Journals Bioorganic & Medicinal Chemist...

Bioorganic & Medicinal Chemistry Letters
Wen Wen, Jiadong Hu, Chenxi Wang, Rui Yang, Yabo Zhang, Baibei Huang, Tingting Qiao, Jiayun Wang, Xin Chen
Histone deacetylase 6 (HDAC6) has drawn more and more attention for its potential application in Alzheimer's disease (AD) therapy. A series of tetrahydro-β-carboline (THβC) hydroxamic acids with aryl linker were synthesized. In enzymatic assay, all compounds exhibited nanomolar IC50 values. The most promising compound 11d preferentially inhibited HDAC6 (IC50 , 8.64 nM) with approximately 149-fold selectivity over HDAC1. Molecular simulation revealed that the hydroxamic acid of 11d could bind to the zinc ion by a bidentate chelating manner...
February 20, 2024: Bioorganic & Medicinal Chemistry Letters
Yue Pan, Qiuyue Fu, Yinyan Li, Jie Yang, Kui Cheng
Influenza and COVID-19 continue to pose global threats to public health. Classic antiviral drugs have certain limitations, coupled with frequent viral mutations leading to many drugs being ineffective, the development of new antiviral drugs is urgent. Meanwhile, the invasion of influenza virus can cause an immune response, and an excessive immune response can generate a large number of inflammatory storms, leading to tissue damage. Toll-like receptor 3 (TLR3) recognizes virus dsRNA to ignite the innate immune response, and inhibit TLR3 can block the excess immune response and protect the host tissues...
February 20, 2024: Bioorganic & Medicinal Chemistry Letters
Yufang Li, Jamal A H Kowah, Meiyan Jiang, Yaqing Wu, Lisheng Wang, Fangfang Yang
Matrine and indole have antibacterial, anticancer, and other biological activities, in order to develop new antibiotics to solve the problem of multi-drug resistant bacteria. In this paper, we synthesized a series of 29 novel matrine derivatives as potential drug candidates by combining indole analogs and matrine. The antibacterial activity of these compounds was evaluated through minimum inhibitory concentration (MIC) assays against five bacterial strains (S. aureus, C. albicans, P. acnes, P. aeruginosa, and E...
February 20, 2024: Bioorganic & Medicinal Chemistry Letters
Stéphanie Courtiol-Legourd, Sandrine Mariano, Johanna Foret, Annette K Roos, Sherry L Mowbray, Laurent Salmon
Because tuberculosis is still a major health threat worldwide, identification of new drug targets is urgently needed. In this study, we considered type B ribose-5-phosphate isomerase from Mycobacterium tuberculosis as a potential target, and addressed known problems of previous inhibitors in terms of their sensitivity to hydrolysis catalyzed by phosphatase enzymes, which impaired their potential use as drugs. To this end, we synthesized six novel phosphomimetic compounds designed to be hydrolytically stable analogs of the substrate ribose 5-phosphate and the best known inhibitor 5-phospho-d-ribonate...
February 19, 2024: Bioorganic & Medicinal Chemistry Letters
Pengpeng Niu, Huiqi Xu, Mengyang Fan
Bcl-2 anti-apoptotic protein family suppresses cell death by deploying a surface groove to capture the critical BH3 α-helix of pro-apoptotic members. Bfl-1 is a relatively understudied member of this family, though it has been implicated in the pathogenesis and chemoresistance of a variety of human cancers. Reported small molecular Bfl-1 inhibitors encountered the issue of either lack in potency or poor selectivity against its most homologous member Mcl-1. In order to tackle this issue, compound library was screened and a hit compound UMI-77 was identified...
February 17, 2024: Bioorganic & Medicinal Chemistry Letters
Nathaniel R Gehrke, Dan Feng, Md Ayub Ali, Mona A Maalouf, Sarah A Holstein, David F Wiemer
Depletion of cellular levels of geranylgeranyl diphosphate by inhibition of the enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential strategy for disruption of protein transport by limiting the geranylgeranylation of the Rab proteins that regulate intracellular trafficking. As such, there is interest in the development of GGDPS inhibitors for the treatment of malignancies characterized by abnormal protein production, including multiple myeloma. Our previous work has explored the structure-function relationship of a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, with modifications having impact on enzymatic, cellular and in vivo activities...
February 17, 2024: Bioorganic & Medicinal Chemistry Letters
Suze Ma, Heng Chen, Shuxun Liu, Xuedong Huang, Tianlu Mo, Wanqiu Liu, Wei Zhang, Wei Ding, Qi Zhang
Gene-encoded aldehyde tag technology has been widely utilized in protein bioorthogonal chemistry and biotechnological application. Herein, we report utilization of the promiscuous rSAM cyclophane synthase SjiB involved in triceptide biosynthesis as a dedicated and highly efficient formylglycine synthase. The new aldehyde tag sequence in this system, YQSSI, is biosynthetically orthogonal to the known aldehyde tag (C/S)x(P/A)xR. The potential use of SjiB/YQSSI aldehyde tag system was further validated in fluorescent labelling of model proteins...
