Article
Chemistry, Physical
Lorena Camargo-Ayala, Efrain Polo-Cuadrado, Edison Osorio, Jorge Soto-Delgado, Yorley Duarte, Luis Prent-Penaloza, Margarita Gutierrez
Summary: The compounds derived from isocyanide-based multicomponent reactions show potential inhibitory activity against cholinesterase enzymes, making them promising candidates for the treatment of Alzheimer's disease.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Materials Science, Biomaterials
Congwei Yu, Ming Zhao, Zuchen Pan, Yiyang Bo, Weiwei Zhao, Xiongkui He, Jiaheng Zhang
Summary: Acute organophosphorus pesticide poisoning (AOPP) is a global health issue that attacks acetylcholinesterase (AChE) and causes harm. Utilizing BChE nanodepots (nBChE) has been shown to effectively block the attack on AChE and demonstrate prophylactic and therapeutic efficiency.
JOURNAL OF MATERIALS CHEMISTRY B
(2021)
Article
Biochemistry & Molecular Biology
Alessandro Pesaresi, Doriano Lamba, Lyubomir Vezenkov, Daniela Tsekova, Valentin Lozanov
Summary: Complex neurological disorders, including Alzheimer's disease, require multitarget drugs for treatment. This study reports on the synthesis and activity profiles of seven multitarget anti-Alzheimer compounds, and investigates their mechanisms using molecular docking simulations and enzyme inhibition kinetics.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Article
Neurosciences
Saritha S. L. Silva, Luciane V. V. Tureck, Leonardo C. Souza, Joao V. V. Mello-Hortega, Ana Luiza Piumbini, Mayza D. Teixeira, Lupe Furtado-Alle, Maria A. B. F. Vital, Ricardo L. R. Souza
Summary: Alzheimer's disease (AD) is a complex disease and the understanding of its pathogenesis is still incomplete. The cholinergic system has been implicated in AD, with alterations in acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and acetyltransferase (ChAT) activities. A rat model of late onset AD (LOAD) induced by intra-cerebroventricular injection of streptozotocin (icv-STZ) was used to study the long-term effects on the cholinergic system. The results showed decreased AChE and BChE activities in the hippocampus of STZ-induced rats euthanized 30 and 120 days after icv-STZ, suggesting that the cholinergic system may not be compromised in the long term.
Article
Medicine, Research & Experimental
Luka Rejc, Vanessa Gomez-Vallejo, Ana Joya, Oscar Moreno, Ander Egimendia, Pilar Castellnou, Xabier Rios-Anglada, Unai Cossio, Zurine Baz, Rossana Passannante, Ignacio Tobalina-Larrea, Pedro Ramos-Cabrer, Albert Giralt, Magdalena Sastre, Estibaliz Capetillo-Zarate, Urban Kosak, Damijan Knez, Stanislav Gobec, Mariel Marder, Abraham Martin, Jordi Llop
Summary: The study investigated the potential of butyrylcholinesterase (BChE) as an early biomarker for Alzheimer's disease (AD) by analyzing its abundance in the brains of AD model animals and controls. The results suggested that BChE accumulation in the brain is associated with amyloid beta deposition, indicating its promising role as an early biomarker for AD.
Article
Biochemistry & Molecular Biology
Ana Mercia Silva Mascarenhas, Raquel Bianca Marchesine de Almeida, Moyses Fagundes de Araujo Neto, Gessica Oliveira Mendes, Jorddy Neves da Cruz, Cleydson Breno Rodrigues dos Santos, Mariana Borges Botura, Franco Henrique Andrade Leite
Summary: This study aimed to identify promising dual inhibitors against hAChE and hBuChE using in silico approaches. By constructing pharmacophore models and conducting molecular docking experiments, several potential dual inhibitors against both enzymes were identified.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Chemistry, Medicinal
Kristin M. Reiland, Todd J. Eckroat
Summary: Polymethylene-linked isatin dimers and 3-indolyl-3-hydroxy-2-oxindole dimers were synthesized as selective BChE inhibitors, with the best compounds showing significant inhibitory activity and moderate blood-brain barrier permeability. These compounds exhibited selectivity towards BChE and demonstrated potential as lead compounds for further exploration.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Pharmacology & Pharmacy
Ana Matosevic, Andreja Radman Kastelic, Ana Mikelic, Antonio Zandona, Maja Katalinic, Ines Primozic, Anita Bosak, Tomica Hrenar
Summary: The study confirmed that quinuclidinium carbamates are promising candidates for further development as CNS-active drugs, particularly for Alzheimer's disease treatment. The synthesized compounds showed good acetylcholinesterase and butyrylcholinesterase inhibitory activity, and were able to pass the blood-brain barrier.
