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Bioorganic & Medicinal Chemistry Letters

https://read.qxmd.com/read/38522589/improved-synthesis-molecular-modeling-and-anti-inflammatory-activity-of-new-fluorinated-dihydrofurano-naphthoquinone-compounds
#1
JOURNAL ARTICLE
Ha Thanh Nguyen, Hai Pham-The, Anh Nguyen Tuan, Ha Nguyen Thi Thu, Tuyet Anh Dang Thi, Giang Le-Nhat-Thuy, Phuong Hoang Thi, Quynh Giang Nguyen Thi, Tuyen Van Nguyen
A series of new fluorinated dihydrofurano-napthoquinone compounds were sucessfully synthesized in good yields using microwave-assisted multi-component reactions of 2-hydroxy-1,4-naphthoquinone, fluorinated aromatic aldehydes, and pyridinium bromide. The products were fully characterized using spectroscopic techniques and evaluated for their anti-inflammatory activity using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Among 12 new compounds, compounds 8b, 8d, and 8e showed high potent NO inhibitory activity in lipopolysaccharide (LPS)-stimulated RAW264...
March 22, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38522588/antiproliferative-activities-through-accelerating-autophagic-flux-by-basidalin-and-its-analogs-in-human-cancer-cells
#2
JOURNAL ARTICLE
Tomoe Matagawa, Yukiko Sasazawa, Koki Agui, Motoki Fujimaki, Sayaka Kawano, Akihiro Ogura, Ken-Ichi Takao, Masayuki Igarashi, Siro Simizu
Basidalin, isolated from the basidiomycete Leucoagaricus naucina, has previously demonstrated antibacterial and antitumor properties against murine cancer cells in vivo, but its effects on human cancer cells remain unknown. In this study, we found that basidalin possesses antiproliferative activity against human cancer cell lines. To elucidate the antiproliferative mechanism of basidalin, we focused on autophagy. Treatment with basidalin led to an increase in LC3-II expression level, and accelerated autophagic flux through an mTOR-independent pathway...
March 22, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38521177/a-psma-targeted-doxorubicin-small-molecule-drug-conjugate
#3
JOURNAL ARTICLE
Hosog Yoon, Emily A Savoy, Nooshin Mesbahi, Aaron T Hendrickson, Gabrielle L March, Melody D Fulton, Brian S Backer, Clifford E Berkman
We developed a model small-molecule drug conjugate (SMDC) that employed doxorubicin as a representative chemotherapeutic targeted to the cell membrane biomarker PSMA (prostate-specific membrane antigen) expressed on prostate cancer cells. The strategy capitalized on the clatherin-mediated internalization of PSMA to facilitate the selective uptake and release of doxorubicin in the target cells. The SMDC was prepared and assessed for binding kinetics, plasma stability, cell toxicity, and specificity towards PSMA expressing prostate cancer cell lines...
March 21, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38521176/synthesis-and-antihepatoma-activity-of-guaianolide-dimers-derived-from-lavandiolide-i
#4
JOURNAL ARTICLE
Xing Wang, Tian-Ze Li, Yun-Bao Ma, Wen-Jing Ma, Dong Xue, Ji-Jun Chen
Guaianolide dimers represent a unique class of natural products with anticancer activities, but their low content in plants has limited in-depth pharmacological studies. Lavandiolide I is a guaianolide dimer isolated from Artemisia species, and had been synthesized on a ten-gram scale in four steps with 60 % overall yield, which showed potent antihepatoma activity on the HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values of 12.1, 18.4, and 17.6 µM, respectively. To explore more active dimers, 33 lavandiolide I derivatives were designed, synthesized, and evaluated for their inhibitory activity on human hepatoma cell lines...
March 21, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38521175/targeting-atp-binding-site-of-wrn-helicase-identification-of-novel-inhibitors-through-pocket-analysis-and-molecular-dynamics-enhanced-virtual-screening
#5
JOURNAL ARTICLE
Hao Yuan, Run-Duo Liu, Zhuo-Yu Gao, Li-Ting Zhong, Ying-Chen Zhou, Jia-Heng Tan, Zhi-Shu Huang, Zhe Li, Shuo-Bin Chen
WRN helicase is a critical protein involved in maintaining genomic stability, utilizing ATP hydrolysis to dissolve DNA secondary structures. It has been identified as a promising synthetic lethal target for microsatellite instable (MSI) cancers. However, few WRN helicase inhibitors have been discovered, and their potential binding sites remain unexplored. In this study, we analyzed potential binding sites for WRN inhibitors and focused on the ATP-binding site for screening new inhibitors. Through molecular dynamics-enhanced virtual screening, we identified two compounds, h6 and h15, which effectively inhibited WRN's helicase and ATPase activity in vitro...
