Molecular Diversity最新文献

{"title":"Discovery and optimization of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel phosphodiesterase 4 inhibitors.","authors":"Zongmin Wu, Furong Zhang, Zhexin Chen, Xue Wang, Xingfu Liu, Guofeng Yang, Sen Wang, Shuheng Huang, Hai-Bin Luo, Yi-You Huang, Deyan Wu","doi":"10.1007/s11030-024-10991-w","DOIUrl":"https://doi.org/10.1007/s11030-024-10991-w","url":null,"abstract":"<p><p>Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC₅₀ of 4.78 ± 0.08 μM). And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC₅₀ of 0.48 ± 0.02 μM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, spectroscopic characterization, DFT calculations, in silico-ADMET and molecular docking analysis of novel quinoline-substituted 5H-chromeno [2,3-b] pyridine derivatives as antibacterial agents.","authors":"Rajesh Kancherla, T N Lohith, Sushma Deshmukh, Shekhar Reddy Mulka, Gouthami Kuruvalli, M B Madhusudana Reddy","doi":"10.1007/s11030-024-10982-x","DOIUrl":"https://doi.org/10.1007/s11030-024-10982-x","url":null,"abstract":"<p><p>A convenient, straightforward, and effective one-step reaction for the synthesis of a three-component compound of biologically relevant novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno[2,3-b] pyridine-3-carbonitrile derivatives was designed and synthesized. The synthesis was developed by the reaction between salicylaldehyde 1, 8-hydroxyquinoline 2, 2-aminopropene-1,1,3-tricarbonitrile 3, and the catalytic amount of triethylamine in ethanol at 78 °C. This methodology has many beneficial features, including the use of inexpensive and non-hazardous starting materials, single-flask reactions, optimized reaction conditions, the termination of intermediate isolation, easy workup, reducing organic waste products, being chromatography-free, and decreasing the reaction time along with quantitative yields with high functional group tolerance. A proposed mechanism with supporting experimental data is presented, including ¹H NMR, ¹³C NMR, 2D NMR (HMBC, COSY, HSQC), mass, and IR spectroscopy, which are used to characterize the complete derivatives. All synthesized compounds were evaluated in vitro for their antibacterial activities against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa bacterial strains via the agar-well diffusion method compared with the reference drug gentamicin. The data indicated that compounds 4A, 4F, 4G, 4 J, and 4K consistently demonstrated strong antimicrobial activity against Gram-positive and Gram-negative bacteria. Furthermore, a molecular docking investigation was carried out to gain insight into the binding mode of the most promising compounds via the crystal structure of the S. aureus DNA gyrase complex with ciprofloxacin (PDB ID: 2XCT). Density functional theory (DFT) calculations were performed to determine the various molecular properties of the synthesized novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno [2,3-b] pyridine-3-carbonitrile derivatives (4A-4 M). On the basis of the reactive sites explored by the molecular electrostatic potential maps, the antibacterial activities of the compounds were screened.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microwave-assisted protocol towards synthesis of heterocyclic molecules: a comparative analysis with conventional synthetic methodologies (years 2019-2023): a review.","authors":"Iffat Almas, Ayesha Malik, Nasir Rasool, Aqsa Kanwal, Tahira Khalid, Hamna Nawaz","doi":"10.1007/s11030-024-10981-y","DOIUrl":"https://doi.org/10.1007/s11030-024-10981-y","url":null,"abstract":"<p><p>Microwave-assisted protocols have become extensively accepted across various scientific and technological domains because of their numerous advantages, shorter reaction times, higher yields, and often milder reaction conditions. In this review, we focus on the synthesis of N, O, and S-containing heterocyclic structural cores, crucial in the development of pharmaceuticals, agrochemicals, and materials science following through conventional and microwave method via eliminating the side products and enhances the product yield that is nowadays the biggest barrier for a synthetic chemist. The major findings emphasizes the substantial advantages of microwave-assisted techniques over conventional synthetic protocols. This comparative study underscores the potential of microwave-assisted techniques to revolutionize heterocyclic compound synthesis, providing insights into optimizing reaction conditions and expanding the scope of chemical synthesis in industrial applications.