Molecular Diversity最新文献

In this study, one-pot multicomponent reactions of novel chromeno[2,3-c]pyrazole derivatives (1-14) were performed using an AlCl₃ catalyst via cyclisation. Various spectral and chromatographic techniques were used to elucidate the structure of the synthesised derivatives (1-14). The synthesised compounds were then inspected for their antibacterial, antioxidant, and tyrosinase inhibition activities. An in silico screening approach was also employed to identify highly potent derivatives. Besides, we utilised density functional theory (DFT) with the B3LYP/6-31G⁺ (d, p) basis set to optimise the newly modified derivatives. This approach was used to calculate various properties, including electron density, electrostatic potential map, interaction strength, frontier molecular orbital energy, and reactivity characteristics. To examine the binding affinity, modes, and stability of the protein-drug complex, molecular docking with the 2Y9X protein structure were employed. The findings from DFT computations, along with physicochemical information and molecular docking binding affinity, showed promising results than standard and low active compound 1. The absorption, metabolism, and cytotoxic characteristics of all the novel derivatives were investigated in the ADMET prediction. Our findings could prove valuable in developing novel drugs for medicinal and pharmaceutical fields.

To overcome T790M mutation, a novel series of 4-indazolypyrimidine derivatives were developed as novel EGFR inhibitors employing a scaffold hopping drug design strategy. The biological activities of the target compounds were evaluated against two tumor cell lines (A431 and NCI-H1975), normal cell 2BS and EGFR^T790M/L858R kinase. The results indicated that the majority of the compounds exhibited promising antitumor activity and low toxicity. Specifically, compounds 4e and 4s displayed the highest efficacy, with IC₅₀ values of 0.55 μM and 0.47 μM, respectively. Moreover, compounds 4e and 4s demonstrated exceptional activity against EGFR^T790M/L858R, with IC₅₀ values of 12.04 and 28.79 nM. Additionally, further studies revealed that compounds 4e and 4s could induce apoptosis in NCI-H1975 cells and arrest the cells in the G2/M phase. Molecular docking studies revealed that compounds 4e and 4s could interact closely with EGFR. These findings lay the groundwork for further investigation of compounds 4e and 4s as potential EGFR inhibitors.

Hydrophobicity is crucial for the interaction between amphipathic antimicrobial peptides and microbial pathogens. However, it is difficult to fully understand the impact of this factor because the biological functions are also influenced by other structural properties, including peptide length, net charge, hydrophilicity, secondary structure, and hydrophobic moment. This study compares three natural antimicrobial peptides-mastoparan C, mastoparan-AF, and mastoparan L-where hydrophobicity varies but other structural features remain nearly identical. Mastoparan C, the most hydrophobic peptide, displays the highest helical content and hemolytic activity, whereas mastoparan-AF, with slightly lower hydrophobicity, demonstrates superior selectivity. In contrast, mastoparan L, the least hydrophobic peptide, exhibits the weakest antimicrobial potency and lowest hemolytic activity, despite showing the least self-assembly. Overall, this study suggests that optimal hydrophobicity, rather than the highest value, enhances antimicrobial efficacy while minimizing hemolytic activity.

