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Journals Bioorganic & Medicinal Chemist...

Bioorganic & Medicinal Chemistry Letters

https://read.qxmd.com/read/39029538/a-chemical-platform-for-the-efficient-screening-of-arylazopyrazole-based-photoswitchable-cenp-e-inhibitors-using-mild-cyclization-reactions
#1
JOURNAL ARTICLE
Kazuya Matsuo, Honoka Ogawa, Shusuke Yamaoka, Tomonori Waku, Akio Kobori
A set of arylazopyrazole-based inhibitors targeting the mitotic motor protein CENP-E was discovered through the chemical platform using the quantitative cyclization of 1,3-diketone intermediate with various hydrazines under mild conditions. Through this efficient platform, the structure-activity relationship pertaining to the pyrazole photoswitch in photoswitchable CENP-E inhibitors not only in vitro but also in cells was successfully clarified.
July 17, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/39019240/discovery-of-ds-1093a-an-oral-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitor-for-the-treatment-of-renal-anemia
#2
JOURNAL ARTICLE
Naoki Tanaka, Takeshi Fukuda, Rieko Takano, Koji Sasaki, Takashi Tsuji, Riki Goto, Takeshi Kuribayashi, Kyoji Yamaguchi, Yoichi Niitsu, Ken Ishii, Masami Hashimoto, Shinichi Takahashi, Hisakuni Obayashi
Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy...
July 15, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/39013490/revisiting-the-dipeptidyl-carboxypeptidase-inhibitor-captopril-as-a-source-of-pan-anti-trypanosomatid-agents
#3
JOURNAL ARTICLE
Jean-Baptiste Garsi, Sofiane Hocine, Raphaël Hensienne, Matthieu Moitessier, Helen Denton, Louise L Major, Terry K Smith, Stephen Hanessian
The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for continued propagation of neglected tropical diseases such as African sleeping sickness, Chagas disease and leishmaniasis respectively. Following a report that captopril targets Leishmania donovani dipeptidyl carboxypeptidase, a series of simple proline amides and captopril analogues were synthesized and found to exhibit 1-2 μM in vitro inhibition and selectivity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp...
July 14, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/39004318/discovery-of-the-first-selective-small-molecule-gfr%C3%AE-2-3-inhibitors-through-dna-encoded-library-technology
#4
JOURNAL ARTICLE
Shea L Johnson, Galen Missig, Minghua Wang, Kosalvisal Ouk, Kushali Gupta, Hanh Nho Nguyen, May Fern Toh, Tammy Szu-Yu Ho, David Gray, Hongjun Zhang, Yong Mi Choi-Sledeski, Claude Barberis, David J Stone, Sokhom Pin, Jongwon Lim
Studies have shown that disrupting the formation of the ligand-RET-GFRα complex could be an effective way of treating pain and itch. Compared to traditional high-throughput screens, DNA encoded libraries (DELs) have distinguished themselves as a powerful technology for hit identification in recent years. The present work demonstrates the use of DEL technology identifying compound 16 as the first GFRa2/GFRa3 small molecule inhibitor (0.1/0.2 μM respectively) selective over RET. This molecule represents an opportunity to advance the development of small-molecule inhibitors targeting the GFRα-RET interface for the treatment of pain and itch...
July 12, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/39004317/design-synthesis-and-evaluation-of-benzodioxolane-compounds-for-antitumor-activity
#5
JOURNAL ARTICLE
Xiu-Jun Wang, Yue Qiao, Zi-Rui Jiang, Jing-Liang He, Bing-Yan Wang, Jia-Rui Wan, Jing Ji, Bin Liu
This study reports the design, synthesis, and comprehensive biological evaluation of 13 benzodioxolane derivatives, derived from the core structure of piperine, a natural product with established antitumor properties. Piperine, primarily found in black pepper, has been noted for its diverse pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects. Leveraging piperine's antitumor potential, we aimed to enhance its efficacy through structural modifications. Among the synthesized compounds, HJ1 emerged as the most potent, exhibiting a 4-fold and 10-fold increase in inhibitory effects on HeLa and MDA-MB-231 cell lines, respectively, compared to piperine...
