Article
Chemistry, Medicinal
Gilda Padalino, Nelly El-Sakkary, Lawrence J. Liu, Chenxi Liu, Danielle S. G. Harte, Rachel E. Barnes, Edward Sayers, Josephine Forde-Thomas, Helen Whiteland, Marcella Bassetto, Salvatore Ferla, George Johnson, Arwyn T. Jones, Conor R. Caffrey, Iain Chalmers, Andrea Brancale, Karl F. Hoffmann
Summary: Recent research has identified a promising anti-schistosomal scaffold in the quinoxaline core, which has shown improved activity and selectivity through chemical optimization. This could potentially serve as an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Thibault Joseph William Jacques Dit Lapierre, Mariza Gabriela Faleiro de Moura Lodi Cruz, Nicolas Peterson Ferreira Brito, Daniela de Melo Resende, Felipe de Oliveira Souza, Eduardo Jorge Pilau, Meryck Felipe Brito da Silva, Bruno Junior Neves, Silvane Maria Fonseca Murta, Celso de Oliveira Rezende Junior
Summary: An early hit-to-lead optimization study was performed on a novel pyrazinylpiperazine series against L. infantum and L. braziliensis. The study focused on the benzoyl fragment of a hit compound (4), and deletion of the meta-Cl led to the synthesis of a para-hydroxyl derivative (12). Further optimization involving disubstituted benzoyl fragments and the hydroxyl substituent of (12) resulted in the identification of an ortho, meta-dihydroxyl derivative (46) as an early lead compound with increased anti-leishmanial potency. In silico ADMET predictions revealed satisfactory profiles for these compounds, indicating potential for further lead optimization.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Celso de Oliveira Rezende Jr, Pablo David Grigol Martinez, Rafael Augusto Alves Ferreira, Paul John Koovits, Bruna Miranda Soares, Leonardo L. G. Ferreira, Simone Michelan-Duarte, Rafael Consolin Chelucci, Adriano D. Andricopulo, An Matheeussen, Natascha Van Pelt, Guy Caljon, Louis Maes, Simon Campbell, Jadel M. Kratz, Charles E. Mowbray, Luiz Carlos Dias
Summary: This study describes the optimization of a 2-aminobenzimidazole hit for the treatment of Chagas disease, focusing on improving potency, selectivity, stability, and lipophilicity. Although the properties of the initial hits were improved, their low solubility and cytotoxicity prevented further efficacy studies in a mouse model of Chagas disease.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Nicole McNamara, Eleanor Saunders, Swapna Varghese, Rebecca Zheng, Kaylene Simpson, Devika M. Varma, Monica M. Johnson, M. Shamim Hasan Zahid, Eric M. Bachelder, Kristy M. Ainslie, Joo Hwan No, Dahae Koh, David Shum, Nirmal Das, Binita Patra, Jayasree Roy, Arindam Talukdar, Dipyman Ganguly, Malcolm McConville, Jonathan Baell
Summary: In this study, the structure-activity relationship of a novel hit compound was explored. The compound showed improved potency with low cytotoxicity against human cells, indicating its potential as a treatment for visceral leishmaniasis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Semih Yagci, Mahmut Gozelle, Selen Gozde Kaya, Yesim Ozkan, Ahmet Bugra Aksel, Filiz Bakar-Ates, Yasemin Dundar, Gokcen Eren
Summary: The study focused on hit-to-lead optimization of a potential SIRT1/2 inhibitor, resulting in improved selectivity for SIRT1 and SIRT2 inhibition. The structural modifications also influenced the cytotoxicity of the compounds against MCF-7 human breast cancer cell line, indicating the impact of SIRT1/2 inhibition on cancer cell viability.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Daiki Erikawa, Nobuaki Yasuo, Masakazu Sekijima
Summary: In this study, a SMILES-based generative model was developed to generate molecules starting from a certain molecule, using Monte Carlo Tree Search and a Recurrent Neural Network. The method was validated using a molecule dataset obtained from the ZINC database, successfully generating molecules optimized for drug-likeness (QED) and penalized octanol-water partition coefficient (PLogP) objectives.
JOURNAL OF CHEMINFORMATICS
(2021)
Article
Chemistry, Medicinal
Koon Mook Kang, Yejin Jang, Sang Soo Lee, Mi Sun Jin, Chang-Duk Jun, Meehyein Kim, Yong-Chul Kim
Summary: This study reports the development of novel SARS-CoV-2 Mpro inhibitors derived from carmofur and their optimization through experimental and simulation methods. Two compounds with strong inhibitory activity were identified, and their antiviral effects against SARS-CoV-2 were confirmed, suggesting their potential as lead compounds for the development of anti-SARS-CoV-2 agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Immunology
Poulami Basu Thakur, Victoria J. Mrotz, Taronna R. Maines, Jessica A. Belser
Summary: Ferrets serve as a valuable model for studying influenza virus and bacterial pathogens, both individually and in coinfection scenarios. By utilizing the ferret model, scientists can gain insights into the dynamic interactions between these pathogens, which can contribute to the prevention and treatment of diseases.
