Search Results (66)

Background/Objectives: This study identifies novel dihydroorotate dehydrogenase (DHODH) inhibitors exhibiting potent broad-spectrum antiviral agents, particularly against influenza A virus (A/PR/8/34(H1N1)) and SARS-CoV-2. Methods: Structure-based virtual screening of 1.6 million compounds (ChemDiv and TargetMol databases) yielded 10 candidates, with compounds 6, 9, and 10 demonstrating significant anti-influenza activity (IC₅₀ = 4.85 ± 0.58, 7.35 ± 1.65, and 1.75 ± 0.28 μM, respectively). Building on these, molecular hybridization principles and scaffold hopping principles were applied to design and synthesize six novel compounds (11–16) through cyclization, coupling, and carboxylate deprotection. Prior to subsequent biological assays, the molecular structures of each compound were elucidated by NMR spectroscopy and MS. Their antiviral activities were subsequently assessed against both influenza virus and SARS-CoV-2. The compound 11, demonstrating the most potent antiviral activity, was further subjected to surface plasmon resonance (SPR) analysis to assess its binding affinity for human DHODH. Results: Compound 11 emerged as the most potent DHODH inhibitor (K_D = 6.06 μM), exhibiting superior broad-spectrum antiviral activities (IC₅₀ = 0.85 ± 0.05 μM, A/PR/8/34(H1N1); IC₅₀ = 3.60 ± 0.67 μM, SARS-CoV-2) to the reported DHODH inhibitor (Teriflunomide, IC₅₀ = 35.02 ± 3.33 μM, A/PR/8/34(H1N1); IC₅₀ = 26.06 ± 4.32 μM, SARS-CoV-2). Mechanistic evaluations via 100 ns MD simulations and QM/MM calculations revealed stable binding interactions, particularly hydrogen bonds with GLN47 and ARG136, while alanine scanning mutagenesis confirmed these residues’ critical roles in binding stability. Conclusions: This work identifies compound 11 as a potent broad-spectrum antiviral compound, offering a promising strategy for broad-spectrum antiviral therapy against RNA viruses by depleting pyrimidine pools essential for viral replication. Full article

Two series of tricyclic thieno[3,2-d]pyrimidines were synthesized, achieving yields of up to 97%. The tricyclic thieno[3,2-d]pyrimidines examined in this study are synthetic analogs of the deoxyvasicinone alkaloids, where the thiophene ring substitutes for the benzene ring. A systematic investigation was conducted on the scaffold-hopping strategy of these alkaloids, emphasizing the selective synthesis and anticancer properties of thieno[3,2-d]pyrimidines. The anticancer evaluation was performed on human cancer cell lines, specifically cervical HeLa and colon HT-29 carcinoma cells. Additional bioassays included cell migration analyses, cell cycle progression, apoptosis, and molecular docking analyses. Furthermore, molecular docking studies showed that the most active small molecule 6e is likely to disrupt the cell cycle process through targeting CDKs (Cyclin-dependent kinases), leading to the inhibition of tumor cell proliferation. Full article

Phosphatidylinositol 3-kinase alpha (PI3Kα) is frequently mutated in head and neck squamous cell carcinoma (HNSCC), leading to the constitutive activation of the PI3K/Akt pathway, which promotes tumor cell proliferation, survival, and metastasis. PI3Kα allosteric inhibitors demonstrate therapeutic potential as both monotherapy and combination therapy, particularly in patients with PIK3CA mutations or resistance to immunotherapy, through the precise targeting of mutant PI3Kα. Compared to ATP-competitive PI3Kα inhibitors such as Alpelisib, the allosteric inhibitor RLY-2608 exhibits enhanced selectivity for mutant PI3Kα while minimizing the inhibition of wild-type PI3Kα, thereby reducing side effects such as hyperglycemia. To date, no allosteric PI3Kα inhibitors have been approved for clinical use. To develop novel PI3Kα inhibitors with improved safety and efficacy, we employed a scaffold hopping approach to structurally modify RLY-2608 and constructed a compound library. Based on the structural information of the PI3Kα allosteric site, we conducted the systematic virtual screening of 11,550 molecules from databases to identify lead compounds. Through integrated approaches, including molecular docking studies, target validation, druggability evaluation, molecular dynamics simulations, and metabolic pathway and metabolite analyses, we successfully identified a promising novel allosteric PI3Kα inhibitor, H-18 (3-(2-chloro-5-fluorophenyl)isoindolin-1-one). H-18 has not been previously reported as a PI3Kα inhibitor, and provides an excellent foundation for subsequent lead optimization, offering a significant starting point for the development of more potent PI3Kα allosteric inhibitors. Full article

