Article
Chemistry, Medicinal
Anze Meden, Damijan Knez, Xavier Brazzolotto, Florian Nachon, Jose Dias, Jurij Svete, Jure Stojan, Uros Groselj, Stanislav Gobec
Summary: The lead optimization of a series of tryptophan-based nanomolar BChE inhibitors resulted in highly potent, achiral, sp(3)-rich tertiary amines with better synthetic accessibility and high selectivity. Introduction of a carbamate warhead allowed conversion to pseudoirreversible inhibitors that covalently bound to BChE. The discovery of a novel leaving group chemotype and the structural analysis provided valuable insights for future optimization of this series.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Xia Jiang, Ziwen Zhang, Jiawei Zuo, Chengyao Wu, Liang Zha, Yingying Xu, Sheng Wang, Jingbo Shi, Xin-Hua Liu, Jing Zhang, Wenjian Tang
Summary: The study identified a potent novel inhibitor C16 with high selectivity for BuChE, possessing various beneficial pharmacological and drug-like properties, and demonstrated significant improvement in cognitive impairment in vivo, showing promising therapeutic effects.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Dawid Panek, Anna Pasieka, Gniewomir Latacz, Paula Zareba, Michal Szczech, Justyna Godyn, Fabien Chantegreil, Florian Nachon, Xavier Brazzolotto, Anna Skrzypczak-Wiercioch, Maria Walczak, Magdalena Smolik, Kinga Salat, Georg Hoefner, Klaus Wanner, Anna Wieckowska, Barbara Malawska
Summary: A highly selective hBuChE inhibitor (29) with potential benefits for treating Alzheimer's disease has been identified through extensive in vitro and in vivo evaluations.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Dan Liu, Honghua Zhang, Yuying Wang, Wencheng Liu, Gaofeng Yin, Degui Wang, Junfang Li, Tao Shi, Zhen Wang
Summary: This study designed and evaluated a series of carbamate derivatives as multifunctional therapeutic agents for Alzheimer's disease. Compound 1g exhibited dual inhibitory activity against AChE and BChE, reduced pro-inflammatory cytokine levels, increased anti-inflammatory cytokine levels, and inhibited the aggregation of A beta(1-42). It showed potential as a multi-functional therapeutic agent for further investigation in AD treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Yuying Wang, Honghua Zhang, Dan Liu, Xuelin Li, Lin Long, Ying Peng, Fujian Qi, Yuqing Wang, Weifan Jiang, Zhen Wang
Summary: Based on a previously studied anti-AD molecule, this work introduces different substituents at different positions to improve drug-like properties and on target activities. A total of 33 N-salicyloyl tryptamine-carbamate hybrids were designed, synthesized, and evaluated as cholinesterase inhibitors. Compound H327 showed the highest potency as a BChE inhibitor and demonstrated neuroprotective, antioxidative, and anti-neuroinflammatory properties. Pharmacokinetics studies revealed that H327 had better pharmacokinetic parameters and higher bioavailability than the lead compound. Behavioral tests showed that H327 significantly improved scopolamine-induced cognitive impairment. Overall, compound H327 is a promising multi-target agent for the treatment of AD.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Raquel B. M. de Almeida, Deyse B. B. Barbosa, Mayra R. R. do Bomfim, Jessika A. O. Amparo, Bruno S. S. Andrade, Silvia L. L. Costa, Joaquin M. Campos, Jorddy N. Cruz, Cleydson B. R. Santos, Franco H. A. Leite, Mariana B. B. Botura
Summary: The compound ZINC390718 was found to exhibit inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and showed low cytotoxicity in vitro. Molecular dynamics (MD) simulation revealed that ZINC390718 interacted with the catalytic residue sites of both enzymes. These findings suggest that ZINC390718 could be a potential chemotype for the development of new dual cholinesterase inhibitors.
