Medicinal ChemistryPub Date : 2025-01-23DOI: 10.2174/0115734064262975241208063806
Zhou Dejun, Zhang Yuying, Liu Xiaoyue, Zheng Huachuan
{"title":"Effective Synthesis of Dopamine Dimer.","authors":"Zhou Dejun, Zhang Yuying, Liu Xiaoyue, Zheng Huachuan","doi":"10.2174/0115734064262975241208063806","DOIUrl":"https://doi.org/10.2174/0115734064262975241208063806","url":null,"abstract":"<p><strong>Background: </strong>Dopamine (1) is a commonly used vasopressor, primarily employed to treat various types of shock, congestive heart failure, and acute renal failure. Dopamine dimer (2) is an impurity generated during the production process of dopamine raw materials or the metabolism of dopamine drugs themselves.</p><p><strong>Methods: </strong>This article presents an effective method for synthesizing dopamine dimer through the condensation of methyl 3,4-dimethoxyphenyl acetate (4) and 3,4-dimethoxyphenylethyl amine (5), followed by reduction and demethylation.</p><p><strong>Results: </strong>The product was synthesized from easily accessible raw materials, achieving a total yield of 48% over five steps.</p><p><strong>Conclusion: </strong>This synthesis method is simple and beneficial for pharmaceutical companies to adopt and implement.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Medicinal ChemistryPub Date : 2025-01-23DOI: 10.2174/0115734064362377241217093427
Dan Wang, Ming-Tao Xia, Jia-Xin Yan, Ling Yu, Shuai Li
{"title":"Advances in Structural Types and Pharmacochemistry of CDK12 Inhibitors.","authors":"Dan Wang, Ming-Tao Xia, Jia-Xin Yan, Ling Yu, Shuai Li","doi":"10.2174/0115734064362377241217093427","DOIUrl":"https://doi.org/10.2174/0115734064362377241217093427","url":null,"abstract":"<p><p>Cyclin-Dependent Kinase (CDK) 12 is a member of the 20-membered CDK family (CDK1-20) and plays a vital role in regulating gene transcription, mRNA splicing, translation, cell cycle, and repair of DNA damage. CDK12 is an emerging therapeutic target due to its role in regulating the transcription of DNA Damage Response (DDR) genes in Cyclin-Dependent Kinase (CDK). However, the development of selective small molecules targeting CDK12 has been challenging due to the high degree of homology between kinase domains of CDK12 and other transcriptional CDKs, most notably CDK13. So far, no CDK12 inhibitors approved by the US FDA have been found, and more novel CDK12 inhibitors have been reported for the treatment of prostate cancer, breast cancer, ovarian cancer, lung adenocarcinoma, stomach cancer, cervical cancer, etc. This review has attempted to summarize the structural characteristics and biological activities of various novel CDK12 inhibitors reported since 2020. Meanwhile, we collated and analyzed the reported CDK12 inhibitors from the perspective of structure, summarized the current clinical application potential of CDK12 inhibitors, and further analyzed their current challenges and future development trends.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Medicinal ChemistryPub Date : 2025-01-23DOI: 10.2174/0115734064345432241120101422
Thaysnara Batista Brito, Luana Marília Santos Oliveira, Rafaela Karolina Viana Nunes, Edson Luis Maistro, Socrates Cabral de Holanda Cavalcanti
{"title":"Synthetic Strategies for the Development of Novel Heterocycles as Larvicides Targeting Aedes aegypti Linn.","authors":"Thaysnara Batista Brito, Luana Marília Santos Oliveira, Rafaela Karolina Viana Nunes, Edson Luis Maistro, Socrates Cabral de Holanda Cavalcanti","doi":"10.2174/0115734064345432241120101422","DOIUrl":"https://doi.org/10.2174/0115734064345432241120101422","url":null,"abstract":"<p><strong>Background: </strong>Owing to their extensive utilization as pesticides, heterocycles assume a fundamental role in the management of vector-borne diseases. Despite the presence of numerous heterocyclic compounds in commercial insecticides and larvicides, resistance to pesticides still demands novel strategies to current pest control methods. Considering these facts, this review aims to survey the synthesis and SAR of heterocyclic molecules with larvicidal activity against Aedes aegypti Linn.</p><p><strong>Methods: </strong>Comprehensive searches across the major databases were conducted to identify heterocyclic compounds exhibiting larvicidal efficacy against Ae. aegypti with the goal to unveil the main characteristics that are essential for exhibiting larvicidal activity.