In response to the urgent need for innovative fungicides to ensure food security and safety, a series of twenty-three novel trifluoromethylpyridine compounds were designed and synthesized using a scaffold hopping strategy derived from dehydrozingerone. This approach involved converting the α, β-unsaturated ketone moiety into a pyridine ring. Bioassay results indicated that the majority of these compounds exhibited promising in vitro antifungal activity, particularly against Rhizoctonia solani and Colletotrichum musae. Notably, compound 17 showed the highest efficacy and broad-spectrum activity, with median effective concentrations (EC₅₀) ranging from 2.88 to 9.09 μg/mL. Phenoxytrifluoromethylpyridine derivatives, including compound 17, exhibited superior antifungal activity compared to benzyloxytrifluoromethylpyridine derivatives. In vivo tests revealed that both compounds 17 and 23 exhibited moderate control effects against C. musae. The degradation half-lives of compounds 17 and 23 in bananas were determined to be 176.9 h and 94.8 h, respectively, indicating the stability of their structures in the environment. Molecular docking studies indicated that compound 23 interacts with succinate dehydrogenase, offering valuable insights for the structural optimization of compound 23. Full article

Background/Objectives: Colony stimulating factor 1 receptor kinase (CSF1R) is a well-validated molecular target in drug discovery for various reasons. Based on the structure of an early lead molecule identified in our lab and the marketed drug Pexidartinib (PLX3397), we merged fragments of Pexidartinib with our pyrrolo[2,3-d]pyrimidine nucleus, and the idea was supported by initial molecular docking studies. Thus, several new compounds were synthesized with Pexidartinib fragments on C4, C5, and C6 on the pyrrolopyrimidine scaffold using molecular hybridization. Methods: Nine final products were synthesized using a combination of Buchwald-Hartwig and Suzuki-Miyaura cross-coupling reactions in three to four steps and in good yields. The analogues were subsequently profiled as CSF1R inhibitors in enzymatic and cellular assays, and ADME properties were evaluated for some derivatives. Results: N-Methyl-N-(3-methylbenzyl)-6-(6-((pyridin-3-ylmethyl)amino)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (12b) emerged as the most potent CSF1R inhibitor, showing low-nanomolar enzymatic activity, cellular efficacy, and favorable ADME properties, highlighting its promise as a lead compound for further development. Conclusions: These findings suggest that combining structural elements from previously reported CSF1R inhibitors such as Pexidartinib could guide the development of improved drug candidates targeting this kinase. Full article

Ulcerative colitis (UC) is a chronic inflammatory condition that affects the intestines. Research has shown that reducing the activity of DDR1 can help maintain intestinal barrier function in UC, making DDR1 a promising target for treatment. However, the development of DDR1 inhibitors as drugs has been hindered by issues such as toxicity and poor binding stability. As a result, there are currently no DDR1-targeting drugs available for clinical use, highlighting the need for new inhibitors. In a recent study, a dataset of 85 DDR1 inhibitors was analyzed to identify key characteristics for effective inhibition. A pharmacophore model was constructed and validated to screen a library of marine natural products for potential DDR1 inhibitors. Through high-throughput virtual screening and precise docking, 17 promising compounds were identified from a pool of over 52,000 molecules in the marine database. To improve binding affinity and reduce potential toxicity, scaffold hopping was employed to modify the 17 compounds, resulting in the generation of 1070 new compounds. These new compounds were further evaluated through docking and ADMET analysis, leading to the identification of three compounds—39713a, 34346a, and 34419a—with superior predicted activity and drug-like properties compared to the original 17 compounds. Further analysis showed that the binding free energy values of the three candidate compounds were less than −12.200 kcal/mol, which was similar to or better than −12.377 kcal/mol of the known positive compound VU6015929, and the drug-like properties were better than those of the positive compounds. Molecular dynamics simulations were then conducted on these three candidate compounds, confirming their stable interactions with the target protein. In conclusion, compounds 39713a, 34346a, and 34419a show promise as potential DDR1 inhibitors for the treatment of ulcerative colitis. Full article