March 21, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38518997/design-synthesis-and-biological-evaluation-of-novel-benzo-6-7-indolo-3-4-c-isoquinolines-as-anticancer-agents-with-topoisomerase-i-inhibition
#6
JOURNAL ARTICLE
Kie Sakai, Taisei Soshima, Yuki Hirose, Fumito Ishibashi, Shotaro Hirao
A novel series of benzo[6,7]indolo[3,4-c]isoquinolines 3a-3f was designed by scaffold hopping of topoisomerase I inhibitor benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), which were developed by structural modification of the natural marine product lamellarin. The unconventional pentacycle was constructed by Bischler-Napieralski-type condensation of amide 11 and subsequent intramolecular Heck reaction. In vitro anticancer activity of the synthesized benzo[6,7]indolo[3,4-c]isoquinolines was evaluated on a panel of 39 human cancer cell lines (JFCR39)...
March 20, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38508325/an-ascidian-polycarpa-aurata-derived-pan-inhibitor-against-coronaviruses-targeting-m-pro
#7
JOURNAL ARTICLE
Jing Zhang, Lili Zhao, Yuxin Bai, Shanshan Li, Meifang Zhang, Bo Wei, Xianyang Wang, Yan Xue, Li Li, Guiliang Ma, Yu Tang, Xin Wang
Coronaviruses (CoVs) are responsible for a wide range of illnesses in both animals and human. The main protease (Mpro ) of CoVs is an attractive drug target, owing its critical and highly conserved role in viral replication. Here, we developed and refined an enzymatic technique to identify putative Mpro inhibitors from 189 marine chemicals and 46 terrestrial natural products. The IC50 values of Polycarpine (1a), a marine natural substance we studied and synthesized, are 30.0 ± 2.5 nM for SARS-CoV-2 Mpro and 0...
March 18, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38494040/hydrazyl-hydroxycoumarins-as-new-potential-conquerors-towards-pseudomonas-aeruginosa
#8
JOURNAL ARTICLE
Jiang-Sheng Zhao, Nisar Ahmad, Shuo Li, Cheng-He Zhou
A class of unique hydrazyl hydroxycoumarins (HHs) as novel structural scaffold was developed to combat dreadful bacterial infections. Some HHs could effectively suppress bacterial growth at low concentrations, especially, pyridyl HH 7 exhibited a good inhibition against Pseudomonas aeruginosa 27,853 with a low MIC value of 0.5 μg/mL, which was 8-fold more active than norfloxacin. Furthermore, pyridyl HH 7 with low hemolytic activity and low cytotoxicity towards NCM460 cells showed much lower trend to induce the drug-resistant development than norfloxacin...
March 15, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38492608/synthesis-biological-evaluation-and-molecular-docking-study-of-pyrimidine-linked-thiazolidinedione-derivatives-as-potential-antimicrobial-and-antitubercular-agents
#9
JOURNAL ARTICLE
M S Raghu, K C B Pradeep Kumar, Yogesh Kumar, M K Prashanth, Fahd Alharethy, Byong-Hun Jeon
The design and development of novel antimicrobial agents are highly desired to combat the emergence of medication resistance against microorganisms that cause infections. A series of new pyrimidine-linked thiazolidinedione derivatives (5a-j) were synthesized, characterized, and their antimicrobial properties assessed in the current investigation. Here, novel pyrimidine-linked thiazolidinedione compounds were designed using the molecular hybridization approach. Elemental and spectral techniques were used to determine the structures of the synthesized hybrids...
March 14, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38490620/c3-symmetric-ligands-in-drug-design-an-overview-of-the-challenges-and-opportunities-ahead
#10
JOURNAL ARTICLE
Maha A Alshubramy, Faez S Alotaibi, Hamad M Alkahtani, Khalid A Alamry, Mahmoud A Hussein
C3-symmetry is a type of star-shaped molecule consisting of a central core and three symmetrically attached chains. These molecules are used in drug discovery due to their unique three-fold rotational symmetry, which allows for specific binding interactions and improved molecular recognition. In this text, we provide an overview of synthetic approaches with C3-symmetry as a pharmaceutical tool: progress, challenges, and opportunities. C3-symmetric ligands offer both challenges and opportunities in drug design...