</p><p><strong>Results: </strong>Active compounds display LC50 values varying from 0.36 to 2907 μM. Fifteen heterocyclic compounds displayed larvicidal activities below 20 μM. Five-membered ring molecules containing nitrogen and oxygen have displayed larvicidal activity according to the position of heteroatoms in the ring. Molecules bearing 1,2,4-oxadiazole and 1,2-oxazole moieties have been shown to be more active than 1,3,4-oxadiazole derivatives. Compounds possessing the indole scaffold have proven to be more potent than isatin and pyrimidine derivatives. Structural characteristics other than a heterocyclic moiety, such as the presence of halogens and less ionized and polar molecules, may also play a role in determining the final larvicidal activity.</p><p><strong>Conclusion: </strong>The rationale behind this review is to stimulate the discovery of innovative heterocyclic larvicides. Thus, it is important to continue synthesizing new scaffolds to comprehensively elucidate the structure-activity relationship for each heterocyclic moiety outlined in this investigation.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exploring the Therapeutic Potential of 1,3-Thiazole: A Decade Overview.","authors":"Ajit Manchare, Swapnali Parit, Mukta Lele, Navnath Hatvate","doi":"10.2174/0115734064365060250116103320","DOIUrl":"https://doi.org/10.2174/0115734064365060250116103320","url":null,"abstract":"<p><p>The escalating prevalence of lifestyle and microbial diseases poses a significant threat to human well-being, necessitating the discovery and development of novel drugs with distinct modes of action. Addressing this challenge involves employing innovative strategies, and one current approach involves utilizing heterocyclic compounds to synthesize hybrid molecules. These hybrids have resulted from the fusion of two or more bioactive heterocyclic moieties into a single molecule. The focus of this review revolves around the strategic incorporation of heterocycles, particularly thiazole derivatives. Thiazole derivatives, due to their unique structural features, are explored in depth within this review paper. The paper comprehensively outlines diverse hybridization strategies of thiazole derivatives, highlighting their vibrant biological activities mainly in the last decade, 2014-2024. By presenting an extensive overview, the review aims to provide valuable insights into the potential of thiazole derivatives as promising candidates for drug development. The insights garnered from this paper are expected to offer valuable guidance for future drug design endeavors, providing a foundation for developing novel and effective drugs to combat lifestyle diseases and microbial resistance.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Medicinal ChemistryPub Date : 2025-01-20DOI: 10.2174/0115734064364749250102024805
Dong Xie, Zhibiao Cai, Junxiang Mao, Xiaodong Qu, Li Cao, Jie Zhou
{"title":"High-prediction QSAR Modeling Study Based on the Efficacy of a Novel 6-hydroxybenzothiazole-2-carboxamide Targeted Monoamine Oxidase B in the Treatment of Neurodegenerative Diseases.","authors":"Dong Xie, Zhibiao Cai, Junxiang Mao, Xiaodong Qu, Li Cao, Jie Zhou","doi":"10.2174/0115734064364749250102024805","DOIUrl":"https://doi.org/10.2174/0115734064364749250102024805","url":null,"abstract":"<p><strong>Background: </strong>Neurodegenerative diseases are a group of disorders characterized by progressive neuronal degeneration and death, of which Alzheimer's disease and Parkinson's disease are the most common. These diseases are closely associated with increased expression of monoamine oxidase B (MAO-B), an important enzyme that regulates neurotransmitter concentration, and its overactivity leads to oxidative stress and neurotoxicity, accelerating the progression of neurodegenerative diseases. Therefore, the development of effective MAO-B inhibitors is important for the treatment of neurodegenerative diseases.</p><p><strong>Objective: </strong>This study aims to improve the prediction of the efficacy of novel 6-hydroxybenzothiazole- 2-carboxamide compounds in inhibiting MAO-B by improving the quantitative constitutive effect relationship (QSAR) modeling and to provide a theoretical basis for the discovery of novel neuroprotective drugs.</p><p><strong>Methods: </strong>The study first optimized the structures of 36 compounds using the heuristic method (HM) in CODESSA software to construct linear QSAR models. Subsequently, key descriptors were screened by using the gene expression programming (GEP) technique to generate nonlinear QSAR models and validate them.