LCN2, a member of the lipocalin family, is associated with various tumors and inflammatory conditions. Despite the availability of known inhibitors, none have been approved for clinical use. In this study, marine compounds were screened for their ability to inhibit LCN2 using pharmacophore models. Six compounds were optimized for protein binding after being docked against the positive control Compound A. Two compounds showed promising results in ADMET screening. Molecular dynamics simulations were utilized to predict binding mechanisms, with Compound 69081_50 identified as a potential LCN2 inhibitor. MM-PBSA analysis revealed key amino acid residues that are involved in interactions, suggesting that Compound 69081_50 could be a candidate for drug development. Full article

Urinary tract infections (UTIs) affect nearly 50% of women in their lifetime. Uropathogenic Escherichia coli (UPEC) expresses F9/Fml pili tipped with the protein FmlH that specifically bind to terminal galactoside and galactosaminoside units in glycoproteins on kidney and bladder cells and colonize host tissues. The traditional UTI treatment using excessive antibiotics has led to the rise in various UPEC antibiotic-resistant strains. An alternative therapeutic approach prevents the initial bacterial attachment on the host cells using competitive FmlH-binding inhibitors. In this study, we used computer-aided drug design techniques to identify novel glycomimetics that are predicted to bind strongly to and inhibit the UPEC FmlH. We performed in silico receptor-based and ligand-based scaffold hopping, and molecular docking to predict novel FmlH-binding glycomimetics with high chemical synthesizability. We replaced the two major scaffolds of the most potent known FmlH-binding ligand to obtain novel compounds. Additionally, we applied global machine-learning models to predict the ADMET properties of the molecules. Compounds with low ADMET risks were subjected to molecular dynamics simulations and a detailed investigation of the FmlH–glycomimetic interactions was performed. We have prepared and supplied a library of 58 novel glycomimetics that can be subjected to further biological activity studies. Full article

By using a scaffold hopping/ring equivalent and intermediate derivatization strategies, a series of compounds of 2,5-diphenyl-1,3-oxazoline with substituent changes at the 5-phenyl position were prepared, and their acaricidal activity was studied. However, the synthesized 2,5-diphenyl-1,3-oxazolines showed lower activity against mite eggs and larvae compared to the 2,4-diphenyl-1,3-oxazolines with the same substituents. We speculate that there is a significant difference in the spatial extension direction of the substituents between the two skeletons of compounds, resulting in differences in their ability to bind to the potential target chitin synthase 1. This work is helpful in inferring the internal structure of chitin synthase binding pockets. Full article

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure–activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R² = 0.980, Q² = 0.765) and comparative molecular similarity index analysis (CoMSIA, R² = 0.997, Q² = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC₅₀ values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was −93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors. Full article