Article
Biochemistry & Molecular Biology
Sri Devi Sukumaran, Shah Bakhtiar Nasir, Jia Ti Tee, Michael J. C. Buckle, Rozana Othman, Noorsaadah Abd Rahman, Vannajan Sanghiran Lee, Syed Nasir Abbas Bukhari, Chin Fei Chee
Summary: A series of C4-substituted tertiary nitrogen-bearing 2 '-hydroxychalcones were synthesized and compound 4c showed the best inhibition against acetylcholinesterase with high selectivity over butyrylcholinesterase. Molecular docking studies and ADMET analysis support the therapeutic potential of compound 4c as a lead compound for Alzheimer's disease treatment.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Selena P. Maxwell, Meghan K. Cash, Sultan Darvesh
Summary: A study found that some octogenarians and older adults maintain normal cognitive function despite a high prevalence of cognitive decline linked to neurodegeneration or aging. The preserved cholinergic neurotransmission in specific brain regions may contribute to their intact cognition.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Article
Chemistry, Medicinal
Bushra Adalat, Fazal Rahim, Wajid Rehman, Zarshad Ali, Liaqat Rasheed, Yousaf Khan, Thoraya A. Farghaly, Sulaiman Shams, Muhammad Taha, Abdul Wadood, Syed A. A. Shah, Magda H. Abdellatif
Summary: Twenty-one analogs based on benzimidazole, incorporating a substituted benzaldehyde moiety (1-21), were synthesized and screened for their acetylcholinesterase and butyrylcholinesterase inhibition profiles. Compound 3 showed the most potent activity due to the presence of chloro groups at the 3 and 4 positions of the phenyl ring. Molecular dynamics simulations revealed that compound 3 formed the most stable complex with both acetylcholinestrase and butyrylcholinesterase, displaying higher binding affinities compared to the standard inhibitor donepezil.
Article
Biochemistry & Molecular Biology
Peng Liu, Maojun Cheng, Jie Guo, Duanyuan Cao, Jinchong Luo, Yang Wan, Yuanying Fang, Yi Jin, Sai-Sai Xie, Jing Liu
Summary: We have developed a series of melatonin-alkylbenzylamine hybrids as multitarget agents for Alzheimer's disease treatment. Most of these compounds showed potent multifunctional effects, including cholinesterase inhibition and antioxidant activity. Compound 5 demonstrated the highest antioxidant capacity (ORAC = 5.13) and acted as a selective inhibitor of BuChE (huBuChE IC50 = 1.20 mu M, huAChE IC50 = 177.49 mu M, SI = 147.91). It also induced the expression of Nrf2 and its downstream markers at the protein level. Moreover, compound 5 exhibited no acute toxicity in mice at doses up to 2500 mg/kg and improved memory function in scopolamine-induced amnesia mice.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Food Science & Technology
Nancy D. Asen, Ogadimma D. Okagu, Chibuike C. Udenigwe, Rotimi E. Aluko
Summary: This study investigated the potential of peptides derived from yellow field pea as inhibitors of BuChE activity in Alzheimer's disease. The results showed that these peptides had a strong affinity for BuChE and could effectively inhibit its activity. The mode of inhibition was through the catalytic triad and/or peripheral anionic site. These findings suggest that yellow field pea peptides could be used as a potential therapy for Alzheimer's disease.
JOURNAL OF FUNCTIONAL FOODS
(2023)
Review
Biochemistry & Molecular Biology
Anna Bubley, Alexaner Erofeev, Peter Gorelkin, Elena Beloglazkina, Alexander Majouga, Olga Krasnovskaya
Summary: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by Aβ aggregation, tau hyperphosphorylation, and loss of cholinergic neurons. AD is also associated with oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. In this review, THA-based hybrids are summarized as potential anti-AD agents, highlighting strategies for drug design that have led to cognitive improvements and reduced hepatotoxicity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Junio G. Silva, Tatiane F. Borgati, Samuel M. G. Lopes, Niels Heise, Sophie Hoenke, Rene Csuk, Luiz C. A. Barbosa
Summary: A series of amides derived from (3aR)-(+)-sclareolide were synthesized and evaluated as inhibitors for AChE or BuChE. Five amides showed strong inhibition towards BuChE, outperforming the positive control galantamine, and exhibited favorable properties for drug development, including permeability across the blood brain barrier and adherence to Lipinski rules.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Tingkai Chen, Tianyu Sun, Yaoyao Bian, Yuqiong Pei, Feng Feng, Heng Chi, Yuan Li, Xu Tang, Shenghu Sang, Chenxi Du, Ying Chen, Yao Chen, Haopeng Sun
Summary: Multitarget drugs may improve the treatment of multifactorial diseases, but there are few on the market or in clinical trials currently, with multitarget peptides showing good effects in various diseases. The design of multitarget peptides involves target combination, peptide selection, lead generation, and lead optimization.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Hui Liu, Weimin Qiu, Tianyu Sun, Lei Wang, Chenxi Du, Yanyu Hu, Wenyuan Liu, Feng Feng, Yao Chen, Haopeng Sun