HMGB1 mediated signalling pathway plays an important role in acute injury and fibrosis in lung tissues. Glycyrrhizic acid (GL) is a HMGB1 inhibitor, and its aglycone (glycyrrhetinic acid, GA) is the major pharmacophore and plays the main role during binding to HMGB1. To improve selectivity for these lung diseases, a series of novel glycyrrhetinic acid glycosides targeting mannose acceptors in the respiratory tract and lung tissues were synthesised, and their biological activities were evaluated in vitro and in vivo. For normal lung cell lines WI-38 and Beas-2B, all the compounds but c6 showed reduced cytotoxicity vs the positive controls (GA and GL), IC₅₀ values were > 800 µM. For three cancer cells, c1 exhibited high selectivity for lung cancer cells A549. In the inflammation assays, compound c1 displayed the strongest activity of NO inhibition, and c4 was next; both them not only down-regulated the expression levels of IL-1β and TNF-α in RAW264.7 cells, but also decreased the levels of TNF-α, IL-1β, HMGB1, RAGE and ROS in A549 cells in a dose-dependent manner. Noteworthy, compound c1 of 50 μM reduced the levels of HMGB1 and RAGE to 38.4 and 37.0% of the LPS group, and it showed much higher binding affinity with HMGB1 than GL, which confirmed by molecular docking; in addition, c1 also inhibited the deposition of α-SMA and Col-1 proteins in TGF-β1-activated A549 cells. In the bleomycin-induced lung fibrosis mouse model, c1 decreased fibrous protein production and deposition in the lung tissues; at a 30 mg/kg dose, it reduced the levels of α-SMA and Col-1 to 48.12 and 56.37% of the BLM group, respectively. The pharmacokinetics tests showed c1 relative distribution rate in lung tissue (at 1 h, 18.86%; at 2 h, 12.80%) is much higher than that of GA (at 1 h, 2.8%; at 2 h, 1.9%). These results show compound c1 is likely to be a candidate for acute lung injury and pulmonary fibrosis.

A series of chalcone derivatives containing 1,2,4-triazole and pyridine were designed and synthesized, and their antiviral activities against tobacco mosaic virus (TMV) were evaluated. Notably, S7 (EC₅₀ = 89.7 μg/mL) exhibited excellent curative activity against the TMV, which was superior to that of ningnanmycin (NNM: EC₅₀ = 201.7 μg/mL). Molecular docking showed that S7 exhibited satisfactory affinities for the TMV coat protein (TMV-CP), with four strong conventional hydrogen bonds with amino acid residues. Further, microscale thermophoresis (MST) showed that S7 (Kd = 0.5340 ± 0.2233 μmol/L) bound more strongly to TMV-CP than NNM (Kd = 5.1186 ± 1.9568 μmol/L). The results of chlorophyll content, malondialdehyde (MDA) content, and biological enzyme activity confirmed that S7 enhanced the disease resistance of tobacco plants by affecting the change of chlorophyll content, interfering with plant lipid peroxidation, and enhancing SOD activity in plants, respectively.

In the past, mechanochemical approaches in organic synthesis were largely overlooked, but their perception within the synthetic community has shifted in recent years, marking a trend toward becoming mainstream. Mechanochemical multicomponent organic synthesis has garnered significant interest from both the academic and industrial chemical sectors. The efficiency and environmental friendliness of procedures conducted through mechanical activation have established mechanical procedures as prominent green techniques. Notably, utilizing solid starting materials under mechanochemical conditions empowers the development of novel multicomponent reactions that are often unfeasible in traditional solution-based processes. This capability not only enhances the diversity of accessible organic compounds but also sparks new avenues for innovative synthetic strategies. This approach facilitates the effective fulfillment of sustainable chemistry goals. In this context, we emphasize the major progress and advancements in mechanochemical multicomponent reactions from 2017 to 2024. This article covers the foremost multicomponent mechanosynthesis for developing organic molecules through carbon-carbon and carbon-heteroatom coupling reactions and multicomponent mechanosynthesis for monocyclic and fused heterocycles.

The aberrant expression of proviral integration site for Moloney murine leukemia virus (PIM) kinases is closely related to various tumors and chemotherapy resistance, making them attractive targets for cancer therapy. However, due to the extremely high homology among the three PIM isoforms (PIM1, PIM2, PIM3) and the limited availability of existing bioactivity data, screening and designing selective PIM inhibitors remain a daunting challenge. To address this issue, this study constructed a multitask regression model that can simultaneously predict the half-maximal inhibitory concentration (IC₅₀ values). The model utilizes an attention mechanism to capture effects within local atomic groups and the interactions between different groups of atoms. Through weight sharing, the model enhances the accuracy of predicting PIM3 inhibitors by leveraging the rich and highly correlated data from PIM1 and PIM2 isoforms. Additionally, visualizing the weights of nodes (atoms in the molecule) in the model helps us to intuitively understand the relationship between molecular features and prediction outcomes, thereby enhancing the interpretability of the model. In summary, this work provides new insights and methods for performing activity prediction tasks for multiple similar targets in low-data scenarios.

