Molecular Diversity最新文献

Factor XIa (FXIa), a key component of the intrinsic coagulation pathway, has recently been recognized as a safe and effective target for antithrombotic therapy. Research indicates that FXIa inhibitors can lower bleeding risk compared to novel oral anticoagulants. In this study, we designed and synthesized a series of novel FXIa inhibitors based on the structure of Asundexian, with a particular focus on optimizing the P2' region to enhance binding to the S2' subsite of FXIa. This strategy led to the discovery of compound F47, which demonstrated significantly greater FXIa inhibition (IC₅₀ = 2.0 nM) compared to Asundexian (IC₅₀ = 5.0 nM). F47 also showed excellent anticoagulant activity in the aPTT assay (EC_2x = 0.4 μM), with strong efficacy and minimal impact on the extrinsic coagulation pathway. Additionally, F47 exhibited inhibitory activity against plasma kallikrein (PKal), with selectivity comparable to that of Asundexian. The compound also displayed acceptable stability in human liver microsomal stability assays. Molecular modeling revealed that F47 binds tightly to the S1, S1', and S2' pockets of FXIa while maintaining key interactions; notably, its P2' moiety forms two additional π-π stacking interactions with the crucial amino acid TYR143. Further studies demonstrated that F47 exhibits dose-dependent antithrombotic efficacy in a rat FeCl₃-induced thrombosis model. Ongoing research aims to further elucidate the potential of compound F47 as a promising lead in antithrombotic therapy.

Escherichia coli (E. coli), a gram-negative bacterium, quickly colonizes in the human gastrointestinal tract after birth and typically sustains a long-term, symbiotic relationship with the host. However, certain virulent strains of E. coli can cause diseases such as urinary tract infections, meningitis, and enteric disorders. The rising antibiotic resistance among these strains has heightened the urgency for an effective vaccine. This study employs immunoinformatics and a reverse vaccinology technique to identify prospective antigens and create an efficient vaccine construct. In this study, we reported the "Attaching and Effacing Protein" a novel outer-membrane protein conserved in all pathogenic E. coli strains, based on proteome screening. We developed an in silico multi-epitope vaccine that includes helper T lymphocyte (HTL), cytotoxic T lymphocyte (CTL), B cell lymphocyte (BCL), and pan HLA DR-binding reactive epitope (PADRE) sequences, along with appropriate linkers and adjuvants. Machine Learning algorithms were used to evaluate antigenicity, solubility, stability, and non-allergenicity of the vaccine construct. Additionally, molecular docking analysis revealed that vaccine construct has a strong predicted binding affinity for human toll-like receptors on the cell surface. In this context, laboratory validations are necessary to demonstrate the effectiveness of the possible vaccine design that showed encouraging findings through computational validation.

The global emergence of New Delhi metallo-β-lactamase-1 (NDM-1) poses a formidable challenge to antibiotic therapy, as it confers resistance to a wide range of β-lactam antibiotics. This study aims to identify potential inhibitors of NDM-1 and thereby restore the effectiveness of the current antibiotics. Employing a comprehensive computational approach integrating molecular docking and molecular dynamics (MD) simulations, a library of phytosterols was screened to identify promising candidates for inhibiting NDM-1 activity. Using the binding energy of meropenem, a frontline carbapenem antibiotic, as a reference, avenasterol, brassicasterol, and stigmasterol emerged as top phytosterol candidates for further investigation. Subsequent MD simulations confirmed the stability of NDM-1 complexes with avenasterol and stigmasterol over the simulation period, indicating their potential efficacy. These findings suggest that avenasterol and stigmasterol may effectively inhibit NDM-1 activity, warranting validation through in vitro and in vivo studies. Furthermore, these phytosterols hold promise as lead compounds for developing novel NDM-1 inhibitors. Their natural origin and potential inhibitory activity against NDM-1 offer compelling avenues for developing alternative antibacterial therapies to combat multidrug-resistant infections. This study underscores the utility of computational methods in drug discovery and highlights the potential of phytosterols as valuable candidates for addressing antibiotic resistance.