July 12, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/39002937/structures-of-small-molecules-bound-to-rna-repeat-expansions-that-cause-huntington-s-disease-like-2-and-myotonic-dystrophy-type-1
#6
REVIEW
Jonathan L Chen, Amirhossein Taghavi, Alexander J Frank, Matthew A Fountain, Shruti Choudhary, Soma Roy, Jessica L Childs-Disney, Matthew D Disney
Trinucleotide repeat expansions fold into long, stable hairpins and cause a variety of incurable RNA gain-of-function diseases such as Huntington's disease, the myotonic dystrophies, and spinocerebellar ataxias. One approach for treating these diseases is to bind small molecules to the structured RNAs. Both Huntington's disease-like 2 (HDL2) and myotonic dystrophy type 1 (DM1) are caused by a r(CUG) repeat expansion, or r(CUG)exp . The RNA folds into a hairpin structure with a periodic array of 1 × 1 nucleotide UU loops (5'CUG/3'GUC; where the underlined nucleotides indicate the Us in the internal loop) that sequester various RNA-binding proteins (RBP) and hence the source of its gain-of-function...
July 11, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/39002936/novel-selective-proline-based-peptidomimetics-for-human-cathepsin-k-inhibition
#7
JOURNAL ARTICLE
Felipe Cardoso Prado Martins, Fernanda Dos Reis Rocho, Vinícius Bonatto, Pedro Henrique Jatai Batista, Jerônimo Lameira, Andrei Leitão, Carlos A Montanari
Human cathepsin K (CatK) stands out as a promising target for the treatment of osteoporosis, considering its role in degrading the bone matrix. Given the small and shallow S2 subsite of CatK and considering its preference for proline or hydroxyproline, we now propose the rigidification of the leucine fragment found at the P2 position in a dipeptidyl-based inhibitor, generating rigid proline-based analogs. Accordingly, with these new proline-based peptidomimetics inhibitors, we selectively inhibited CatK against other human cathepsins (B, L and S)...
July 11, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38996941/discovery-of-l15-as-a-novel-vif-protac-degrader-with-antiviral-activity-against-hiv-1
#8
JOURNAL ARTICLE
Dan Luo, Ronghua Luo, Weilin Wang, Rui Deng, Shirui Wang, Xinyu Ma, Chunlan Pu, Yuanyuan Liu, Hongjia Zhang, Su Yu, Qing Huang, Liumeng Yang, Yu Tong, Yongtang Zheng, Rui Li
Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported...
July 10, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38996940/2-piperidin-3-yl-phthalimides-reduce-classical-markers-of-cellular-inflammation-in-lps-challenged-raw-264-7-cells-and-also-demonstrate-potentially-relevant-sigma-and-serotonin-receptor-affinity-in-membrane-preparations
#9
JOURNAL ARTICLE
Michael T Scerba, David Tweedie, Nigel H Greig
Herein, we report the synthesis of new 4-amino-2-(piperidin-3-yl)isoindoline-1,3-diones and their biological evaluation in a series of in vitro experiments. The synthetic production of these materials was initiated upon the condensation of appropriate nitrophthalic acid derivatives with various 3-aminopiperidines; subsequent reduction provided the final products in moderate to good yields. Readily available chiral pool reagents facilitated entry into optically enriched samples, while the piperidine scaffold furnished a variety of amide and alkylated entries...
July 10, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38996939/novel-inhibitor-n-cyclopropyl-4-4-4-trifluoromethyl-phenyl-sulfonyl-piperazin-1-yl-methyl-benzamide-attenuates-rankl-mediated-osteoclast-differentiation-in-vitro
#10
JOURNAL ARTICLE
Alessandra Marie Encarnacion, Nithin Pootheri, Hongyuan Yao, Zhihao Chen, Sunwoo Lee, Eunae Kim, Tae-Hoon Lee
Both cyclopropyl amide and piperazine sulfonamide functional groups are known for their various biological properties used for drug development. Herein, we synthesized nine new derivatives with different substituent groups incorporating these moieties and screened them for their anti-osteoclast differentiation activity. After analyzing the structure-activity relationship (SAR), the inhibitory effect against osteoclastogenesis was determined to be dependent on the lipophilicity of the compound. Derivative 5b emerged as the most effective dose-dependent inhibitor after TRAP staining with an IC50 of 0...