Summary: This article introduces the advantages of small molecule inhibitors in the treatment of glioblastoma and discusses the related targets of major pathways. It also discusses the recent advances in temozolomide resistance and drug combination, and reviews the research progress of other therapeutic methods to provide a more comprehensive understanding of the treatment landscape of glioblastoma.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Chemistry, Multidisciplinary
Xianglai Liu, Yingying Song, Ao Liu, Yueer Zhou, Qian Zhu, Yetong Lin, Huiyong Sun, Kaidi Zhu, Wei Liu, Ning Ding, Weijia Xie, Haopeng Sun, Biao Yu, Peng Xu, Wei Li
Summary: The study demonstrates that PTFAI can serve as a stereodirecting group for 1,2-cis alpha-glycosylation, leading to improved selectivity in glycosylation reactions. The involvement of 6-PTFAI in remote participation was confirmed using low-temperature NMR, shedding light on the reaction mechanism. This strategy shows promise for the synthesis of complex carbohydrates and derivatives.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Review
Biochemistry & Molecular Biology
Yuanyuan Wang, Baichen Xiong, Shuaishuai Xing, Ying Chen, Qinghong Liao, Jun Mo, Yao Chen, Qi Li, Haopeng Sun
Summary: Tyrosinase is a bifunctional enzyme involved in melanogenesis. It is targeted for various applications such as skin whitening, anticancer treatment, antibacterial properties, and fruit and vegetable preservation. Medicinal chemists have developed diverse tyrosinase inhibitors with novel scaffolds and synergistic effects to regulate multiple targets. This review covers natural and synthetic tyrosinase inhibitors with potential applications in various fields.
CURRENT MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Xuemei Wei, Guoqi Yu, Hualiang Shen, Yanjuan Luo, Tianbo Shang, Runpu Shen, Meiyang Xi, Haopeng Sun
Summary: Phosphodiesterase 4 (PDE4), highly expressed in mammalian brain, selectively hydrolyzes cAMP, a key regulator of brain functions such as learning and memory. Inhibiting PDE4 can improve cognitive deficits, but its clinical development is hindered by adverse effects. Research on PDE4 subtypes and the development of subtype-specific inhibitors show promise for improved therapeutic benefits and safety.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Yang Liu, Yuting Chen, Jiheng Jiang, Xianglin Chu, Qinglong Guo, Li Zhao, Feng Feng, Wenyuan Liu, Xiaolong Zhang, Siyu He, Peng Yang, Pengfei Fang, Haopeng Sun
Summary: AKR1C3 is overexpressed in hormone-related cancers and is correlated with tumor development and aggressiveness. A new class of AKR1C3 inhibitors with potent inhibitory activity and selectivity for closely related isoforms has been developed. Co-administration of these inhibitors with doxorubicin can significantly reverse drug resistance in breast cancer cells. These AKR1C3 inhibitors may serve as effective adjuvants to overcome drug resistance in breast cancer treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Chemistry, Multidisciplinary
Xianqing Deng, Haopeng Sun, Bahaa G. M. Youssif
FRONTIERS IN CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Hualiang Shen, Xinde Xu, Yalong Bai, Xiaoping Wang, Yibin Wu, Jia Zhong, Qiyi Wu, Yanjuan Luo, Tianbo Shang, Runpu Shen, Meiyang Xi, Haopeng Sun
Summary: The Kynurenine pathway (KP) is the primary pathway of L-tryptophan metabolism in mammals, and it produces neuroactive metabolites such as kynurenic acid (KA) and quinolinic acid (QA). Imbalance in KP has been associated with aging and neurodegenerative diseases (NDs), leading to the interest in targeting KP enzymes and metabolite-associated receptors, particularly kynurenine monooxygenase (KMO). Although several agents have shown significant improvement in animal models, only one aryl hydrocarbon receptor (AHR) agonist 30 (laquinimod) has entered clinical trials for treating Huntington's disease (HD). This review provides an overview of neuroactive KP metabolites, discusses KP dysregulation in aging and NDs, and summarizes the development of KP regulators in preclinical and clinical studies, offering insights into the potential of targeting KP for NDs treatment in the future.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xu Tang, Shuaishuai Xing, Mingkang Ma, Ziwei Xu, Qianwen Guan, Yuting Chen, Feng Feng, Wenyuan Liu, Tingkai Chen, Yao Chen, Haopeng Sun