Article
Biochemistry & Molecular Biology
Shuaishuai Xing, Ying Chen, Baichen Xiong, Weixuan Lu, Qi Li, Yuanyuan Wang, Mengxia Jiao, Feng Feng, Yao Chen, Wenyuan Liu, Haopeng Sun
Summary: 2513-4169, a promising lead compound, shows potential inhibitory activity and neuroprotective effect for treating Alzheimer's disease.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Biochemistry & Molecular Biology
Sultan Darvesh, Scott Banfield, Maeve Dufour, Katrina L. Forrestall, Hillary Maillet, G. Andrew Reid, Dane Sands, Ian R. Pottie
Summary: The study aimed to determine whether the KR histochemical method could be used to evaluate probes at the site of pathology. The results suggest that the KR method may provide an efficient means to screen compounds as probes for imaging AD-associated ChEs.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Honghua Zhang, Yuying Wang, Yuqing Wang, Xuelin Li, Shuzhi Wang, Zhen Wang
Summary: Alzheimer's disease is the fourth leading cause of death among the elderly worldwide, posing enormous challenges to society. Developing multi-target directed ligands has become a major strategy in combating AD due to its complex pathogenesis. Carbamate moiety, which shares structural similarity to the neurotransmitter acetylcholine, has received significant attention in the discovery of multifunctional cholinesterase inhibitors. Preclinical studies have shown that carbamate-based cholinesterase inhibitors can effectively increase the level of acetylcholine and improve cognitive impairments and behavioral deficits, providing a promising approach for AD treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Physical
Zeinab Faghih, Soghra Khabnadideh, Amirhossein Sakhteman, Ali Khohadel Shirazi, Hojat Allah Yari, Ali Chatraei, Zahra Rezaei, Sara Sadeghian
Summary: A series of novel carbazole-benzylpiperazine hybrids were synthesized and their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The results showed that the type of linker and substitutions greatly affected the inhibitory activity and selectivity of the compounds. Compound 7a with meta and para fluorine substitution exhibited the highest inhibitory activity against AChE, while compounds 7h and 7k with meta fluorine and meta methyl substitutions showed the strongest inhibition against BuChE. Kinetic analysis and molecular modeling studies revealed that compound 7e acted as a mixed-type inhibitor against AChE, interacting with both the catalytic active site and the peripheral anionic site.
JOURNAL OF MOLECULAR STRUCTURE
(2023)
Article
Biochemistry & Molecular Biology
Nguyen Manh Cuong, Pham Ngoc Khanh, Le Thi Hong Nhung, Nguyen Xuan Ha, Tran Thu Huong, Katarina Bauerova, Young Ho Kim, Do Dinh Tung, Trinh Thi Thuy, Nguyen Thi Hoang Anh
Summary: From the root bark of Pinus krempfii Lecomte, four flavonoids were isolated and evaluated for their inhibitory activities against AChE and BChE enzymes in vitro and in silico. Tectochrysin (1) showed the highest inhibition activity against AChE and formed stable complexes with the protein. Galangin (2) exhibited significant inhibitory activity against BChE and formed hydrogen bonds with the protein. The study provided new insights for drug discovery and the development of neuroprotective substances for Alzheimer's disease treatment.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Nutrition & Dietetics
Qazi Mohammad Sajid Jamal, Mohammad Imran Khan, Ali H. H. Alharbi, Varish Ahmad, Brijesh Singh Yadav
Summary: Alzheimer's disease (AD), the most common type of dementia, is associated with memory and thinking problems. Flavonoids in apple have been identified as potential inhibitors for AD. This study found that CID: 12000657 could be used as an AChE inhibitor and CID: 135398658 as a BuChE inhibitor for the treatment of AD and other neurological disorders.
Article
Chemistry, Medicinal
Francois-Xavier Toublet, Julien Lalut, Berenice Hatat, Cedric Lecoutey, Audrey Davis, Marc Since, Sophie Corvaisier, Thomas Freret, Jana Sopkova-de Oliveira Santos, Sylvie Claeysen, Michel Boulouard, Patrick Dallemagne, Christophe Rochais
Summary: Novel multitarget directed ligands are being developed in the field of Alzheimer's disease treatment to address the complexity of the disease. In this context, a new pleiotropic carbamate has been developed as a covalent inhibitor of BuChE and a precursor to a potent 5-HT6 receptors antagonist, showing promising in silico and in vitro results as well as first in vivo findings in restoring working memory.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Patrick Masson, Zukhra Shaihutdinova, Oksana Lockridge
Summary: Butyrylcholinesterase (BChE) is an enzyme found in plasma and various cells and organs, with unclear physiological function(s). It has pharmacological and toxicological importance due to its broad substrate specificity and capability to hydrolyze a wide range of substances. The existence of genetic poly-allelism affecting BChE's catalytic properties can lead to clinical complications when using certain drugs catabolized by BChE. However, there is limited quantitative data available for most drugs, and the impact of BChE genetic mutations on catalytic parameters is largely unknown.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Ante Milicevic, Goran Sinko
Summary: This study developed QSAR models based on simple descriptors to estimate BChE inhibition potency of different compounds, achieving good correlation with certain topological and constitutional descriptors.