A series of novel methylxanthine Mannich base derivatives containing substituted piperazine groups were synthesized through Mannich reaction. The structures of these new compounds were confirmed by NMR, HRMS or elemental analyses, and X-ray single crystal diffraction. Bioassay results showed that some of the compounds exhibit favorable fungicidal and insecticidal potentials. Particularly, compounds IIk, IIq, IIs and compounds If, IIk against Physalospora piricola and Rhizoctonia cerealis, respectively, were comparable with Azoxystrobin and Chlorothalonil; compound Ik exhibited higher potency than Triflumuron against Plutella xylostella L., suggesting its potential as a lead compound for further development in insecticidal applications. Despite possessing weak herbicidal activities, the target compounds, especially the methylxanthine S-Mannich base derivatives I displayed remarkable inhibitory activities toward ketol-acid reductoisomerase (KARI); compounds Ib, If, and Ik which had K_i values of 2.41-8.08 µmol/L can be novel potent KARI inhibitors for deeper exploration. The SARs were analyzed in detail. The molecular docking studies on the highly active inhibitors with KARI provided possible binding modes between inhibitor and the target enzyme. The physicochemical parameter predictions indicated that compounds Ik, IIk, IIq and IIs have "druglike structure" features. The research results in this article may bring a new inspiration to the extensive explorations on new methylxanthine derivatives in pesticide area.

Neurological dysfunction in association with aging, dementia, and cognitive impairment is the major cause of Alzheimer's disease (AD). Current AD therapies often yield unsatisfactory results due to their poor mechanism in treating the underlying mechanism of the disease. Recent studies suggested that metabolites from the gut microbiota facilitate brain-gut communication. A systematic network pharmacology study and the structure- and analog-based approaches are employed to investigate the metabolites produced by gut microbiota to treat AD. The microbiota metabolites available in the gutMGene database were considered in this study. Two servers, namely Swiss Target Prediction (STP) and Similarity Ensemble Approach (SEA), were used to identify the possible AD targets for the selected metabolites. Detailed KEGG pathway and Gene Ontology (GO) analysis on identified hub genes highlighted the importance of IL6, AKT1, and GSK3B in AD pathophysiology. MMTSp (Microbiota Metabolites Target Signaling pathways) network analysis elucidated that there is a strong relationship with microbiota (Paraprevotella xylaniphila YIT 11841, Bifidobacterium dentium, Paraprevotella clara YIT 11840, Enterococcus sp. 45, Bacteroides sp. 45, Bacillus sp. 46, Escherichia sp. 33, Enterococcus casseliflavus, Bacteroides uniformis, Alistipes indistinctus YIT 12060, Bacteroides ovatus, Escherichia sp. 12, and Odoribacter laneus YIT 12061) and AD pathogenesis. In addition to this, we performed molecular docking to study the metabolite interactions in the AD drug targets. The ADME/T properties of these metabolites were also calculated and the results are discussed in detail.

The synthesis of sulfonamides, a class of compounds with significant pharmaceutical and medicinal applications, has seen remarkable advancements with the advent of magnetic nanocatalysts. Magnetic nanocomposites are one of the most efficient and widely used catalysts, and they are in complete harmony with the principles of modern green chemistry from the point of view of catalysis. These catalysts, typically composed of metal complexes supported on magnetic nanoparticles, offer unique advantages such as ease of recovery and reusability, which are crucial for sustainable and eco-friendly chemical processes. This review comprehensively examines recent developments in applying magnetic nanocatalysts to prepare sulfonamides. Key focus areas include the design and synthesis of various magnetic nanocatalysts (MNC), their catalytic performance in different reaction conditions, and mechanistic insights into their catalytic activity. By summarizing the latest research and technological advancements, this article aims to provide a valuable resource for researchers and practitioners in catalysis and pharmaceutical chemistry.