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142278587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of small molecules disrupting dengue virus assembly by inhibiting capsid protein and blocking RNA encapsulation.","authors":"Hrithika Panday, Abhimanyu Kumar Jha, Vivek Dhar Dwivedi","doi":"10.1007/s11030-024-10980-z","DOIUrl":"https://doi.org/10.1007/s11030-024-10980-z","url":null,"abstract":"<p><p>Dengue fever is a significant global public health concern, causing substantial morbidity and mortality worldwide. The disease can manifest in various forms, from mild fever to potentially life-threatening complications. Developing effective treatments remains a critical challenge to healthcare systems. Despite extensive research, no antiviral drugs have been approved for either the prevention or treatment of dengue. Targeting the virus during its early phase of attachment is essential to inhibit viral replication. The capsid protein plays a crucial role in the virus's structural integrity, assembly, and viral genome release. In the present study, we employed a computational approach focused on the capsid protein to identify possible potent inhibitors against the dengue virus from a library of FDA-approved drugs. We employed high-throughput virtual screening on FDA-approved drugs to identify drug molecules that could potentially combat the disease and save both cost and time. The screening process identified four drug molecules (Nordihydroguaiaretic acid, Ifenprodil tartrate, Lathyrol, and Safinamide Mesylate) based on their highest binding affinity and MM/GBSA scores. Among these, Nordihydroguaiaretic acid showed higher binding affinity than the reference molecule with - 11.66 kcal/mol. In contrast, Ifenprodil tartrate and Lathyrol showed similar results to the reference molecule, with binding energies of - 9.42 kcal/mol and - 9.29 kcal/mol, respectively. Following the screening, molecular dynamic simulations were performed to explore the molecular stability and conformational possibilities. The drug molecules were further supported by post-molecular simulation analysis. Furthermore, binding energies were also computed using the MM/GBSA approach, and the free energy landscape was used to calculate the different transition states, revealing that the drugs exhibited significant transition states. Specifically, Nordihydroguaiaretic acid and Ifenprodil tartrate displayed higher flexibility, while Lathyrol and Safinamide Mesylate showed more predictable and consistent protein folding. This significant breakthrough offers new hope against dengue, highlighting the power of computational drug discovery in identifying potent inhibitors and paving the way for novel treatment approaches.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142278586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stereo-selectivity of enantiomeric inhibitors to ubiquitin-specific protease 7 (USP7) dissected by molecular docking, molecular dynamics simulations, and binding free energy calculations.","authors":"Yusheng Zhang, Wenwen Dou, Ziqi Zhao, Guozhen Li, Chunlong Li, Xiangyu Chen, Linkai Mou","doi":"10.1007/s11030-024-10948-z","DOIUrl":"https://doi.org/10.1007/s11030-024-10948-z","url":null,"abstract":"<p><p>The ubiquitin-specific protease 7 (USP7), as a member of deubiquitination enzymes, represents an attractive therapeutic target for various cancers, including prostate cancer and liver cancer. The change of the inhibitor stereocenter from the S to R stereochemistry (S-ALM → R-ALM34) markedly improved USP7 inhibitory activity. However, the molecular mechanism for the stereo-selectivity of enantiomeric inhibitors to USP7 is still unclear. In this work, molecular docking, molecular dynamics (MD) simulations, molecular mechanics/Generalized-Born surface area (MM/GBSA) calculations, and free energy landscapes were performed to address this mystery. MD simulations revealed that S-ALM34 showed a high degree of conformational flexibility compared to the R-ALM34 counterpart, and S-ALM34 binding led to the enhanced intradomain motions of USP7, especially the BL1 and BL2 loops and the two helices α4 and α5. MM/GBSA calculations showed that the binding strength of R-ALM34 to USP7 was stronger than that of S-ALM34 by - 4.99 kcal/mol, a similar trend observed by experimental data. MM/GBSA free energy decomposition was further performed to differentiate the ligand-residue spectrum. These analyses not only identified the hotspot residues interacting with R-ALM34, but also revealed that the hydrophobic interactions from F409, K420, H456, and Y514 play the major determinants in the binding of R-ALM34 to USP7. This result is anticipated to shed light on energetic basis and conformational dynamics information to aid in the design of more potent and selective inhibitors targeting USP7.