Article
Chemistry, Medicinal
Pooja V. D. Hegde, Michael D. Howe, Matthew Zimmerman, Helena L. M. Boshoff, Sachin Sharma, Brianna Remache, Ziyi D. Jia, Yan Pan, Anthony C. Baughn, Veronique Dartois, Courtney Aldrich
Summary: Tuberculosis is a deadly infectious disease with limited treatment options. Researchers have developed prodrugs and modified the structure of para-Aminosalicylic acid (PAS) to improve its oral bioavailability and reduce rapid clearance. These innovations have the potential to enhance the therapeutic effectiveness of PAS.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Shiwei Lu, Feng Zhang, Jiahao Gong, Jian Huang, Guanghao Zhu, Yitian Zhao, Qi Jia, Yiming Li, Bo Li, Kaixian Chen, Weiliang Zhu, Guangbo Ge
Summary: This study discovered potent and orally active hCYP3A4 inhibitors from chalcone derivatives and tested their effects on hCYP3A4 in vitro and in vivo. The isoquinoline chalcones were found to have excellent anti-hCYP3A4 effects after screening and optimization. SAR studies revealed the structural requirements for enhancing the anti-CYP3A4 effect. A lead compound, C6, was identified as the most potent hCYP3A4 inhibitor and showed good metabolic stability and safety profiles. In vivo tests demonstrated the efficacy of C6 in increasing drug exposure and prolonging drug half-life. Overall, this study offers valuable insights into developing novel CYP3A4 inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Tingting Jin, Peipei Wang, Xiubing Long, Kailong Jiang, Pinrao Song, Wenbiao Wu, Gaoya Xu, Yubo Zhou, Jia Li, Tao Liu
Summary: In this study, a series of potent novel diaminopyrimidine CHK1 inhibitors were designed, synthesized, and evaluated. Compound 13 exhibited favorable CHK1 inhibition both in vitro and in vivo, showing potential as an anticancer therapeutic agent. Furthermore, compound 13 demonstrated robust inhibition of CHK1 autophosphorylation, indicating its promise as a CHK1 inhibitor.
Article
Chemistry, Medicinal
Jian-Jun Xi, Yu Cao, Ruo-Yu He, Jian-Kang Zhang, Yan-Mei Zhao, Qiao Tong, Jian-Feng Bao, Yi-Chen Dong, Rang-Xiao Zhuang, Jin-Song Huang, Yongping Chen, Shou-Rong Liu
Summary: A series of glycosylated silibinin derivatives were identified as novel anti-tumor agents, showing better water solubilities than silibinin. Compound 15 exhibited inhibitory activity against DU145 cells by arresting cell cycle at G2/M phase and inducing apoptosis. Moreover, it displayed appropriate pharmacokinetic parameters in mice, suggesting that glycosylation of silibinin is a valid strategy for anti-tumor drug development.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2023)
Article
Chemistry, Medicinal
Mingfeng Yu, Theodosia Teo, Yuchao Yang, Manjun Li, Yi Long, Stephen Philip, Benjamin Noll, Gary K. Heinemann, Sarah Diab, Preethi Eldi, Laychiluh Mekonnen, Abel T. Anshabo, Muhammed H. Rahaman, Robert Milne, John D. Hayball, Shudong Wang
Summary: CDK8 plays a crucial role in transcriptional regulation and its dysregulation is associated with various types of cancer. Inhibition of CDK8 with compound 38 showed potent anti-proliferative effects on acute myeloid leukaemia cells without systemic toxicity in preclinical studies. Further research on compound 38 as an anticancer agent is warranted.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
James M. Apgar, Robert R. Wilkening, Dann L. Parker, Dongfang Meng, Kenneth J. Wildonger, Donald Sperbeck, Mark L. Greenlee, James M. Balkovec, Amy M. Flattery, George K. Abruzzo, Andrew M. Galgoci, Robert A. Giacobbe, Charles J. Gill, Ming-Jo Hsu, Paul Liberator, Andrew S. Misura, Mary Motyl, Jennifer Nielsen Kahn, Maryann Powles, Fred Racine, Jasminka Dragovic, Weiming Fan, Robin Kirwan, Shu Lee, Hao Liu, Ahmed Mamai, Kingsley Nelson, Michael Peel
Summary: By optimizing the chemical structure of MK-5204, researchers discovered ibrexafungerp, which showed significantly improved oral efficacy and is a superior clinical candidate for Aspergillus and Candida infections.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Karol Sikora, Marta Bauer, Sylwia Bartoszewska, Damian Neubauer, Wojciech Kamysz
Summary: This study investigates the effect of glycosylation on the biological activity of ultrashort cationic lipopeptides (USCLs). It shows that glycosylation does not necessarily enhance antimicrobial activity or decrease hemolytic and cytotoxic activities, but in some cases, glycosylated USCLs (gUSCLs) exhibit superior activity compared to their unmodified counterparts (USCLs).