July 10, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38996938/plakevulin-a-induces-apoptosis-and-suppresses-il-6-induced-stat3-activation-in-hl60-cells
#11
JOURNAL ARTICLE
Misaki Kabasawa, Masateru Furuta, Yuuka Ibayashi, Kaori Kanemaru, Haruki Kohatsu, Fumiyo Kuramochi, Kenji Yamatoya, Kazuya Nakata, Yoshikazu Nakamura, Shusuke Tomoshige, Kenji Ohgane, Yuuki Furuyama, Ryoko Takasawa, Susumu Kobayashi, Fumio Sugawara, Masahiko Ikekita, Kouji Kuramochi
(+)-Plakevulin A (1), an oxylipin isolated from an Okinawan sponge Plakortis sp. inhibits enzymatic inhibition of DNA polymerases (pols) α and δ and exhibits cytotoxicity against murine leukemia (L1210) and human cervix carcinoma (KB) cell lines. However, the half-maximal inhibitory concentration (IC50 ) value for cytotoxicity significantly differed from those observed for the enzymatic inhibition of pols α and β, indicating the presence of target protein(s) other than pols. This study demonstrated cytotoxicity against human promyelocytic leukemia (HL60), human cervix epithelioid carcinoma (HeLa), mouse calvaria-derived pre-osteoblast (MC3T3-E1), and human normal lung fibroblast (MRC-5) cell lines...
July 10, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38996937/n-methylmorpholine-incorporation-into-the-structure-of-biphenyl-leads-to-the-bioactive-inhibitor-of-pd-1-pd-l1-interaction
#12
JOURNAL ARTICLE
Julia Zaber, Lukasz Skalniak, Ganna P Gudz, Aleksandra Hec-Galazka, Magdalena Zarnik, Urszula Tyrcha, Malgorzata Stec, Maciej Siedlar, Tad A Holak, Tomasz Sitar, Damian Muszak
We present new small-molecular probes targeting the human PD-L1 protein. The molecules were designed by incorporating a newly discovered N-methylmorpholine substituent into a known biphenyl-based structure. Four prototype derivatives of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (STD4), comprising a morpholine substituent fused with a biphenyl core at different orientations were first verified for their potential binding to PD-L1 using the molecular docking method. A more favorable 7-phenyl derivative of STD4 was then equipped with an amide bond, pyridine, and either a tris(hydroxymethyl)aminomethane or serinol tail leading to two final molecules...
July 10, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38996936/identification-of-coumarin-benzimidazole-hybrids-as-potential-antibacterial-agents-synthesis-in-vitro-and-in-vivo-biological-assessment-and-admet-prediction
#13
JOURNAL ARTICLE
C G Arya, Raj Kishore, Pooja Gupta, Ramesh Gondru, Jesu Arockiaraj, Mukesh Pasupuleti, Munugala Chandrakanth, V P Punya, Janardhan Banothu
The direct-linked coumarin-benzimidazole hybrids, featuring aryl and n-butyl substituents at the N1-position of benzimidazole were synthesized through a Knoevenagel condensation reaction. This reaction involved the condensation of 1,2-diaminobenzene derivatives with coumarin-3-carboxylic acids in the presence of polyphosphoric acid (PPA) at 154 °C. The in vitro antibacterial potency of the hybrid molecules against different gram-positive and gram-negative bacterial strains led to the identification of the hybrids 6m and 6p with a MIC value of 6...