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142278588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A network pharmacology-based approach to understand the mechanism of action of anti-mycobacterial activity of Acacia nilotica: a modelling and experimental study","authors":"Madhumitha Suresh, Kadambari Vijay Sai, Kartik Mitra, Radhika Ravindran, Mukesh Doble","doi":"10.1007/s11030-024-10985-8","DOIUrl":"https://doi.org/10.1007/s11030-024-10985-8","url":null,"abstract":"<p>The rapid rise in drug-resistant tuberculosis poses a serious threat to public health and demands the discovery of new anti-mycobacterial agents. Medicinal plants are a proven potential source of bioactive compounds; however, identifying those responsible for the putative anti-mycobacterial action still remains a challenging task. In this study, we undertook a systematic network pharmacology approach to identify and evaluate anti-mycobacterial compounds from a traditional plant, <i>Acacia nilotica</i>, as a model system. The protein–protein interaction network revealed 17 key pathways in <i>M. tuberculosis</i> encompassing 40 unique druggable targets that are necessary for its growth and survival. The phytochemicals of <i>A. nilotica</i> were preferentially found to interfere with the cell division and cell wall biogenesis proteins, especially FtsZ and Mur. Notably, the compounds epigallocatechin, ellagic acid, chlorogenic acid, and D-pinitol were found to exhibit a potential polypharmacological effect against multiple proteins. Further, in vitro studies confirmed that the selected candidates, chlorogenic acid, and ellagic acid exhibited potent anti-mycobacterial activity (against <i>M. smegmatis</i>) with specific inhibition of purified <i>M.tb</i> FtsZ enzyme. Taken together, the present study demonstrates that network pharmacology combined with molecular docking can be utilized as an efficient approach to identify potential bioactive phytochemicals from natural products along with their mechanism of action. Hence, the compounds identified in this study can be potential lead candidates for developing novel anti-mycobacterial drugs, while the key proteins identified here can be potential drug targets.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":"77 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metal complexes containing vitamin B6-based scaffold as potential DNA/BSA-binding agents inducing apoptosis in hepatocarcinoma (HepG2) cells","authors":"Almuhrah A. N. Alroba, Elham Shafik Aazam, Mehvash Zaki","doi":"10.1007/s11030-024-10986-7","DOIUrl":"https://doi.org/10.1007/s11030-024-10986-7","url":null,"abstract":"<p>A ligand (<b>HL</b>) was synthesized from the pyridoxal hydrochloride (vitamin B6 form) and 1-(2-Aminoethyl)piperidine in one single step. The metal complexes [Zn(L)(Bpy)]NO₃ (<b>1</b>), [Cu(L)(Bpy)]NO₃ (<b>2</b>), and [Co(L)(Bpy)]NO₃ (<b>3</b>) were prepared by tethering <b>HL</b> and 2,2′-bipyridine. The synthesized <b>HL</b> and metal complexes <b>1–3</b> were thoroughly characterized using spectroscopic techniques such as ¹H NMR, ¹³C NMR, FTIR, EI-MS, molar conductance, and magnetic moment, in addition to CHN elemental analysis. The geometry of complexes was square pyramidal around the metal ions {Zn(II), Cu(II), and Co(II)}. The interaction of ligand and metal complexes with DNA and BSA macromolecules was accomplished by UV–Vis absorption and fluorescence spectroscopy in vitro. The hyperchromism in band at 303–325 with no shift supports the groove binding with some partial intercalation in grooves. Similarly, in BSA-binding studies, complex <b>2</b> shows greater binding potential in the hydrophobic core probably near the Trp-212 in the subdomain IIA. Furthermore, complex <b>2</b> shows excellent cytotoxicity on HepG2 cancer cells with IC₅₀ = 25.0 ± 0.45 µM. The detailed analysis by cell-cycle studies shows cell arrest at the G2/M phase. The type of cell death was authenticated by an annexin V-FTIC dual staining experiment that reveals maximum death by apoptosis together with non-specific necrosis.