February 13, 2024: Bioorganic & Medicinal Chemistry Letters
Emily A Savoy, Feyisola P Olatunji, Nooshin Mesbahi, Ryanne K Ballard, Christine L Lovingier, Aaron T Hendricksen, Melody D Fulton, Clifford E Berkman
Herein, we report the modular synthesis and evaluation of a prostate-specific membrane antigen (PSMA) targeted small molecule drug conjugate (SMDC) carrying the chemotherapeutic agent, SN38. Due to the fluorogenic properties of SN38, payload release kinetics from the platform was observed in buffers representing the pH conditions of systemic circulation and cellular internalization. It was found that this platform is stable with minimal payload release at physiological pH with most rapid payload release observed at pH values representing the endosome complex...
February 13, 2024: Bioorganic & Medicinal Chemistry Letters
Huiqiong Li, Jianjun Cheng
The use of privileged scaffolds in medicinal chemistry is an effective way to accelerate the drug discovery process, especially at the hit/lead optimization stage. 2-Phenylcyclopropylmethylamine (PCPMA) is a less commonly used chemical scaffold in medicinal chemistry, but many PCPMA-containing compounds exert therapeutic effects for various diseases, in particular central nervous system (CNS) diseases such as depression, schizophrenia, sleep disorder, and Parkinson's disease. The backbone of the PCPMA scaffold enables a unique structure of an amino group linked to a benzene ring through an alkyl linker, making it a useful template for the design of bioactive compounds especially for CNS drug targets including aminergic GPCRs and transporters...
February 13, 2024: Bioorganic & Medicinal Chemistry Letters
Dongxu Zuo, Mannkyu Hong, Aeran Jung, Sunho Lee, Nayeon Do, Sungwon Jung, Yubum Jeon, Ji Won Jeong, Guocheng Huang, Li-Xuan Li, Peter M Blumberg, Hongryul Yoon, Yoonji Lee, Jihyae Ann, Jeewoo Lee
To discover mode-selective TRPV1 antagonists as thermoneutral drug candidates, the previous potent antagonist benzopyridone 2 was optimized based on the pharmacophore A- and C-regions. The structure activity relationship was investigated systematically by modifying the A-region by incorporating a polar side chain on the pyridone and then by changing the C-region with a variety of substituted pyridine and pyrazole moieties. The 3-t-butyl and 3-(1-methylcyclopropyl) pyrazole C-region analogs provided high potency as well as mode-selectivity...
February 12, 2024: Bioorganic & Medicinal Chemistry Letters
Yanfang Wang, Shilong Hu, Yuhao Chen, Meiyuan Chen, Di Zhang, Wencheng Liu, Chunxia Chen, Yu Gan, Menglan Luo, Bowen Ke
The NaV 1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and NaV 1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV 1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the NaV 1...
February 11, 2024: Bioorganic & Medicinal Chemistry Letters
Hye Ree Yoon, Anand Balupuri, Jinwoo Lee, Chaeeun Lee, Dong-Hyun Son, Re Gin Jeoung, Kyung Ah Kim, Sungwook Choi, Nam Sook Kang
Mixed-lineage protein kinase 3 (MLK3) is implicated in several human cancers and neurodegenerative diseases. A series of 3H-imidazo[4,5-b]pyridine derivatives were designed, synthesized and evaluated as novel MLK3 inhibitors. A homology model of MLK3 was developed and all designed compounds were docked to assess their binding pattern and affinity toward the MLK3 active site. Based on this knowledge, we synthesized and experimentally evaluated the designed compounds. Majority of the compounds showed significant inhibition of MLK3 in the enzymatic assay...
February 10, 2024: Bioorganic & Medicinal Chemistry Letters
Sihan Meng, Yu Gao, Guowei Qiang, Zhiwei Hu, Qi Shan, Juxian Wang, Yucheng Wang, Jie Mou
A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0...
February 9, 2024: Bioorganic & Medicinal Chemistry Letters
Kotaro Sakamoto, Takatsugu Hirokawa
Peptides are mid-size molecules (700-2000 g/mol) and have attracted particular interest as therapeutic modalities as they are superior in controlling protein-protein interactions, a process that is a typical drug target category, compared with small molecules (<500 g/mol). In 2020, we identified KS-58 (1333 g/mol) as a K-Ras(G12D)-inhibitory bicyclic peptide and suggested its cell membrane permeability. However, the membrane permeability mechanism had not been elucidated. In this study, we aim to clarify the mechanism by molecular dynamics (MD) simulations...
