Molecular Diversity最新文献

Obesity is widely recognized as a major public health issue and is one of the leading causes of death worldwide. Overweight and obesity are prominent lifestyle ailments that not only give rise to additional health issues but also play a role in the development of other chronic diseases, such as cancer, diabetes, metabolic syndrome, and cardiovascular diseases. Orlistat is now the only pharmaceutical drug for the management of obesity. However, prolonged use of orlistat has been associated with detrimental consequences, hence necessitating the development of a new drug with reduced or no adverse reactions. Pancreatic Lipase is a critical enzyme in lipid metabolism. Using naturally occurring compounds as PL inhibitors has garnered significant attention because of their diverse structure and low toxicity. The present work investigates the inhibitory action of flavonoids on PL using in silico and in vitro methods. Thirteen flavonoid derivatives and orlistat were docked with PL. The ADME properties of the flavonoid derivatives were studied, and most of the compounds are in admire range. The stability of the best-docked complexes was checked by REMD. The in silico study demonstrated favorable inhibitory activity of flavonoids compared to orlistat. Consequently, an enzyme inhibitory experiment was conducted to authenticate the in silico results. The lipase inhibitory activity was assessed by using p-nitrophenyl butyrate as the substrate. Kaempferol exhibited significant inhibitory activity against PL, as shown by its IC₅₀ value of 72.7 ± 3 µM. This study proposed a natural drug candidate with promising inhibitory efficacy against PL for obesity.

In screening for natural-derived fungicides, a series of 32 novel tetrahydroisoquinoline derivatives were designed and synthesized based on tetrahydroisoquinoline alkaloids. Their structures were verified by ¹H NMR, ¹³C NMR, HRMS, and single X-ray crystal diffraction analysis. Most of the target products exhibited medium to excellent antifungal activity against 6 phytopathogenic fungi in vitro at a concentration of 50 mg/L. Interestingly, compounds A13 and A25 with EC₅₀ values of 2.375 and 2.251 mg/L against A. alternate were similar to boscalid (EC₅₀ = 1.195 mg/L). The in vivo experiments revealed that A13 presented 51.61 and 70.97% protection activities against A. alternate at the dosage of 50 and 100 mg/L, respectively, which were equal to that of boscalid (64.52 and 77.42%). SDH enzyme assays and molecular docking studies indicated that compound A13 may act on SDH. In addition, the SEM analysis showed that compound A13 could strongly damage the mycelium morphology. These results revealed that A13 may be a promising lead compound for the development of natural-derived fungicides.

The emergence of new SARS-CoV-2 variants with a higher contagious capability and faster transmissible speed has imposed an incessant menace on global health and the economy. The SARS-CoV-2 infection might reoccur and last much longer than expected. Thence, there is a high possibility that COVID-19 can cause long-term health problems. This condition needs to be investigated thoroughly, especially the post-COVID-19 complications. Respiratory tract disorders are common and typical complications after recovery. Until now, there has been a lack of data on specialized therapeutic medicine for post-COVID-19 complications. The clinical efficacy of NRICM101 has been demonstrated in hospitalized COVID-19 patients. This herbal medicine may also be a promising therapy for post-COVID-19 complications, thanks to its phytochemical constituents. The potential pharmacological mechanisms of NRICM101 in treating post-COVID-19 respiratory complications were investigated using network pharmacology combined with molecular docking, and the results revealed that NRICM101 may exert a beneficial effect through the three primary pathways: PI3K/AKT, HIF-1, and TNF signaling pathways. Flavonoids (especially quercetin) have a predominant role and synergize with other active compounds to produce therapeutic effectiveness. Most of the main active compounds exist in three chief herbal ingredients, including Liquorice root (Glycyrrhiza glabra), Scutellaria root (Scutellaria baicalensis), and Mulberry leaf (Morus alba). To our knowledge, this is the first study of the NRICM101 effect on post-COVID-19 respiratory complications. Our findings may provide a better understanding of the potential mechanisms of NRICM101 in treating SARS-CoV-2 infection and regulating the immunoinflammatory response to improve post-COVID-19 respiratory complications.