JOURNAL OF INFECTIOUS DISEASES
(2023)
Article
Chemistry, Physical
Huafeng Xu, Timothy Palpant, Cody Weinberger, David E. Shaw
Summary: A key step in the emergence of human pandemic influenza strains is the switch of viral glycoprotein HA's binding preference from avian to human receptors. Molecular dynamics simulations revealed diverse receptor conformations and predicted mutations that increased HA affinity for human receptors.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Virology
Pinar Yazici ozkaya, Ese Eda Turanli, Hamdi Metin, Ayca Aydin Uysal, Candan cicek, Bulent Karapinar
Summary: This study aimed to identify the clinical features and mortality associated with severe influenza A and B virus infections in children admitted to the pediatric intensive care unit (PICU) between 2012 and 2019. The study found that although the proportion of influenza A cases admitted to the PICU was higher, the percentage of cases requiring PICU admission was nearly two times higher in influenza B cases. Additionally, there was no statistically significant difference in disease severity and complications in patients with influenza A and influenza B.
JOURNAL OF MEDICAL VIROLOGY
(2022)
Article
Chemistry, Medicinal
John R. Cashman, Daniel Ryan, Wesley L. McKeithan, Karl Okolotowicz, Jorge Gomez-Galeno, Mark Johnson, Kevin J. Sampson, Robert S. Kass, Arash Pezhouman, Hrayr S. Karagueuzian, Mark Mercola
Summary: Ventricular cardiac arrhythmia can occur in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a congenital form of VA caused by cardiac sodium channel SCN5A mutations. Mexiletine can inhibit I-NaL and shorten the QT interval, but can also prolong the cardiac action potential at therapeutic doses.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Zhenzhen Wang, Zhenhua Li, Weiwei Shi, Dashuai Zhu, Shiqi Hu, Phuong-Uyen C. Dinh, Ke Cheng
Summary: The combination of SARS-CoV-2 virus-like particle (VLP) vaccine with inactivated influenza A virus provides protection against COVID-19, influenza, and co-infection, inducing strong immune responses and neutralization activity.
Article
Chemistry, Medicinal
Elli-Anna Stylianaki, Christiana Magkrioti, Eleni M. Ladopoulou, Konstantinos D. Papavasileiou, Panagiotis Lagarias, Georgia Melagraki, Martina Samiotaki, George Panayotou, Skarlatos G. Dedos, Antreas Afantitis, Vassilis Aidinis, Alexios N. Matralis
Summary: Robust experimental evidence has shown the importance of the ATX/LPA axis in chronic inflammatory conditions, fibroproliferative diseases, and cancer. Various ATX inhibitors have been discovered, with the first-in-class inhibitor currently in advanced clinical trials for idiopathic pulmonary fibrosis. The mode of inhibition and binding mechanism of these inhibitors to ATX have been studied.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Veterinary Sciences
Samantha J. Hau, Daniel W. Nielsen, Kathy T. Mou, David P. Alt, Steven Kellner, Susan L. Brockmeier
Summary: Influenza A virus (IAV) is a critical pathogen in porcine respiratory disease complex (PRDC) infections. This study investigated the impact of IAV infection on the nasal microbiota of pigs and found minimal changes in diversity and community structure within the first 10 days post-infection. However, substantial differences in microbial populations were observed between IAV infected and control groups on days 14 and 21, suggesting potential implications for host susceptibility to secondary bacterial respiratory infections.
VETERINARY RESEARCH
(2023)
Review
Chemistry, Medicinal
Xin Wen, Xinyuan Wu, Rui Jin, Xiaojie Lu
Summary: It is well known that heterocyclic compounds play a key role in improving drug activity, target selectivity, physicochemical properties as well as reducing toxicity. In this review, we summarized the representative heterocyclic structures involved in hit compounds which were obtained from DNA-encoded library from 2013 to 2021. The state of the art in heterocycle-based DEL synthesis and hit-to-lead optimization are highlighted in some examples. We hope that more and more novel heterocycle-based DEL toolboxes and in-depth pharmaceutical research on these lead compounds can be developed to accelerate the discovery of new drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Shuang Mei, Su Jiang, Yuting Wang, Han Jing, Peng Yang, Miao-Miao Niu, Jindong Li, Kai Yuan, Yan Zhang
Summary: This study identifies a dual-targeting peptide, AP-1, that effectively inhibits variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. The findings suggest that AP-1 could be a promising broad-spectrum agent for treating emerging VOCs of SARS-CoV-2.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Hyeonjun Lee, Ju Yeon Lee, Hyunsoo Jang, Hye Young Cho, Minhee Kang, Sang Hyun Bae, Suin Kim, Eunji Kim, Jaebong Jang, Jin Young Kim, Young Ho Jeon