Two novel series of quinazolinone based isoxazole and isoxazoline hybrid compounds were synthesized from 6-aminoquinazolinone as a key precursor. The title compounds were achieved in synthetic routes via propargylation and allylation reactions of the precursor followed by cyclization with various chloroximes. The new compounds 4a-g and 6a-g were screened for their antimicrobial activity against two Gram-positive bacteria, two Gram-negative bacteria and two fungi by employing Ampicillin and Itraconazole as standard reference. Among all, the 4-bromosubstituted analogues in isoxazole series 4d and in isoxazoline series 6d demonstrated potent activity against all bacterial and fungal strains compared to Ampicillin as well as Itraconazole. The MIC of these compounds were determined as 0.012 μM. The antioxidant investigation revealed that compounds 4f and 6f with dimethyl substitution, exhibited significant activity. Their respective IC₅₀ values were 1.28 ± 0.33, 1.39 ± 0.38 µM and 1.07 ± 0.24, 1.10 ± 0.26 µM, when compared to Ascorbic acid. The compounds 4 g and 6 g with dichloro substitution, exhibited promising results with IC₅₀ values were 2.72 ± 0.34 µM and 2.78 ± 0.41 µM for 4 g, and 2.24 ± 0.93 µM and 2.45 ± 0.53 µM for 6 g, respectively. Their antimicrobial and antioxidant activities were authenticated by the molecular docking study against crystal structure of DNA gyrase and NADPH oxidase. The predicted ADME properties of these molecules progressed favourable drug-likeness properties.

Acute myeloid leukemia (AML) is an aggressive cancer with complex issues of drug resistance and a poor prognosis; thus, effective therapeutics is urgently needed for AML. In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML.

Parasitic diseases remain a significant global health challenge, especially in developing countries, contributing to approximately one million deaths annually. Notably, among the 143 FDA-approved antiparasitic drugs, thirty-four possess chlorine in their chemical structure, highlighting the importance of chlorine substitution. This underscores the significance of chlorine atoms in elucidating structure-activity relationships crucial for drug discovery, aiming to develop safer, more selective, and environmentally friendly molecules with enhanced efficacy. Of particular interest some are naturally occurring chlorinated metabolites derived from PKS, NRPS, and PKS-NRPS biosynthetic pathways, which offer the potential for further manipulation. However, there is limited literature on antiparasitic chlorinated compounds from microbial sources. To address this, we conducted a comprehensive literature survey from 1963 to the present, identifying 28 chlorinated compounds with confirmed antiparasitic properties. This review underscores the potential of enzymatic machinery for selective chlorine substitution, offering insights for biochemists and synthetic chemists to develop versatile chlorinated compounds through synthetic biology, combinatorial chemistry, and organic synthesis.

Proteolytic enzymes are closely associated with cancer and are important in different phases, including tumor growth, angiogenesis, and metastasis. Despite efforts to target matrix metalloproteases (MMPs), clinical trials have often resulted in various side effects such as musculoskeletal pain, joint stiffness, and tendinitis, making them less optimal for chronic cancer treatment. Thus, there is a need for the identification of other protease targets that would provide different approaches towards the management of cancer. Of these targets, Cathepsin L (CatL) is a lysosomal cysteine protease that has been identified as a therapeutic target that is implicated in cancer development and metastasis. In this study, we performed an integrated approach of virtual screening and molecular dynamics (MD) simulations to identify the potential inhibitors of CatL from a library of drugs that have been used for different treatments. Towards this goal, we performed virtual screening of the DrugBank database and found two repurposed drugs, Irinotecan and Nilotinib, against CatL based on their docking profiles, favorable docking scores, and specific interaction with the CatL binding pocket. MD simulations of the Irinotecan and Nilotinib bound structures with CatL were carried out, and the analysis showed that both these compounds could function as CatL inhibitors as the protein-ligand interactions were stable for 300 ns. This study highlights the robustness of these drugs bound to CatL and indicates that they could be repurposed for the treatment of cancer. These findings endorse the use of computer-based approaches for the identification of new inhibitors, and the present study will be a useful resource for future experimental research towards the targeting of CatL in cancer therapeutics.