The SARS-CoV-2 outbreak highlights the persistent vulnerability of humanity to epidemics and emerging microbial threats, emphasizing the lack of time to develop disease-specific treatments. Therefore, it appears beneficial to utilize existing resources and therapies. Computational drug repositioning is an effective strategy that redirects authorized drugs to new therapeutic purposes. This strategy holds significant promise for newly emerging diseases, as drug discovery is a lengthy and expensive process. Through this study, we present an ensemble method based on the convolutional neural network integrated with genetic algorithm and deep forest classifier for virus-drug association prediction (CGDVDA). We generated feature vectors by combining drug chemical structure and virus genomic sequence-based similarities, and extracted prominent deep features by applying the convolutional neural network. The convoluted features are optimized using the genetic algorithm and classified using the ensemble deep forest classifier to predict novel virus-drug associations. The proposed method predicts drugs for COVID-19 and other viral diseases in the dataset. The model could achieve ROC-AUC scores of 0.9159 on fivefold cross-validation. We compared the performance of the model with state-of-the-art approaches and classifiers. The experimental results and case studies illustrate the efficacy of CGDVDA in predicting drugs against viral infectious diseases.

A novel series of 7-(trifluoromethyl)indolizine derivatives (4a-4n) was synthesized using a 1,3-Dipolar cycloaddition reaction. Structure elucidation of the synthesized compounds was done using various spectroscopic techniques. Compounds were assessed for their larvicidal activity against Anopheles arabiensis. Exposure of Anopheles arabiensis larvae to a series of 7-(trifluoromethyl)indolizine at 4 µg/mL for 24 and 48 h resulted in moderate to high larval mortality rates. Among them, compounds 4b, 4a, 4g, and 4m exhibited the most promising larvicidal activities, with mortality rates of 94.4%, 93.3%, 80.00%, and 85.6%, respectively, compared to controls, Acetone and Temephos. The structural activity relationship analysis of the evaluated compounds revealed that substitution with halogens or electron-withdrawing groups (CN, F, Cl, Br) at the para position of the benzoyl group is crucial for achieving promising larvicidal activity. Molecular docking studies were carried out involving six potential larvicidal target proteins to predict how the tested compounds might work. Compounds 4a and 4b showed strong binding to the Mosquito Juvenile Hormone-Binding Protein (5V13). Molecular dynamics (MD) simulations confirmed the stability of the protein-ligand complexes over the simulation period, reinforcing the reliability of the docking results. Compounds 4a and 4b also exhibited favourable ADMET profiles, showing high oral bioavailability, good permeability, moderate distribution, low plasma protein binding, sufficient metabolic stability, efficient renal clearance and low toxicity. Given the crucial role of Juvenile Hormone in regulating gene expression and developmental pathways through receptor interactions, compounds 4a and 4b show promise as inhibitors of this protein. Inhibiting this process could hinder larval growth and reproduction, presenting a promising approach for early-stage mosquito larvicidal activity. Therefore, compounds 4a and 4b represent lead candidates for further optimization and the development of new larvicidal agents.

Alzheimer's disease (AD) is the most common form of dementia and the fifth leading cause of death globally. Aggregation and deposition of neurotoxic Aβ fibrils in the neural tissues of the brain is a key hallmark in AD pathogenesis. Destabilisation studies of the amyloid-peptide by various natural molecules are highly relevant due to their neuroprotective and therapeutic potential for AD. We performed molecular dynamics (MD) simulation to investigate the destabilisation mechanism of amyloidogenic protofilament intermediate by Baicalein (BCL), a naturally occurring flavonoid. We found that the BCL molecule formed strong hydrophobic contacts with non-polar residues, specifically F19, A21, V24, and I32 of Chain A and B of the pentameric protofibril. Upon binding, it competed with the native hydrophobic contacts of the Aβ protein. BCL loosened the tight packing of the hydrophobic core by disrupting the hydrogen bonds and the prominent D23-K28 inter-chain salt bridges of the protofibril. The decrease in the structural stability of Aβ protofibrils was confirmed by the increased RMSD, radius of gyration, solvent accessible surface area (SASA), and reduced β-sheet content. PCA indicated that the presence of the BCL molecule intensified protofibril motions, particularly affecting residues in Chain A and B regions. Our findings propose that BCL would be a potent destabiliser of Aβ protofilament, and may be considered as a therapeutic agent in treating AD.