</p><p><strong>Results: </strong>The R², F-value, and R²cv of the linear model were 0.5724, 10.3752, and 0.4557, respectively, whereas the nonlinear model constructed by the GEP algorithm showed higher prediction accuracies by achieving R² values of 0.89 and 0.82, and mean squared errors (MSE) of 0.0799 and 0.1215 for the training and test sets, respectively. In addition, molecular docking experiments confirmed that the novel compound 31 was tightly bound to the MAO-B active site with significant inhibitory activity.</p><p><strong>Conclusion: </strong>In this study, we successfully improved the prediction ability of the efficacy of novel 6-hydroxybenzothiazole-2-carboxamide compounds to inhibit MAO-B by improving the QSAR model. This not only provides new drug candidates for the treatment of neurodegenerative diseases, but also provides important theoretical guidance for subsequent drug design and development, which can help accelerate the process of new drug discovery and reduce the disease burden of patients.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Medicinal ChemistryPub Date : 2025-01-20DOI: 10.2174/0115734064361520250115090651
Pratibha Yadav, Kamal Shah
{"title":"Recent Advancements in the Synthetic Chemistry of Oxazole Derivatives and their Significant Medicinal Applications.","authors":"Pratibha Yadav, Kamal Shah","doi":"10.2174/0115734064361520250115090651","DOIUrl":"https://doi.org/10.2174/0115734064361520250115090651","url":null,"abstract":"<p><p>The five-membered oxazole motif heterocyclic aromatic ring has been gaining considerable attention due to its bioisosterism property and unusually wide range of desired biological properties. Thus, it is a perfect pre-built platform for the discovery of new scaffold development in medicinal chemistry. In recent years, the potential of oxazoles has garnered significant attention from medicinal chemists, resulting in the development of several synthetic and plant-based drugs currently in the market. Interest in the biological applications of oxazoles has notably intensified over the past fifteen years. This overview aims to provide a comprehensive, systematic summary of recent advancements in the synthetic chemistry of oxazole-based compounds, highlighting significant progress in their biological applications during this period as well as outlining prospects for further development. In summary, we overview literature in synthetic chemistry and explore structure- activity relationships and mechanisms of action with medicinal applications for the development of oxazole derivatives that hold promise for discovering new and effective drug candidates.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Medicinal ChemistryPub Date : 2025-01-20DOI: 10.2174/0115734064309469240806104435
Aniqa Moveed, Shagufta Parveen, Nusrat Shafiq, Awais Ali, Maryam Rashid, Mohammed Bourhia, Fouad Msanda, Ahmad Mohammad Salamatullah, Simone Brogi
{"title":"Natural Compounds from Alhagi maurorum as Potential HCC and HepG2 Inhibitors: An Integrated Study using Pharmacophore Development, Molecular Docking, MD Simulation, and DFT Approaches.","authors":"Aniqa Moveed, Shagufta Parveen, Nusrat Shafiq, Awais Ali, Maryam Rashid, Mohammed Bourhia, Fouad Msanda, Ahmad Mohammad Salamatullah, Simone Brogi","doi":"10.2174/0115734064309469240806104435","DOIUrl":"https://doi.org/10.2174/0115734064309469240806104435","url":null,"abstract":"<p><strong>Background: </strong>The rise in the frequency of liver cancer all over the world makes it a prominent area of research in the discovery of new drugs or repurposing of existing drugs.</p><p><strong>Methods: </strong>This article describes the pharmacophore-based structure-activity relationship (3DQSAR) on the secondary metabolites of Alhagi maurorum to inhibit human liver cancer cell lines Hepatocellular carcinoma (HCC) and hepatoma G2 (HepG2) which represents the molecular level understanding for isolated phytochemicals of Alhagi maurorum. The definite features, such as hydrophobic regions, average shape, and active compounds' electrostatic patterns, were mapped to screen phytochemicals. The 3D-QSAR model generates pharmacophore-based descriptors and alignment of active compounds. Further, docking studies were performed on the active compounds to check out their binding affinity with the active site of the target proteins. It was further validated by applying molecular simulations, and the results were found to be accurate. The geometrical optimization and energy gap of the hit compound were calculated by the density functional theory (DFT). Then, ADMET was performed on this hit compound for drug-like features and toxicity.