Article
Chemistry, Multidisciplinary
Hiroshi Kitamura, Yuma Otake, Naoto Sugisawa, Hiroki Sugisawa, Tomonori Ida, Hiroyuki Nakamura, Shinichiro Fuse
Summary: In this study, a sequential nucleophilic substitution reaction was demonstrated in a continuous-flow reactor, where the occurrence of over nucleophilic substitution during the reaction was suppressed by the addition of imidazole. The findings suggest that the presence of imidazole significantly improves the selectivity of the reaction.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Review
Pharmacology & Pharmacy
Ryo Kunimoto, Juergen Bajorath, Kazumasa Aoki
Summary: Artificial intelligence and data science are starting to influence drug discovery. A pilot study at Daiichi Sankyo Company has attempted to integrate data science into practical medicinal chemistry and quantify its impact. The results indicate the potential of data-driven medicinal chemistry and suggest new models for training next-generation medicinal chemists.
DRUG DISCOVERY TODAY
(2022)
Review
Chemistry, Applied
Hisashi Masui, Shinichiro Fuse
Summary: Peptides have gained increasing importance as drugs and drug candidates. Microflow synthesis, with an inner tube diameter of <=1 mm, offers advantages such as precise control of reaction time and temperature, as well as easy scale-up. The combination of microflow technology, automated synthesis, and online monitoring has improved synthetic efficiency and provided reliable data for machine learning models.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Article
Multidisciplinary Sciences
Yoshinori Tsumura, Yu Tsushima, Azusa Tamura, Hirotsugu Kato, Tsunefumi Kobayashi
Summary: A diabetic animal model with diminished efficacy after long-term treatment with a glucokinase activator was identified, and the mechanism underlying this diminished efficacy was analyzed. Disruptions in hepatic glucose metabolism were found to be involved in the diminished efficacy of glucokinase activators.
Article
Chemistry, Multidisciplinary
Hirotomo Moriwaki, Shin Saito, Tomoya Matsumoto, Takayuki Serizawa, Ryo Kunimoto
Summary: In drug discovery, predicting activity and absorption, distribution, metabolism, excretion, and toxicity parameters is crucial. Recent research has focused on prediction methods using deep learning and non-deep learning approaches. This study compared and discussed the prediction results of activity using both methods on in-house assay data for hundreds of kinases. The multitask graph neural network (GNN) model outperformed the non-deep learning model and showed extrapolative validity. The findings suggest that ligand-based prediction methods can be used for activity prediction and drug design.
Article
Chemistry, Multidisciplinary
Yuma Otake, Kyohei Adachi, Yoshiaki Yamashita, Natsumi Iwanaga, Hirokatsu Sunakawa, Taiki Shamoto, Jun-ichi Ogawa, Atsushi Ito, Yutaka Kobayashi, Keiichi Masuya, Shinichiro Fuse, Daisuke Kubo, Hidenosuke Itoh
Summary: In this study, an automated continuous-flow liquid-phase peptide synthesizer was developed for the preparation of C-terminal free peptides. The synthesizer comprised an amidation unit, extraction unit, concentration unit, and control unit. The system successfully synthesized crude dipeptides and tripeptides by using a stepwise approach. The stability of the flow system was continuously monitored, and peptide synthesis was monitored using a near-infrared (NIR) sensor. This strategy enables liquid-phase continuous-flow peptide synthesis and in-line NIR monitoring of peptide-bond formation, contributing to enhanced efficiency in peptide production.