March 13, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38484804/synthesis-and-biological-evaluation-of-hydantoin-derivatives-as-potent-antiplasmodial-agents
#11
JOURNAL ARTICLE
Ee-Zhen Chin, Wei-Jin Chang, Hui-Yin Tan, Sook Yee Liew, Yee-Ling Lau, Yee-Ling Ng, Mohd Azlan Nafiah, Thomas Kurz, Siow-Ping Tan
Malaria, a devastating disease, has claimed numerous lives and caused considerable suffering, with young children and pregnant women being the most severely affected group. However, the emergence of multidrug-resistant strains of Plasmodium and the adverse side effects associated with existing antimalarial drugs underscore the urgent need for the development of novel, well-tolerated, and more efficient drugs to combat this global health threat. To address these challenges, six new hydantoins derivatives were synthesized and evaluated for their in vitro antiplasmodial activity...
March 12, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38479483/novel-ether-derivatives-of-11-azaartemisinins-with-high-order-antimalarial-activity-against-multidrug-resistant-plasmodium-yoelii-in-swiss-mice
#12
JOURNAL ARTICLE
Komal Rathi, Mohammad Hassam, Chandan Singh, Sunil K Puri, Jawahar L Jat, Ved Prakash Verma
This study investigates cutting-edge synthetic chemistry approaches for designing and producing innovative antimalarial drugs with improved efficacy and fewer adverse effects. Novel amino (-NH2 ) and hydroxy (-OH) functionalized 11-azaartemisinins 9, 12, and 14 were synthesized along with their derivatives 11a, 13a-e, and 15a-b through ART and were tested for their AMA (antimalarial activity) against Plasmodium yoelii via intramuscular (i.m.) and oral routes in Swiss mice. Ether derivative 13c was the most active compound by i...
March 11, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38452827/synthesis-and-biological-evaluation-of-radioiodinated-benzoxazole-and-benzothiazole-derivatives-for-imaging-myelin-in-multiple-sclerosis
#13
JOURNAL ARTICLE
Hiroyuki Watanabe, Miho Ikawa, Masashi Kakae, Hisashi Shirakawa, Shuji Kaneko, Masahiro Ono
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that results from destruction of the myelin sheath. Due to heterogeneity of the symptoms and course of MS, periodic monitoring of disease activity is important for diagnosis and treatment. In the present study, we synthesized four radioiodinated benzoxazole (BO) and benzothiazole (BT) derivatives, and evaluated their utility as novel myelin imaging probes for single photon emission computed tomography (SPECT). In a biodistribution study using normal mice, three compounds ([125 I]BO-1, [125 I]BT-2, and [125 I]BO-2) displayed moderate brain uptake (2...
March 5, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38452826/design-synthesis-%C3%AE-amylase-and-glucose-diffusion-inhibition-and-molecular-docking-studies-of-new-indenopyrazolones-bearing-benzothiazole-derivatives
#14
JOURNAL ARTICLE
Ravinder Punia, Satbir Mor, Suchita Sindhu, Deepak Kumar, Priyanku Pradip Das, Deepak Kumar Jindal, Ashwani Kumar, Rajni Mohil, Komal Jakhar
An eco-friendly facile synthesis of a series of twenty 1-(4/6-substitutedbenzo[d]thiazol-2-yl)-3-(phenyl/substitutedphenyl)indeno[1,2-c]pyrazol-4(1H)-ones 7a-t was achieved by the reaction of 2-(benzoyl/substitutedbenzoyl)-(1H)-indene-1,3(2H)-dione 3a-t and 2-hydrazinyl-4/6-substitutedbenzo[d]thiazole 6a-t in presence of freshly dried ethanol and glacial acetic acid under reflux conditions in good yields. The newly synthesized derivatives were well characterized using different physical and spectral techniques (FTIR, 1 H NMR &13 C NMR, and HRMS)...
March 5, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38447786/identification-of-two-novel-chemical-classes-of-autotaxin-atx-inhibitors-using-enalos-asclepios-knime-nodes
#15
JOURNAL ARTICLE
Elli-Anna Stylianaki, Varnavas D Mouchlis, Christiana Magkrioti, Konstantinos D Papavasileiou, Antreas Afantitis, Alexios N Matralis, Vassilis Aidinis
Autotaxin is a secreted lysophospholipase D which is a member of the ectonucleotide pyrophosphatase/phosphodiesterase family converting extracellular lysophosphatidylcholine and other non-choline lysophospholipids, such as lysophosphatidylethanolamine and lysophosphatidylserine, to the lipid mediator lysophosphatidic acid. Autotaxin is implicated in various fibroproliferative diseases including interstitial lung diseases such as idiopathic pulmonary fibrosis and hepatic fibrosis, as well as in cancer. In this study, we present an effort of identifying ATX inhibitors that bind to allosteric ATX binding sites using the Enalos Asclepios KNIME Node...