</p><p><strong>Result: </strong>Out of 59 compounds, eight ligands were found active after the 3D-QSAR study. After that, molecular docking was performed on the active compounds F72, F52, F54, F29, F37, F38, F25, and F29, which were recognized as potential targets, and the docking results showed that compound F52 (also an FDA-approved drug) was the best hit. F52 was found to be the best hit against liver cancer cell lines HCC and HepG2.</p><p><strong>Conclusion: </strong>This study would be helpful for early drug discovery optimization and lead identification.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Medicinal ChemistryPub Date : 2025-01-17DOI: 10.2174/0115734064337582241103172720
Kemal Alp Nalcı, Cihat Mete, Zeynep Demir, İshak Bildirici, Adnan Cetin
{"title":"Promising Anticancer Activity of Pyrazole Compounds against Glioblastoma Multiforme: Their Synthesis, In vitro, and Molecular Docking Studies.","authors":"Kemal Alp Nalcı, Cihat Mete, Zeynep Demir, İshak Bildirici, Adnan Cetin","doi":"10.2174/0115734064337582241103172720","DOIUrl":"https://doi.org/10.2174/0115734064337582241103172720","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma Multiforme (GBM), a highly aggressive and prevalent brain cancer with a higher incidence in males, has limited treatment success due to drug resistance, inadequate targeting and penetration of cancer cells, and an incomplete understanding of its molecular pathways. GBM is a highly aggressive brain cancer with limited treatment options. This study investigates the anticancer potential of synthesized pyrazole compounds against GBM cells.</p><p><strong>Methods: </strong>A series of pyrazole derivatives were synthesized and tested for their efficacy against GBM using MTT assays. Molecular docking studies were conducted to explore the binding interactions of these compounds with GBM receptors.</p><p><strong>Results: </strong>Compounds 3 and 5 demonstrated significant anticancer activity, reducing cell viability more effectively than the control group. MTT assay results confirmed their potency. Molecular docking studies revealed strong binding interactions with GBM receptors, highlighting their potential as anticancer agents.</p><p><strong>Conclusion: </strong>The study evaluated the anticancer activity of synthesized compounds on human GBM cells, with compounds 3 and 5 showing the most promising results. Pyrazole 3 significantly reduced cell viability at high concentrations, while both pyrazoles 3 and 5 required higher doses to achieve substantial effects, as indicated by their IC50 values. Molecular docking studies confirmed strong binding interactions with the GBM receptor, and the pharmacokinetic properties suggest their potential as anticancer agents. These results highlight compounds 3 and 5 as candidates for further investigation.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Medicinal ChemistryPub Date : 2025-01-13DOI: 10.2174/0115734064311430240906112547
Md Saddam Hossain, Md Mosahaq Ali, Prithbey Raj Dey, Md Parvez Khondokar, S M Jahurul Haque, Yousef A Bin Jardan, Samir Ibenmoussa, Mohammed Bourhia
{"title":"Identification of Natural Terpenoid Compounds as Potential Inhibitors of Nucleoprotein of Influenza A Virus using in silico Approach: ADMET, Molecular Docking, and Molecular Dynamic Simulation.","authors":"Md Saddam Hossain, Md Mosahaq Ali, Prithbey Raj Dey, Md Parvez Khondokar, S M Jahurul Haque, Yousef A Bin Jardan, Samir Ibenmoussa, Mohammed Bourhia","doi":"10.2174/0115734064311430240906112547","DOIUrl":"10.2174/0115734064311430240906112547","url":null,"abstract":"<p><strong>Background: </strong>We continue to struggle with the prevention and treatment of the influenza virus. The 2009 swine flu pandemic, caused by the H1N1 strain of influenza A, resulted in numerous fatalities. The threat of influenza remains a significant concern for global health, and the development of novel drugs targeting these viruses is highly desirable.</p><p><strong>Objective: </strong>The objective of this study is to explore the inhibitory potential of terpenoid compounds against the Nucleoprotein (NP) of influenza A virus, which is a highly effective drug target due to its ability to facilitate the transcription and replication of viral RNA.