Firstly, a structure‑based pharmacophore model of the protein active site cavity was generated to identify possible candidates, followed by virtual screening with a significant database Drugbank. After the docking protocol validation, a virtual screening by molecular docking was carried out and a total of 11 top hits were reported. Detailed analysis of the best scoring molecules was performed with ADME/T analysis and molecular dynamics simulation. Furthermore, the Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) technique has been utilized to evaluate the free binding energy. Based on the finding, one newly obtained compound in this study, namely DB15187, may serve as a lead compound for the discovery of IL-6 inhibitors.Communicated by Ramaswamy H. Sarma.

IL(interleukin)-6 is a multifunctional cytokine crucial for immunological, hematopoiesis, inflammation, and bone metabolism. Strikingly, IL-6 has been shown to significantly contribute to the initiation of cytokine storm-an acute systemic inflammatory syndrome in Covid-19 patients. Recent study has showed that blocking the IL-6 signaling pathway with an anti-IL-6 receptor monoclonal antibody (mAb) can reduce the severity of COVID-19 symptoms and enhance patient survival. However, the mAb has several drawbacks, such as high cost, potential immunogenicity, and invasive administration due to the large-molecule protein product. Instead, these issues could be mitigated using small molecule IL-6 inhibitors, but none are currently available. This study aimed to discover IL-6 inhibitors based on the PPI with a novel camelid Fab fragment, namely 68F2, in a crystal protein complex structure (PDB ID: 4ZS7). The pharmacophore models and molecular docking were used to screen compounds from DrugBank databases. The oral bioavailability of the top 24 ligands from the screening was predicted by the SwissAMDE tool. Subsequently, the selected molecules from docking and MD simulation illustrated a promising binding affinity in the formation of stable complexes at the active binding pocket of IL-6. Binding energies using the MM-PBSA technique were applied to the top 4 hit compounds. The result indicated that DB08402 and DB12903 could form strong interactions and build stable protein-ligand complexes with IL-6. These potential compounds may serve as a basis for further developing small molecule IL-6 inhibitors in the future.

Alzheimer’s disease (AD) is a neurodegenerative illness that affects the brain and is linked to cognitive decline, memory problems, and behavioral changes. It is highly prevalent in the elderly, with a constantly growing number of new cases worldwide. In affluent nations with aging populations, AD has been a major source of economic and social problems. As a result, the discovery of novel treatment methods for this disease is now crucial. With advances in research on the pathological mechanisms of AD, many new drug targets have been proposed and focused on in-depth investigations. AD has now been identified as a multifactorial disease. Therefore, the goal of therapeutic drug development has largely been directed at acting on multiple therapeutic targets of the disease at the same time. Computational modeling is a potent and robust method in the discovery and development of pharmacological drugs. Recently, this approach has played an increasingly important role in the search for new medications to treat AD. Computational modeling helps conserve experimental resources and dramatically accelerates advances in drug research. In this chapter, various computational modeling methods utilized in designing multi-targeting inhibitors as anti-Alzheimer agents would be described.

Diabetes mellitus is one of the top ten causes of death worldwide, accounting for 6.7 million deaths in 2021, and is one of the most rapidly growing global health emergencies of this century. Although several classes of therapeutic drugs have been invented and applied in clinical practice, diabetes continues to pose a serious and growing threat to public health and places a tremendous burden on those affected and their families. The strategy of reducing carbohydrate digestibility by inhibiting the activities of α-glucosidase and α-amylase is regarded as a promising preventative treatment for type 2 diabetes. In this study, we investigated the dual inhibitory effect against two polysaccharide hydrolytic enzymes of flavonoid derivatives from an in-house chemical database. By combining molecular docking and structure–activity relationship analysis, twelve compounds with docking energies less than or equal to − 8.0 kcal mol−1 and containing required structural features for dual inhibition of the two enzymes were identified and subjected to chemical synthesis and in vitro evaluation. The obtained results showed that five compounds exhibited dual inhibitory effects on the target enzymes with better IC50 values than the approved positive control acarbose. Molecular dynamics simulations were performed to elucidate the binding of these flavonoids to the enzymes. The predicted pharmacokinetic and toxicological properties suggest that these compounds are viable for further development as type 2 diabetes drugs.

AcrAB-TolC tripartite efflux pump, which belongs to the RND superfamily, is a main multi-drug efflux system of Escherichia coli (E. coli) because of the broad resistance on various antibiotics. With the discovering of efflux pump inhibitors (EPIs), a combination between these and antibiotics is one of the most promising therapies. Therefore, building a virtual screening model with prediction capacities for the efflux pump inhibitory activities of candidates from DrugBank and ZINC15 dataset, is one of the key goals of this project. Based on the database of 170 diverse chemical structures collected from 28 research journals, two 2D-QSAR models and a 3D-pharmacophore model have been performed. On the AcrB protein (PDB 4DX7), two binding sites have been discovered that match to the hydrophobic trap in the distal pocket and the switch loop in the proximal pocket. After virtual screening processes, twenty candidate AcrAB-TolC inhibitors have been subjected to molecular dynamics simulations, binding free energy calculations and ADMET predictions. The results indicate that three compounds namely DB09233, DB02581, and DB15224 are potential inhibitors with Delta G(bind) of -42.30 +/- 4.58, -40.76 +/- 7.30 and -31.06 +/- 7.63 kcal.mol(-1), respectively.Communicated by Ramaswamy H. Sarma

Diabetes mellitus is a chronic metabolic disease relating to steady hyperglycemia resulting from the impairment of the endocrine and non-endocrine systems. Many new drugs having varied targets were discovered to treat this disease, especially type 2 diabetes. Among those, α-glucosidase inhibitors showed their effects by preventing the digestion of carbohydrates through their inhibition against α-amylase and α-glucosidase. Recently, chalcones have attracted considerable attention as they have a simple structure, are easily synthesized as well as have a variety of derivatives. Some reports suggested that chalcone and its derivates could inhibit α-amylase and α-glucosidase. This narrative review provides a comprehensive evaluation of the inhibition of chalcone and its derivatives against α-amylase and α-glucosidase that were reviewed and reported in published scientific articles. Twenty-eight articles were reviewed after screening 207 articles found in four databases, including PubMed, Google Scholar, VHL (Virtual Health Library), and GHL (Global Health Library). This review presented the inhibitory effects of varied chalcones, including chalcones with a basic structural framework, azachalcones, bis-chalcones, chalcone oximes, coumarin-chalcones, cyclohexane chalcones, dihydrochalcones, and flavanone-coupled chalcones. Many of these chalcones had significant inhibition against α-amylase as well as α-glucosidase that were comparable to or even stronger than standard inhibitors. This suggested that such compounds could be potential candidates for the discovery of new anti-diabetic remedies in the years to come.