Deep learning-based generative adversarial network (GAN) frameworks have recently been developed to expedite the drug discovery process. These models generate novel molecules from scratch and validate them through molecular docking simulation to identify the most promising candidates for a given drug target. In this study, the SARS-CoV-2 main protease (M^pro) was selected as the drug target. Two distinct GAN algorithms were employed to generate novel small molecules. One approach utilized experimental electron density (ED-based) data of ligands for training to generate drug-like molecules, while the second approach leveraged the target binding pocket to capture spatial and bonding relationship between atoms within the binding pockets. The ED-based approach generated approximately 26,000 molecules, whereas the binding pocket-based method produced around 100 molecules. These generated molecules were subsequently ranked based on molecular docking results using the glide XP score (both flexible and rigid docking) and AutoDock Vina. To identify the most potent GAN-derived molecules, molecular docking was also performed on co-crystallized inhibitor molecules of M^pro. The six most promising molecules from these GAN approaches were further evaluated for stability, interactions, and MM-GBSA binding free energy through molecular dynamics simulations. This analysis led to the identification of four potent M^pro inhibitor molecules, all featuring a 2-benzyl-6-bromophenol scaffold. The binding free energies of these compounds were compared with those of other M^pro inhibitors, revealing that our compounds demonstrated better affinity for M^pro than some broad-spectrum protease inhibitors. The dynamic cross-correlation matrix plot indicated strongly correlated and anti-correlated regions, potentially linked to ligand binding.

HtrA protein is a member of a serine protease family with dual functions as a protease and molecular chaperone. It is a virulence factor in many bacteria, including the food-borne pathogen Listeria monocytogenes (Lm), which induces listeriosis in humans. Hence, inhibitors of LmHtrA protease have great importance in the control of infection. Many natural compounds have been used in the inhibition studies of proteases; here, we have performed the inhibition studies of LmHtrA with 31 compounds from different origins. The spectrophotometric assays revealed that plant compounds are promising inhibitors of LmHtrA protease activity compared to other tested peptides and synthetic compounds. The green tea catechin, EGCG has been identified as an inhibitor of protease activity of LmHtrA with a low IC₅₀ value of 0.754 ± 0.2 μM. The substrate cleavage analysis by SDS-PAGE and SPR experiments corroborates the spectrophotometric results by exhibiting protease inhibition and showing the micromolar affinity of EGCG with LmHtrA, respectively. The interaction between rLmHtrA and EGCG was investigated by fluorescence spectroscopy. The binding constant and the number of binding sites were determined as 1.86 × 10⁽⁵⁾ M^(-1) and 1.2, respectively. The molecular docking and dynamics results of LmHtrA-inhibitor complexes have provided new insights into the inhibition mechanism of LmHtrA compared with other serine proteases. The findings of this study may open up new avenues for the development of natural compound-based derivatives of LmHtrA inhibitors that might be more potent and less harmful to humans.

The tumor microenvironment and immune evasion function in a complex cellular network profoundly challenge the clinical outcome of promising therapies. Our recently published study reported that the subset of genes upregulated in ccRCC due to H3K4me1 and DNA demethylation potentially leads to an immunosuppressive environment. Thus, modulating H3K4me1 chromatin modifier SETD7 with a natural inhibitor in combination with immunotherapy might improve the immune landscape for a better therapeutic outcome. The present study was conducted via virtual screening and MD simulation using compounds from the literature, IMPPAT, and SuperNatural database. The phytochemical IMPHY002979 showed better binding affinity and lower energy than the reported R-PFI-2 and cyproheptadine inhibitors. The phytochemicals interact with the SET domain through H-bonding, as confirmed by MD simulation and molecular interaction analysis. Further, the compound was assessed using ADME parameters and free energy estimation, showing better pharmacokinetic properties. Therefore, the non-accessibility of the histone methyltransferase activity domain of SET7 with IMPHY002979 can downregulate H3K4me1 and, thereby, the expression of genes potentially responsible for immunosuppressive TME. Thus, patient stratification based on molecular markers for immunotherapy and combining epigenetic modulators with therapeutic drugs will improve the efficacy of immunotherapy in ccRCC.