Article
Biochemistry & Molecular Biology
Letizia Crocetti, Gabriella Guerrini, Maria Paola Giovannoni, Fabrizio Melani, Silvia Lamanna, Lorenzo Di Cesare Mannelli, Elena Lucarini, Carla Ghelardini, Junjie Wang, Gerhard Dahl
Summary: The channel protein Panx-1 plays a significant role in various pathologies, and this study reports the findings on new chemical compounds as Panx-1 blockers. Compounds 4 and 13 were identified as the most potent blockers, with promising results in alleviating neuropathic pain in mice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Yinhu Wang, Ping Wu, Fangquan Liu, Junjie Chen, Jie Xue, Yinhui Qin, Fang Chen, Shuo Wang, Lusha Ji
Summary: This study reported the design, synthesis, and evaluation of novel honokiol derivatives as mimics of antimicrobial peptides. These mimics showed potent antimicrobial properties against Gram-positive bacteria and could inhibit biofilm formation. The most promising compound 13b exhibited excellent antibacterial activity and rapid bactericidal properties, while avoiding antibiotic resistance and host cell cytotoxicity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Paola Oliva, Romeo Romagnoli, Barbara Cacciari, Stefano Manfredini, Chiara Padroni, Andrea Brancale, Salvatore Ferla, Ernest Hamel, Diana Corallo, Sanja Aveic, Noemi Milan, Elena Mariotto, Giampietro Viola, Roberta Bortolozzi
Summary: In this study, two series of compounds were found to exhibit moderate to potent antiproliferative activity against cancer cells. The interaction with tubulin led to cell apoptosis and inhibition of cell growth.
Article
Chemistry, Medicinal
Xiujin Chang, Min Wang, Di Zhang, Yuqing Zhang, Jubo Wang, Zhiyu Li, Jinlei Bian, Xi Xu
Summary: Tumor cells undergo metabolic reprogramming to support their rapid growth and proliferation. A novel series of GLS1 allosteric inhibitors were designed and synthesized using structure-based drug design approaches. Compound LWG-301 exhibited moderate antitumor effects by blocking glutamine metabolism and inducing apoptosis. This paper provides valuable insights and a new design strategy for the development of GLS1 allosteric inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Qiongna Cai, Qian Yu, Wanxin Liang, Haizhou Li, Jiayong Liu, Hongxia Li, Yongzhi Chen, Shanfang Fang, Rongcui Zhong, Shouping Liu, Shuimu Lin
Summary: Antibiotic resistance is a global public health concern, and the development of novel antimicrobials is urgently needed. In this study, a series of new peptidomimetic antimicrobials were designed and synthesized, with compound 51 identified as the lead compound due to its potent antibacterial activity, low toxicity, and avoidance of bacterial resistance development. Compound 51 also significantly reduced microbial burden in a murine model of keratitis infected by Staphylococcus aureus or Pseudomonas aeruginosa. This design strategy provides a promising and effective solution to overcome antibiotic resistance.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Organic
Jacob St-Gelais, Denis Giguere
Summary: This study presents a protecting-group-free synthesis method for a galectin inhibitor GB1107 and its analogues, starting from inexpensive levoglucosan and utilizing a Payne rearrangement/azidation process as a key step, while also exploring a novel lipophilicity assessment method.