Summary: By using liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance experiments, we identified new chemical moieties that bind to the target sites of the protein of interest, allowing for reversible binding and protein degradation. This method has the potential to expand the application of PROTAC technology.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Yingying Li, Xiyou Du, Xinru Kong, Yuelin Fang, Zhijing He, Dongzhu Liu, Hang Wu, Jianbo Ji, Xiaoye Yang, Lei Ye, Guangxi Zhai
Summary: This study proposes a novel nanoplatform based on the autophagy cascade to overcome the obstacles in chemo-immunotherapy. The platform combines chemotherapy and starvation therapy to initiate pro-death autophagy and enhance antigen presentation, while also remodeling the immunosuppressive tumor microenvironment. Furthermore, the study discovers a new therapeutic direction for the respiration inhibitor 3-bromopyruvic acid (3BP) in cancer treatment. Overall, this study offers an opportunity to improve antitumor efficacy and boost immune responses.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Bingsi Wang, Mingxu Ma, Yusen Dai, Pengfei Yu, Liang Ye, Wenyan Wang, Chunjie Sha, Huijie Yang, Yingjie Yang, Yunjing Zhu, Lin Dong, Shujuan Wei, Linlin Wang, Jingwei Tian, Hongbo Wang
Summary: Breast cancer is a common malignant tumor in women, and drug resistance remains a clinical challenge. In this study, a novel compound, G-5b, was developed with potent antagonistic and degradation activities comparable to the current drug fulvestrant. G-5b also showed improved stability and solubility. Mechanistically, G-5b engages the proteasome pathway to degrade ER, inhibiting the ER signaling pathway and inducing apoptosis and cell cycle arrest. In animal models, G-5b exhibited superior pharmacokinetics and pharmacodynamics properties. Overall, G-5b is a promising long-acting SERD worthy of further investigation and optimization.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Karoline B. Waitman, Larissa C. de Almeida, Marina C. Primi, Jorge A. E. G. Carlos, Claudia Ruiz, Thales Kronenberger, Stefan Laufer, Marcia Ines Goettert, Antti Poso, Sandra V. Vassiliades, Vinicius A. M. de Souza, Monica F. Z. J. Toledo, Neuza M. A. Hassimotto, Michael D. Cameron, Thomas D. Bannister, Leticia Costa-Lotufo, Joa o A. Machado-Neto, Mauricio T. Tavares, Roberto Parise-Filho
Summary: A series of hybrid inhibitors combining pharmacophores of known kinase inhibitors and benzohydroxamate HDAC inhibitors were synthesized and evaluated for their anticancer activity and pharmacokinetic properties. Compounds 4d-f exhibited promising cytotoxicity against hematological cells and moderate activity against solid tumor models. Compound 4d showed potent inhibition of multiple kinase targets and had stable interactions with HDAC and members of the JAK family. These compounds showed selective cytotoxicity with minimal effects on non-tumorigenic cells and favorable pharmacokinetic profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Michal Sulik, Diana Fontinha, Dietmar Steverding, Szymon Sobczak, Michal Antoszczak, Miguel Prudencio, Adam Huczynski
Summary: This study describes the synthesis of the first-in-class ivermectin derivatives obtained through derivatization of the C13 position, along with the unexpected rearrangement of the macrolide ring. These derivatives show potential for antiparasitic activity and are important for the development of new antiparasitic agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Jun Liu, Qiu-Xian Chen, Wen-Fu Wu, Dong Wang, Si -Yu Zhao, Jia-Hao Li, Yi-Qun Chang, Shao-Gao Zeng, Jia-Yi Hu, Yu-Jie Li, Jia-Xin Du, Shu-Meng Jiao, Hai-Chuan Xiao, Qiang Zhang, Jun Xu, Jian-Fu Zhao, Hai -Bo Zhou, Yong-Heng Wang, Jian Zou, Ping-Hua Sun
Summary: A new anti-infective drug strategy has been discovered to attenuate virulence and modulate inflammation caused by drug-resistant Pseudomonas aeruginosa infections. Compound 5f inhibits biofilm formation, macrophage migration, and inflammatory response induced by P. aeruginosa, showing potential as a novel candidate against drug-resistant infections.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Liuzeng Chen, Ke Wang, Lingyun Wang, Wei Wang, Lifan Wang, Jia Li, Xiaohan Liu, Mengya Wang, Banfeng Ruan
Summary: In this study, a series of novel anti-inflammatory compounds were designed and synthesized based on the natural product pterostilbene skeleton. Among them, compound 8 showed the highest activity and exhibited its effects through inhibition of pro-inflammatory cytokines by blocking the NF-KB/MAPK signaling pathway. Compound 8 also demonstrated a good relieving effect on acute colitis in mice and showed good safety in acute toxicity experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Si-Min Liang, Gui-Bin Liang, Hui-Ling Wang, Hong Jiang, Xian-Li Ma, Jian-Hua Wei, Ri-Zhen Huang, Ye Zhang
Summary: A series of novel multi-target antitumor agents were designed, synthesized, and evaluated. Some compounds exhibited significant antitumor activity and one compound showed excellent efficacy, limited toxicity, and low resistance. Further mechanism studies revealed that the compound exerted antitumor effects through multiple pathways.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)