March 4, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38432288/2-3-indolyl-acetamides-and-their-oxazoline-analogues-anticancer-sar-study
#16
JOURNAL ARTICLE
Dmitrii A Aksenov, Jadyn L Smith, Alexander V Aksenov, Lidiya A Prityko, Nicolai A Aksenov, Iliya K Kuzminov, Elena V Alexandrova, Puppala Sathish, Nakya Mesa-Diaz, Alexandra Vernaza, Angela Zhang, Liqin Du, Alexander Kornienko
We previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group. We investigated the structure-activity relationship in both series of compounds and found that the 2-naphthyl is a preferred group at C-2 of the indole in the amide series, whereas the tetralin moiety is favorable in the same location in the oxazoline series...
March 1, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38432287/self-assembly-of-amphiphilic-helical-coiled-peptide-nanofibers-and-inhibition-of-fibril-formation-with-curcumin
#17
JOURNAL ARTICLE
Grace Daniel, George Hilan, Lisa Ploeg, David Sabatino
Amphiphilic peptide sequences are conducive to secondary structures that self-assemble into higher-ordered peptide nanostructures. A select set of amphiphilic polycationic peptides displayed stable helical-coiled structures that self-assembled into peptide nanofibers. The progression of peptide fibril formation revealed short protofibrils that extended into thin filaments and into an entangled network of nanofibers over an extended (5 days) incubation period. Ligand binding with 8-anilinonaphthalene-1-sulfonic acid (ANS) and Congo Red (CR) confirmed the amphiphilic helical-coiled peptide structure assembly into nanofibers, whereas curcumin treatment led to inhibition of fibril formation...
March 1, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38428537/-protac-modified-dihydroquinolizinones-dhqs-that-causes-degradation-of-papd-5-and-inhibition-of-hepatitis-a-virus-and-hepatitis-b-virus-in-vitro
#18
JOURNAL ARTICLE
You Li, Nicky Hwang, Andrew Snedeker, Stanley Lemon, Daisy Noe, Liren Sun, Jason A Clement, Tianlun Zhou, Liudi Tang, Timothy Block, Yanming Du
Dihydroquinolizinones (DHQs) that inhibit cellular polyadenylating polymerases 5 and 7 (PAPD5 & 7), such as RG7834, have been shown to inhibit hepatitis A and B virus (HAV, HBV) in vitro and in vivo. In this report, we describe RG7834-based Proteolysis Targeting Chimeras (PROTACs), such as compound 12b, (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azapentacosan-25-yl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid...
February 28, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38423371/synthesis-sars-cov-2-main-protease-inhibition-molecular-docking-and-in-silico-adme-studies-of-furanochromene-quinoline-hydrazone-derivatives
#19
JOURNAL ARTICLE
Blake M Shellenberger, Olivia N Basile, Joel Cassel, Morgan R Olsen, Joseph M Salvino, Luis J Montaner, Ian Tietjen, Geneive E Henry
Seven furanochromene-quinoline derivatives containing a hydrazone linker were synthesized by condensing a furanochromene hydrazide with 2-, 3-, 4-, 5-, 6-, and 8-quinoline carbaldehydes, including 8-hydroxyquinoline-2-carbaldehye. Structure-activity correlations were investigated to determine the influence of the location of the hydrazone linker on the quinoline unit on SARS-CoV-2 Mpro enzyme inhibition. The 3-, 5-, 6- and 8-substituted derivatives showed moderate inhibition of SARS-CoV-2 Mpro with IC50 values ranging from 16 to 44 μM...
February 27, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38417632/the-discovery-of-novel-and-potent-indazole-nlrp3-inhibitors-enabled-by-dna-encoded-library-screening
#20
JOURNAL ARTICLE
George Hartman, Paul Humphries, Robert Hughes, Andrew Ho, Rusty Montgomery, Aditi Deshpande, Maitriyee Mahanta, Sarah Tronnes, Samantha Cowdin, Xu He, Fangchao Liu, Lifang Zhang, Chuan Liu, Dengfeng Dou, Jin Li, Aleksander Spasic, Rebecca Coll, Michael Marleaux, Inga V Hochheiser, Matthias Geyer, Paul Rubin, Kristen Fortney, Kevin Wilhelmsen
NLRP3 is an intracellular sensor protein that detects a broad range of danger signals and environmental insults. Its activation results in a protective pro-inflammatory response designed to impair pathogens and repair tissue damage via the formation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent secretory release of the pro-inflammatory cytokines IL-1β and IL-18 as well as to gasdermin d-mediated pyroptotic cell death. Herein, we describe the discovery of a novel indazole series of high affinity, reversible inhibitors of NLRP3 activation through screening of DNA-encoded libraries and the potent lead compound 3 (BAL-0028, IC50 = 25 nM) that was identified directly from the screen...
February 26, 2024: Bioorganic & Medicinal Chemistry Letters
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