Summary: Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which is the most common genetic risk factor for PD. This publication provides a comprehensive overview of the structure, function, and mutations of LRRK2, as well as recent advances and challenges in developing LRRK2 inhibitors. The binding mechanisms, structure-activity relationships, and pharmacokinetic features of inhibitors are emphasized to guide the rational design of LRRK2 inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Lu Lu, Jingyi Chen, Wenxiang Tao, Zhimei Wang, Dan Liu, Jiahui Zhou, Xiaoxing Wu, Haopeng Sun, Wei Li, Genzoh Tanabe, Osamu Muraoka, Bo Zhao, Liang Wu, Weijia Xie
Summary: We attempted double-spot structural modification on a side-chain moiety of sulfonium-type alpha-glucosidase inhibitors isolated from Salacia genus. We designed and synthesized a series of sulfonium salts with benzylidene acetal linkage at the C3 ' and C5 ' positions. In vitro enzyme inhibition evaluation showed that compounds with a strong electron-withdrawing group attached at the ortho position on the phenyl ring have stronger inhibitory activities. Notably, the most potent inhibitor 21b showed excellent hypoglycemic effects in mice, comparable to acarbose. Molecular docking of 21b revealed the importance of the newly introduced benzylidene acetal moiety in anchoring the molecule in the enzyme's concave pocket. The identification of 21b as a lead compound may enable structure modification and diversification of sulfonium-type alpha-glucosidase inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Haojie Dong, Xiuquan Ye, Yasheng Zhu, Hao Shen, Hongtao Shen, Weijiao Chen, Minghui Ji, Mingming Zheng, Keren Wang, Zeyu Cai, Haopeng Sun, Yibei Xiao, Peng Yang
Summary: In this study, a series of Osimertinib derivatives were designed as fourth-generation inhibitors targeting Osimertinib-resistant NSCLC. The top candidate D51 showed potent inhibition against EGFR mutants, selectivity against wild-type forms, and favorable in vivo druggability.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Weimin Qiu, Hui Liu, Yijun Liu, Xin Lu, Lei Wang, Yanyu Hu, Feng Feng, Qi Li, Haopeng Sun
Summary: Alzheimer's disease (AD) is a difficult to treat progressive neurodegenerative disease characterized by the accumulation of amyloid beta (A beta) plaques in the brain. A beta interacts with various receptors on the plasma membrane and mediates signaling pathways that contribute to the development of AD. Despite ongoing research, there are currently no effective medications for AD. This review discusses the importance of A beta in the pathogenesis of AD, recent progress in targeting A beta-related receptors and compounds, and the challenges and opportunities in developing effective therapies for AD.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Chang Liu, Manxing Zou, Jianguo Zuo, Huanfang Xie, Weiping Lyu, Jian Xu, Feng Feng, Haopeng Sun, Wenyuan Liu, Xueyang Jiang
Summary: The FDA has approved donepezil, a selective AChE inhibitor, as a first-line drug for mild to moderate AD, but patients taking donepezil often experience peripheral side effects. This study introduces a series of novel thiazole salt AChE inhibitors with nanomolar inhibitory effect on human AChE. Thiamine disulfide prodrugs based on these inhibitors are developed and shown to be converted into thiazole salt AChE inhibitors in the brain, with high brain exposure and stronger inhibitory effects compared to intestinal AChE in vivo. This study provides a possible basis for centrally targeted thiazole salt inhibitors in the treatment of neurodegenerative diseases.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Siyu He, Xianglin Chu, Yujia Wu, Jiheng Jiang, Pengfei Fang, Yuting Chen, Yang Liu, Zhixia Qiu, Yibei Xiao, Zhiyu Li, Di Pan, Qian Zhang, Huanfang Xie, Shuaishuai Xing, Feng Feng, Wenyuan Liu, Qinglong Guo, Li Zhao, Peng Yang, Haopeng Sun
Summary: Aldo-keto reductase 1C3 (AKR1C3) has been found to be associated with tumor development and chemotherapy resistance. Inhibition of AKR1C3 activity can restore the chemosensitivity in ANT-resistant cancers. Biaryl-containing AKR1C3 inhibitors, particularly S07-1066, selectively block AKR1C3-mediated reduction and significantly enhance the cytotoxicity of doxorubicin (DOX) in MCF-7 cells overexpressing AKR1C3. The synergistic effect of S07-1066 and DOX has been demonstrated in vitro and in vivo, suggesting that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xu Tang, Shuaishuai Xing, Mingkang Ma, Ziwei Xu, Qianwen Guan, Yuting Chen, Feng Feng, Wenyuan Liu, Tingkai Chen, Yao Chen, Haopeng Sun
Summary: Parkinson's disease is a neurodegenerative disorder that affects millions of people worldwide. Mutations in the LRRK2 gene are the most common genetic risk factor for PD. Elevated LRRK2 kinase activity is found in both idiopathic and familial PD cases. LRRK2 mutations are involved in various PD pathogeneses, including dysregulation of mitochondrial homeostasis and ciliogenesis.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