SYNTHESIS-STUTTGART
(2021)
Article
Chemistry, Medicinal
Hongxia Li, Jiayong Liu, Chuan-Fa Liu, Haizhou Li, Jiachun Luo, Shanfang Fang, Yongzhi Chen, Rongcui Zhong, Shouping Liu, Shuimu Lin
Summary: This study designed and synthesized a series of new membrane-active bakuchiol derivatives, with compound 28 showing potent antibacterial activity against various bacteria and strong in vivo antibacterial efficacy in murine corneal infection models. This design strategy is expected to provide an effective solution to the antibiotic crisis.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Xiao Liang, Xue Li, Zhiyuan Zhao, Yiming Nie, Zefu Yao, Wandi Ren, Xinying Yang, Xuben Hou, Hao Fang
Summary: In this study, a series of hydantoin derivatives were designed and synthesized as novel Mcl-1 inhibitors. Compound M23 and M24 showed good binding affinities against Mcl-1. Additionally, these compounds exhibited good selectivity and stability.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Maree T. Smith, Dehui Kong, Andy Kuo, Mohammad Z. Imam, Craig M. Williams
Summary: This article discusses the limitations and problems associated with strong opioid analgesics and describes international efforts to discover new and safer opioids. It focuses on medicinal chemistry strategies using structurally diverse compounds derived from natural sources as lead molecules and elaborates on the current research status and approaches in the discovery of novel opioid ligands that retain analgesic effects with improved safety and reduced adverse effects, particularly addiction liability.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Minze Zhu, Andrew K. Whittaker, Felicity Y. Han, Maree T. Smith
Summary: Biodegradable polymers have been used as carriers in drug delivery systems for over four decades. They have applications at different scales, from macroscale to nanoscale. These materials have been approved for human use and achieved commercial success. Current research focuses on developing new formulation types for improved drug delivery.
APPLIED SCIENCES-BASEL
(2022)
Article
Instruments & Instrumentation
Weizhi Xu, Faheem Maqbool, Vinod Kumar, James R. Falconer, Cedric S. Cui, Trent M. Woodruff, Karin Borges, Andrew K. Whittaker, Maree T. Smith, Felicity Y. Han
Summary: A sustained-release formulation of ketamine, known as KSL, was developed with high loading and demonstrated prolonged release in mice after intravenous administration. The formulation showed high encapsulation efficiency and drug loading, achieving 100% release in vitro within 8 hours.
DRUG DELIVERY AND TRANSLATIONAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Dehui Kong, Alaa A. Saqer, Matheus Carpinelli de Jesus, Nemat Khan, Alun Jones, Joanne T. Blanchfield, Maree T. Smith, Craig M. Williams
Summary: Multiple sclerosis-associated central neuropathic pain (MS-CNP) is difficult to alleviate and requires novel treatments. A study found that (R)-alpha lipoic acid (ALA) may have pain relief efficacy, but with poor oral bioavailability. By designing and synthesizing biocompatible ester prodrugs of (R)-ALA, a promising candidate (PD-ALA4 HCl salt) was identified.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Mohammad Zafar Imam, Andy Kuo, Sussan Ghassabian, Yunxin Cai, Yajuan Qin, Tingyou Li, Maree T. Smith
Summary: CYX-5 is a novel opioid peptide that acts as a G-protein biassed MOP receptor agonist, DOP receptor antagonist, and KOP receptor agonist. It provides pain relief, reduces stool output, and does not cause respiratory depression. The mechanism underlying its constipation effect may involve factors other than beta-arrestin2 recruitment.
PHARMACOLOGICAL REPORTS
(2023)
Review
Pharmacology & Pharmacy
Rafia Ali, Huimin Shao, Pegah Varamini
Summary: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a high risk of metastasis and therapeutic resistance. Targeting the tumor microenvironment (TME) using nanoparticles is a promising approach to improve treatment outcomes. Various nanotherapeutics have been investigated to mitigate microenvironment-induced angiogenesis, therapeutic resistance, and tumor progression.