February 8, 2024: Bioorganic & Medicinal Chemistry Letters
Yulin Ren, Elizabeth N Kaweesa, Joshua M Henkin, Kongmany Sydara, Mouachanh Xayvue, Pankaj Pandey, Amar Gopal Chittiboyina, Zulfiqar Ali, Daneel Ferreira, Djaja D Soejarto, Joanna E Burdette, A Douglas Kinghorn
Two leuconoxine-type diazaspiroindole alkaloids, the known compound, (+)-melodinine E (1), and its new analogue, (+)-11-chloromelodinine E (2), were isolated from the stems of Cryptolepis dubia (Burm.f.) M.R. Almeida (Apocynaceae), collected in Laos. The chemical structures of these compounds were determined by analysis of their spectroscopic data and by comparison these data with literature values, of which the molecular structure of 1 has been determined previously by analysis of its single-crystal X-ray diffraction data...
February 8, 2024: Bioorganic & Medicinal Chemistry Letters
Chunlei Tang, Jie Wang, Dong Wang, Huabing Wang, Shengkai Cui, Tianxin Xiao, Weizheng Fan, Yan Zhang
In the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance is a major factor that affects the efficacy of third-generation epidermal growth factor receptor (EGFR) inhibitors like Osimertinib. To overcome the L858R/T790M/C797S mutation, taking the Brigatinib as the positive control, two classes of 20 target compounds were designed and synthesized with 2-phenylaminopyrimidine as the core structure on the basis of summarizing the structure-activity relationship (SAR), following the basic principles of drug design...
February 6, 2024: Bioorganic & Medicinal Chemistry Letters
Seynabou Sokhna, Natacha Mérindol, Marc Presset, Insa Seck, Marie-Pierre Girard, Seydou Ka, Samba Fama Ndoye, Aïcha Lalla Ba, Issa Samb, Lionel Berthoux, Erwan Le Gall, Isabel Desgagné-Penix, Matar Seck
Dengue fever is an infectious disease caused by the dengue virus (DENV), an RNA Flavivirus transmitted by the mosquitoes Aedes aegypti and Aedes albopictus widespread in tropical, subtropical and also temperate regions. Symptoms range from a simple cold to a severe, life-threatening haemorrhagic fever. According to the WHO, it affects around 390 million people per year. No antiviral treatment for DENV is available, and the Dengvaxia vaccine is only intended for people over 9 years of age who have contracted dengue one time in the past, and shows serotype-specific effectiveness...
February 6, 2024: Bioorganic & Medicinal Chemistry Letters
Xuan Wang, Mei Zhao, Yuanyuan Chang, Sumeng Guan, Mengyu Li, Hua Yang, Moran Sun
The overexpression of neddylation modification is frequently observed in human tumor cells. Targeting the neddylation pathway has been recognized as a promising anticancer therapeutic strategy, thus discovering potent and selective neddylation inhibitors is of great importance. In this study, we designed and synthesized a series of novel neddylation inhibitors bearing benzothiazole scaffolds by molecular hybridization strategy and all compounds were evaluated for antiproliferative activity against MGC-803, MCF-7, A549 and KYSE-30 cell lines...
February 4, 2024: Bioorganic & Medicinal Chemistry Letters
Zizhen Ye, Jixiang Li, Jiarui Shi, Yuguang Song, Yangping Liu, Jingli Hou
Hydrogen sulfide (H2 S) plays a critical role in cancer biology. Herein, we developed a series of glycosidase-triggered hydrogen sulfide (H2 S) donors by connecting sugar moieties (including glucose, galactose and mannose) to COS donors via a self-immolative spacer. In the presence of corresponding glycosidases, H2 S was gradually released from these donors in PBS buffer with releasing efficiencies from 36 to 67%. H2 S release was also detected by H2 S probe WSP-1 after treatment HepG2 cells with Man1. Cytotoxicities of these glycosylated H2 S donors were evaluated against HepG2 by MTT assay...
February 3, 2024: Bioorganic & Medicinal Chemistry Letters
József Levente Petró, Gyula Bényei, Péter Bana, Nikolett Linke, Ferenc Horti, Judit Eszter Szabó, Krisztina Katalin Szalai, Gábor Hornyánszky, István Greiner, János Éles
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a key role in cell death and inflammation. RIPK1 is a well-established therapeutic target, due to the presence of a unique kinase-regulating allosteric pocket, which enables selective inhibition. Herein we used GSK2982772 as our starting point in our discovery campaign. Applying isosteric replacement, we successfully identified the malonamide scaffold, instead of the well-established serine template. Further structural optimization led to the design and synthesis of a series of analog inhibitors...
February 3, 2024: Bioorganic & Medicinal Chemistry Letters
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