Aurones, particular polyphenolic compounds belonging to the class of minor flavonoids and overlooked for a long time, have gained significative attention in medicinal chemistry in recent years. Indeed, considering their unique and outstanding biological properties, they stand out as an intriguing reservoir of new potential lead compounds in the drug discovery context. Nevertheless, several physicochemical, pharmacokinetic, and pharmacodynamic (P3) issues hinder their progression in more advanced phases of the drug discovery pipeline, making lead optimization campaigns necessary. In this context, scaffold hopping has proven to be a valuable approach in the optimization of natural products. This review provides a comprehensive and updated picture of the scaffold-hopping approaches directed at the optimization of natural and synthetic aurones. In the literature analysis, a particular focus is given to nitrogen and sulfur analogues. For each class presented, general synthetic procedures are summarized, highlighting the key advantages and potential issues. Furthermore, the biological activities of the most representative scaffold-hopped compounds are presented, emphasizing the improvements achieved and the potential for further optimization compared to the aurone class. Full article

The existing kinase inhibitors for hepatocellular carcinoma (HCC) have conferred survival benefits but are hampered by adverse effects and drug resistance, necessitating the development of novel agents targeting distinct pathways. To discover potent new anti-HCC compounds, we leveraged scaffold hopping from Sorafenib and introduced morpholine/piperidine moieties to develop ureido-substituted 4-phenylthiazole analogs with optimized physicochemical properties and binding interactions. Notably, compound 27 exhibited potent cytotoxicity against HepG2 cells (IC₅₀ = 0.62 ± 0.34 μM), significantly exceeding Sorafenib (IC₅₀ = 1.62 ± 0.27 μM). Mechanistic investigations revealed that compound 27 potently inhibited HCC cell migration and colony formation, and it induced G2/M arrest and early-stage apoptosis. Kinase profiling revealed IGF1R as a key target, which compound 27 potently inhibited (76.84% at 10 μM). Molecular modeling substantiated compound 27’s strong binding to IGF1R via multiple hydrogen bonds. Computational predictions indicate favorable drug-like properties for compound 27. These findings provide a promising drug candidate for the treatment of HCC patients. Full article

Herbicides are useful tools for managing weeds and promoting food production and sustainable agriculture. In this study, we report on the development of a novel class of lipophilic pyrimidine-biphenyl (PMB) herbicides. Firstly, three PMBs, Ia, IIa, and IIIa, were rationally designed via a scaffold hopping strategy and were determined to inhibit acetohydroxyacid synthase (AHAS). Computational simulation was carried out to investigate the molecular basis for the efficiency of PMBs against AHAS. With a rational binding mode, and the highest in vitro as well as in vivo potency, Ia was identified as a preferable hit. Furthermore, these integrated analyses guided the design of eighteen new PMBs, which were synthesized via a one-step Suzuki–Miyaura cross-coupling reaction. These new PMBs, Iba-ic, were more effective in post-emergence control of grass weeds compared with Ia. Interestingly, six of the PMBs displayed 98–100% inhibition in the control of grass weeds at 750 g ai/ha. Remarkably, Ica exhibited ≥ 80% control against grass weeds at 187.5 g ai/ha. Overall, our comprehensive and systematic investigation revealed that a structurally distinct class of lipophilic PMB herbicides, which pair excellent herbicidal activities with new interactions with AHAS, represent a noteworthy development in the pursuit of sustainable weed control solutions. Full article

Bacterial infections are the second-leading cause of death, globally. The prevalence of antibacterial resistance has kept the demand strong for the development of new and potent drug candidates. It has been demonstrated that Src protein tyrosine kinases (TKs) play an important role in the regulation of inflammatory responses to tissue injury, which can trigger the onset of several severe diseases. We carried out a search for novel Src protein TK inhibitors, commencing from reported highly potent anti-bacterial compounds obtained using the Mannich reaction, using a combination of e-pharmacophore modeling, virtual screening, ensemble docking, and core hopping. The top-scoring compounds from ligand-based virtual screening were modified using protein structure-based design approaches, and their binding to the Src homology-2 domain of p56^lck TK was predicted using ensemble molecular docking. We have prepared a database of 202 small molecules and have identified six novel top hits that can be subjected to further investigation. We have also performed in silico ADMET property prediction for the hit compounds. This combined computer-aided drug design approach can serve as a starting point for identifying novel TK inhibitors that could be further subjected to in vitro studies and validation of antimicrobial activity. Full article

Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson–Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors. Full article