</p><p><strong>Method: </strong>In silico research was performed to identify potential inhibitors of NP. Molecular docking studies were conducted to assess the binding of terpenoid compounds to the active site residues of the target protein. The most promising hits were then subjected to molecular dynamics simulations to examine the stability of the protein-ligand complexes. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies and Lipinski's rule of five were employed to evaluate the drug safety and druglikeness of the compounds.</p><p><strong>Result: </strong>Docking studies revealed that the terpenoid compounds bind strongly to the active site residues of the NP protein. Molecular dynamics simulations demonstrated the stability of the proteinligand complexes for the best-hit compounds. ADMET studies and Lipinski's filter indicated that the compounds exhibit desirable drug safety and drug-likeness profiles.</p><p><strong>Conclusion: </strong>This work may contribute significantly to drug discovery and the development of therapeutic agents against the influenza A virus. The identification of terpenoid compounds that bind strongly to the NP protein and exhibit favorable drug-like properties through in silico studies provides a promising foundation for further research and the development of potential inhibitors targeting this critical viral protein.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Medicinal ChemistryPub Date : 2025-01-13DOI: 10.2174/0115734064310145240822060730
Haruna Isiyaku Umar, Zainab Ashimiyu-Abdusalam, Neeraj Kumar, Najwa Ahmad Kuthi, Omoboyede Victor, Zainab Naeem Abdulsalam, Elizabeth Oluwabunmi Aribo, Ridwan Opeyemi Bello, Yousef A Bin Jardan, Hiba-Allah Nafidi, Mohammed Bourhia
{"title":"An Integrative Computational Approach for the Identification of C-Abl Kinase Inhibitors from Anti-Parkinson Plant-Derived Bioactive.","authors":"Haruna Isiyaku Umar, Zainab Ashimiyu-Abdusalam, Neeraj Kumar, Najwa Ahmad Kuthi, Omoboyede Victor, Zainab Naeem Abdulsalam, Elizabeth Oluwabunmi Aribo, Ridwan Opeyemi Bello, Yousef A Bin Jardan, Hiba-Allah Nafidi, Mohammed Bourhia","doi":"10.2174/0115734064310145240822060730","DOIUrl":"https://doi.org/10.2174/0115734064310145240822060730","url":null,"abstract":"<p><strong>Background: </strong>Oxidative stress is strongly linked to neurodegeneration through the activation of c-Abl kinase, which arrests α-synuclein proteolysis by interacting with parkin interacting substrate (PARIS) and aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2). This activation, triggered by ataxia-telangiectasia mutated (ATM) kinase, leads to dopaminergic neuron loss and α-synuclein aggregation, a critical pathophysiological aspect of Parkinson's disease (PD). To halt PD progression, pharmacological inhibition of c-Abl kinase is essential. Despite three generations of tyrosine kinase inhibitors (TKIs) being explored for PD treatment, they present significant concerns including poor blood-brain barrier penetration, off-target effects, and severe side effects. Notably, there are currently no FDA-approved c-Abl kinase inhibitors in clinical usage for PD treatment, highlighting the urgent need for potent, safe, and cost-effective alternatives.</p><p><strong>Objective: </strong>This study aims to identify potential c-Abl kinase inhibitors from plant-derived compounds with reported anti-Parkinson's potential and their derivatives using molecular docking, molecular dynamics simulations (MDS), and in silico pharmacokinetics and toxicity profiling.</p><p><strong>Methods: </strong>Seventy-eight compounds sourced from literature were docked against c-Abl kinase using Maestro 12.5. The top three hit compounds, along with nilotinib (control drug), were subjected to drug-likeness, ADMET profiling using the AI Drug Lab server and 100 ns MDS using Desmond.</p><p><strong>Results: </strong>Amburoside A, diarylheptanoid MS13, and dimethylaminomethyl-substituted-curcumin showed binding affinities close to nilotinib, with values of -12.615, -12.556, and -11.895 kcal/mol respectively, compared to nilotinib's -16.826 kcal/mol. The three plant-derived compounds exhibited excellent structural stability and favorable ADMET profiles, including optimal blood-brain barrier permeation Conclusion: The three hit compounds identified in this study show potential as c-Abl kinase inhibitors. Given the absence of FDA-approved c-Abl kinase inhibitors for PD, these findings are significant as they could contribute new therapeutic options for the treatment and management of PD. However, further in vitro and in vivo experiments are necessary to validate these findings.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}