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":"56 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, bioactivity and action mechanism of N-substituted N′-phenylpicolinohydrazides against phytopathogenic fungi","authors":"Yuhao Zhang, Ruofei Bai, Tengyi Du, Yiwei Wang, Bohang Zhou, Congwei Zhou, Le Zhou","doi":"10.1007/s11030-024-10984-9","DOIUrl":"https://doi.org/10.1007/s11030-024-10984-9","url":null,"abstract":"<p><i>N</i>′-phenylpicolinohydrazide has been proven to be a promising lead compound for research and development of novel fungicides for agriculture in our previous study. As our continuing research, in this study, a series of <i>N</i>-substituted derivatives of <i>N</i>′-phenylpicolinohydrazide were synthesized and explored for the inhibition activity on nine phytopathogenic fungi and action mechanism. The results found that eleven of the compounds had excellent antifungal activity with more than 80% inhibition rates at 50 <i>µ</i>g/mL on part or most of the fungi, especially <i>A. solani</i> and <i>P. piricola</i>. Compounds <b>5i</b>, <b>5j</b> and <b>5k</b> showed EC₅₀ values of &lt; 8.0 µg/mL against <i>A. solani</i> superior to positive control carbendazim (EC₅₀ = 36.0 µg/mL) while <b>5p</b> and <b>5q</b> exhibited the highest activity with EC₅₀ values of 2.72 and 2.80 µg/mL against <i>P. piricola</i> superior to positive control boscalid (EC₅₀ &gt; 50.0 µg/mL). Furthermore, <b>5k</b> also showed significant protective effect against <i>A. solani</i> infection on tomatoes in a concentration-dependent manner. Action mechanism research showed that <b>5k</b> was able to increase the intracellular ROS level, change both MMP and permeability of cell membrane and damage mycelial morphology. Molecular docking studies showed that <b>5k</b> could bind into ubiquinone-binding region of succinate dehydrogenase by hydrogen bonds, π-cation, π–π stacked, π-alkyl, and alkyl interactions. Additionally, the antibacterial activity was also investigated. Thus, <i>N</i>-substituted derivatives of <i>N</i>′-phenylpicolinohydrazide were emerged as novel and highly promising antifungal molecular skeletons to develop new fungicides for crop protection.</p><h3 data-test=\"abstract-sub-heading\">Graphic abstract</h3>\u0000","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":"23 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI and ML for small molecule drug discovery in the big data era II","authors":"Kunal Roy","doi":"10.1007/s11030-024-10983-w","DOIUrl":"10.1007/s11030-024-10983-w","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":"28 4","pages":"1847 - 1848"},"PeriodicalIF":3.9,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142278585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmental pollutant Di-(2-ethylhexyl) phthalate induces asthenozoospermia: new insights from network toxicology","authors":"Lei Xu, Menghua Shi, Guozheng Qin, Xuyao Lin, Bin Huang","doi":"10.1007/s11030-024-10976-9","DOIUrl":"https://doi.org/10.1007/s11030-024-10976-9","url":null,"abstract":"<p>The global decline in sperm quality in men is closely associated with environmental exposure to the plasticizer Di-(2-ethylhexyl) phthalate (DEHP), but the molecular mechanisms underlying its induction of asthenozoospermia (AZS) remain incompletely understood. By integrating the toxicological targets of DEHP and differential genes in AZS patients, and combining machine learning, molecular docking, and dynamics simulations, this study successfully identified hub genes and signaling pathways induced by DEHP in AZS, aiming to provide new strategies for the prevention and treatment of this disease. A total of 26 toxicological targets were identified, with FGFR1, MMP7, and ST14 clearly defined as playing crucial regulatory roles in DEHP-induced AZS. This study also reveals that DEHP may induce reproductive system inflammation, affecting the proliferation and survival of reproductive cells, and subsequently impacting sperm vitality, possibly through regulating the mTORC1 pathway, TNF-α signaling via the NF-κB pathway, and MYC targets v1 pathway. Furthermore, changes in the immune microenvironment revealed the significant impact of immune status on testicular function. In conclusion, this study provides important scientific evidence for understanding the molecular mechanisms of AZS and developing prevention and treatment strategies based on toxicological targets.</p><h3 data-test=\"abstract-sub-heading\">Graphical abstract</h3>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":"10 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}