REACTION CHEMISTRY & ENGINEERING
(2023)
Article
Chemistry, Multidisciplinary
Otoka Shamoto, Keiji Komuro, Naoto Sugisawa, Ting-Ho Chen, Hiroyuki Nakamura, Shinichiro Fuse
Summary: In this study, we propose a unconventional approach to peptide cyclization using acylammonium species generated from inexpensive and less wasteful Me2NBn and ClCO(2)i-Pr. Our method shows rapid activation of the C-terminus of cyclization precursors by an acylammonium ion, enabling rapid cyclization of difficult peptides without degradation or dimerization. Compared to previous reports, our approach demonstrates superior ease of purification, productivity, and reaction mass efficiency. Furthermore, we successfully synthesized a previously reported versicotide D analogue and propose the revision of its assigned stereostructure based on our data.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Organic
Naoto Sugisawa, Kohei Nakabayashi, Hiroki Sugisawa, Shinichiro Fuse
Summary: We have developed one-step syntheses for unsymmetrical sulfamides and N-substituted sulfamate esters by modifying the nucleophile and tertiary amine. Symmetrical sulfite formation was prevented by changing the tertiary amine during the synthesis of N-substituted sulfamate esters. The impact of tertiary amines was explained using linear regression. Our approach allows for rapid production (<= 90 s) of desired products with labile acidic and/or basic groups under mild (20 degrees C) conditions, eliminating the need for tedious purification.
Review
Chemistry, Multidisciplinary
Hiroshi Kitamura, Shinichiro Fuse
Summary: PCl3 and POCl3 are important sources of phosphorus-containing compounds and have wide industrial applications. However, their high reactivity often leads to overreactions and poses significant risks. Phosphoramidites have been developed as phosphorylating reagents with mild electrophilicity, but they suffer from high costs, generation of waste, and long reaction times. Continuous-flow technology, particularly micro-flow technology, offers a promising solution by enabling precise control of reaction conditions and allowing safe operation with PCl3 and POCl3.
Article
Chemistry, Organic
Shinichiro Fuse, Ren Okabe
Summary: In this study, smaller cyclic peptides containing non-proteinogenic amino acids were synthesized in a rapid manner (60.5 min) by switching the substrate concentrations. Expensive transition-metals and coupling agents were not required. This is the first report of synthesizing smaller (≤16-membered) cyclic N-methylated peptides via a dimerization-cyclization strategy.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Naoto Sugisawa, Akira Ando, Shinichiro Fuse
Summary: Short peptides play a crucial role in drug development and the synthesis of longer peptides. Traditional methods of solid- and liquid-phase synthesis are time-consuming, expensive, and require tedious purification. In this study, we introduce a novel approach called one-flow, three-component coupling (3CC) that utilizes alpha-amino acid N-carboxy anhydrides (alpha-NCAs) as both electrophiles and nucleophiles. We successfully synthesized 17 tripeptides and achieved gram-scale synthesis of a tripeptide without the need for column chromatographic purification. By preparing alpha-NCA in situ from readily available protected amino acids, we achieved significant reductions in time and cost compared to solid-phase synthesis.
Article
Chemistry, Multidisciplinary
Hisashi Masui, Sena Kanda, Shinichiro Fuse
Summary: The authors examined previously reported preparations of (1H-indol-3-yl)methyl halides, clarified inconsistencies within the literature, and developed a highly versatile nucleophilic substitution method using microflow technologies, enabling the synthesis of various indole derivatives.
COMMUNICATIONS CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Shinichiro Fuse, Sena Kanda, Hisashi Masui
Summary: Valuable indole derivatives were synthesized via the sequential 1,2-addition/nucleophilic substitution of indolyl-3-carbaldehydes. Microflow technology was used to suppress undesired reactions caused by unstable intermediates, leading to higher yields and reproducibility. The study provides a rapid and efficient method for the synthesis of structurally diverse indole derivatives.
CHEMISTRY-AN ASIAN JOURNAL
(2023)
Article
Chemistry, Organic
Hisashi Masui, Shinichiro Fuse
Summary: Acyl ammonium cations can be prepared easily from inexpensive and commercially available nucleophilic tertiary amines and acid chlorides or chloroformates. The electrophilic nature of these cations allows rapid acylations, but also undesired reactions. The use of micro-flow technologies enables precise control over reaction time and temperature, suppressing undesired reactions and leading to more efficient and cost-effective syntheses of peptides and amino acid derivatives.
JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN
(2022)
Article
Chemistry, Organic
Ren Okabe, Naoto Sugisawa, Shinichiro Fuse
Summary: This study demonstrated the rapid dual activation of an alpha-amino acid N-carboxyanhydride and alkyl chloroformate in the synthesis of a urethane-protected alpha-amino acid N-carboxyanhydride using a micro-flow reactor. The use of two amines and proper timing activation was the key to success. Various urethane-protected alpha-amino acid N-carboxyanhydrides were synthesized in high yields.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