Developing new fungicides to compensate for the deficiencies of existing fungicides resistance in phytopathogenic fungi is a research hotspot in the field of pesticides. Aiming to discover novel template small molecules with excellent antifungal activity, thirty-eight arylthiazolamine derivatives were synthesized through bromination, cyclization, halogenation, and acylation reactions. The synthesized compounds were screened for antifungal activity against ten typical fungal pathogens, and some halogenated arylthiazolamines and amides exhibited excellent broad-spectrum antifungal activity, especially compounds 4m (3.96-47.76 μg/mL), 5k (0.10-7.70 μg/mL) and 5n (2.08-11.21 μg/mL). Among them, compound 5k provided comparable protection and curative effects to chloroticonil and boscalid against B. dothidea and V. mali infection in apple and apple tree branches, respectively, and it could exert antifungal effects by inhibiting the differentiation of mycelium spores, spore germination, and bud tube growth. This study provides high-efficiency and inexpensive candidate compounds for managing of diseases caused by plant pathogenic fungi.

Alzheimer's disease (AD) is a multifactorial neurological disorder that involves multiple enzymes in the process of developing. Conventional monotherapies provide relief, necessitating alternative multi-targeting approaches to address AD complexity. Therefore, we synthesize N-(benzo[d]thiazol-2-yl) benzamide-based compounds and tested against monoamine oxidases (MAO-A and MAO-B). In the in vitro experimental evaluation of MAO, all the compounds displayed remarkable potency, having IC₅₀ values in the lower micromolar range. The most potent MAO-A inhibitor was (3e) with an IC₅₀ value of 0.92 ± 0.09 μM, whereas, (3d) was the most potent inhibitor of MAO-B with an IC₅₀ value of 0.48 ± 0.04 μM. Moreover, Enzyme kinetics studies revealed that the potent inhibitors of MAO-A and MAO-B showed competitive mode of inhibition. Furthermore, molecular docking studies were also performed to confirm the mode of inhibition and obtain an intuitive picture of potent inhibitors. It also revealed several important interactions, particularly hydrogen bonding interaction. All the newly synthesized compounds showed good ADME pharmacokinetic profile and followed Lipinski rule; these compounds represent promising hits for the development of promising lead compounds for AD treatment.

Qiling Baitouweng Tang (QLBTWT) is a traditional clinical formula for treating diffuse large B-cell lymphoma (DLBCL), but its molecular action is not fully understood. This research is utilized in silico analysis and liquid chromatography tandem mass spectrometry (LC‒MS/MS) to identify the active constituents of QLBTWT with anti-DLBCL properties and their targets. The study identified 14 compounds, including quercetin, naringenin, and astilbin, as potentially effective against DLBCL. Molecular modeling highlighted the favorable interaction of quercetin with the JAK2 protein. In vitro studies confirmed the ability of quercetin to inhibit DLBCL cell growth and migration while inducing apoptosis and causing G2/M phase cell cycle arrest. Molecular dynamics simulations revealed that quercetin binds to JAK2 as a type II inhibitor. In vivo studies in U2932 xenograft models demonstrated that QLBTWT inhibited tumor growth in a dose-dependent manner, which was associated with the JAK2/STAT3 signaling pathway. Overall, this study elucidates the therapeutic effect of QLBTWT on DLBCL through quercetin-mediated suppression of the JAK2/STAT3 pathway, offering novel therapeutic insights for DLBCL.

We report the synthesis and extensive characterization of Diazepane and Oxazepane derivatives, followed by their biological evaluation. These compounds were assessed for in vitro and in vivo antimicrobial, anti-inflammatory, and anticancer activities. Among the synthesized molecules, compound 5b demonstrated remarkable antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis with MIC values of 20 and 40 μg/mL, respectively. Additionally, 5b exhibited potent anti-inflammatory effects both in vitro and in vivo. Advanced computational studies, including DFT, MEP, RDG, and ELF analyses, were performed to understand the electronic distribution and molecular interactions. The bioactivity and physicochemical properties of these derivatives were further predicted using PASS and pkCSM platforms, emphasizing their potential as promising lead molecules in drug development.