Letter
Pharmacology & Pharmacy
Mohammad Zafar Imam, Sussan Ghassabian, Andy Kuo, Yunxin Cai, Yajuan Qin, Tingyou Li, Maree T. Smith
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS
(2023)
Article
Chemistry, Medicinal
Rachel J. J. Stephenson, Istvan Toth
Summary: Cocaine is a widely used illegal drug that has significant medical and social consequences. The lack of effective pharmacological treatments has led to the development of anti-cocaine vaccines. Despite years of research, no approved pharmacological treatments exist to help individuals overcome cocaine addiction or prevent relapse.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Maree T. Smith, Dehui Kong, Andy Kuo, Mohammad Z. Imam, Craig M. Williams
Summary: The opioid crisis has increased the demand for novel opioid analgesics that have superior profiles compared to morphine. This Perspective reviews and discusses the multitargeted opioid ligand strategy for discovering such analgesics. Dual-targeted mu-opioid/delta-opioid (MOP/DOP) ligands with strong DOP antagonist potency and without DOP or kappa-opioid (KOP) agonist activity are promising candidates. Dual-targeted MOP/NOP partial agonists also show potential. The pharmacologic template of cebranopadol, a full agonist at MOP, DOP, and NOP receptors, and a partial agonist at KOP receptor, should be avoided due to its poor therapeutic indices.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Plant Sciences
Joanne T. Blanchfield, Maribel G. Nonato, Richard J. Clark
JOURNAL OF NATURAL PRODUCTS
(2023)
Article
Instruments & Instrumentation
Frazer Sinclair, Anjuman A. Begum, Charles C. Dai, Istvan Toth, Peter M. Moyle
Summary: The CRISPR/Cas9 genome editing system is a groundbreaking technology that has revolutionized genome editing for therapeutic, diagnostic, and precision medicine applications. The safe and efficient delivery of the CRISPR/Cas9 system has been a critical challenge. Viral vectors have shown promise, but face limitations for clinical applications. Nonviral delivery vectors, such as lipid, polymer, peptides, and inorganic nanoparticle-based systems, have emerged as viable alternatives. This review discusses the molecular mechanisms of CRISPR/Cas9, current delivery strategies, approaches for reducing off-target editing, and future directions for clinical trials.
DRUG DELIVERY AND TRANSLATIONAL RESEARCH
(2023)
Review
Immunology
Chen Chen, Maree T. Smith
Summary: Chronic pain is a common health problem that is difficult to adequately treat. Recent research suggests that the NLRP3 inflammasome plays a significant role in the pathophysiology of chronic pain, particularly in neuropathic and inflammatory pain conditions.
INFLAMMOPHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Harrison Y. R. Madge, Suzy Alexander, Armira Azuar, Jiahui Zhang, Prashamsa Koirala, Thomas H. Burne, Istvan Toth, Rachel J. Stephenson
Summary: Researchers have developed a peptide-based anti-cocaine vaccine that can induce immune responses in mice, providing a platform for the development of effective anti-drug vaccines.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Matheus Carpinelli de Jesus, Taylah Church, Johanna A. Wapling, Raelene Collins, Gregory J. Leach, David Leach, James J. De Voss, Joanne T. Blanchfield
Summary: Haemodorum coccineum, commonly known as scarlet bloodroot, is a plant used for dyeing garments and treating snake bites. This study characterized the chemical composition of the plant for the first time, identifying sugars and compounds belonging to the PhP family. The crude extract showed significant inhibition of bacterial growth.
Article
Materials Science, Multidisciplinary
Adel Szerlauth, Arpad Varga, Tamara Madacsy, Daniel Sebok, Sahra Bashiri, Mariusz Skwarczynski, Istvan Toth, Jozsef Maleth, Istvan Szilagyi
Summary: Incorporation of antioxidant enzymes into nanostructures provides a highly efficient and robust biocatalytic system for scavenging reactive oxygen species. The immobilized enzymes effectively reduce intracellular oxidative stress and prevent DNA damage induced by hydrogen peroxide. These findings are important for designing complex nanostructures with multienzymatic antioxidant activities.
ACS MATERIALS LETTERS
(2023)