July 10, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38977107/discovery-of-1-2-3-triazole-based-pleuromutilin-derivatives-as-potent-gram-positive-antibacterial-agents
#14
JOURNAL ARTICLE
Jiahua Zhang, Shaorui Chen, Xiaoya Liu, Xudong Yu, Na Gu, Aijun Li
A novel class of pleuromutilin derivatives possessing 1,2,3-triazole as the linker connected to phenyl analogues were designed. The antibacterial properties of the prepared compounds were assessed in vitro against five strains (E. coli, S. aureus, S. epidermidis, and E. faecalis). Most of the tested compounds displayed potent antibacterial activities against gram-positive bacteria and 14-O-[2-(4-((2,4-dinitrophenoxy)-methyl-1H-1,2,3-triazol-1-yl) acetamide)-2-methylpropan-2-yl) thioacetyl]mutilin (7c) exerted antibacterial activities against S...
July 6, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38977106/synthesis-biosimulation-and-pharmacological-evaluation-of-benzimidazole-derivatives-with-antihypertensive-multitarget-effect
#15
JOURNAL ARTICLE
Abraham Gutiérrez-Hernández, Samuel Estrada-Soto, Carlos Martínez-Conde, Emmanuel Gaona-Tovar, José L Medina-Franco, Emanuel Hernández-Núñez, Sergio Hidalgo-Figueroa, Patricia Castro-Moreno, Maximiliano Ibarra-Barajas, Gabriel Navarrete-Vazquez
In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1 R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1 H NMR, 13 C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel...
July 6, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38964520/semisynthetic-derivatives-of-the-fungal-metabolite-eupenifeldin-via-targeting-the-tropolone-hydroxy-groups
#16
JOURNAL ARTICLE
Zeinab Y Al Subeh, Herma C Pierre, Ross H Bockbrader, Robert J Tokarski, Amanda C Maldonado, Monica A Haughan, Manuel E Rangel Grimaldo, Cedric J Pearce, Joanna E Burdette, James R Fuchs, Nicholas H Oberlies
Eupenifeldin (1) is a fungal secondary metabolite possessing bis-tropolone moieties that demonstrates nanomolar cytotoxic activity against a number of cancer cell types. As a potential anticancer lead, this meroterpenoid was used to access 29 semisynthetic analogues via functionalization of the reactive hydroxy groups of the bis-tropolones. A series of ester (2-6), carbonate (7-8), sulfonate (9-16), carbamate (17-20), and ether (21-30) analogues of 1 were generated via 22 reactions. Most of these compounds were disubstituted, produced via functionalization of both of the tropolonic hydroxy moieties, although three mono-functionalized analogues (6, 8, and 24) and one tri-functionalized analogue (3) were also obtained...
July 2, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38964519/synthesis-and-activity-of-benzimidazole-n-acylhydrazones-against-trypanosoma-cruzi-leishmania-amazonensis-and-leishmania-infantum
#17
JOURNAL ARTICLE
Laís G Ramos, Kátia R de Souza, Juliana M C Barbosa, Kelly Salomão, Policarpo A Sales Junior, Valéria Rêgo Alves Pereira, Silvane M F Murta, Rafaela S Ferreira, Talita C D Bernardes, Solange M S V Wardell, James L Wardell, Nubia Boechat, Samir A Carvalho
In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50 /120 h of 0.033 μM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50 /120 h = 1...
July 2, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38964518/synthesis-and-biological-evaluation-of-novel-penindolone-derivatives-as-potential-antiproliferative-agents-against-sclc-in-vitro
#18
JOURNAL ARTICLE
Jiaqi Lin, Yongqing Han, Bohan Li, Wenrui Gai, Zhengjie Wang, Qi Wang, Yueling Teng, Jing Li, Dehai Li
Small cell lung cancer (SCLC) keeps on the leading cause of cancer mortality world widely, while there is lack of efficient therapeutic drugs especially for the resistant ones. In this work, a compound named penindolone (PND) with new skeleton was found to show weak inhibitory effect (IC50  = 42.5 µM) on H69AR cells (SCLC, adriamycin-resistant) proliferation by screening our in-house compound library. With the aim of improving its low potency, a series of PND derivatives were synthesized and biologically evaluated by the Sulforhodamine B (SRB) assay...
July 2, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38955244/high-yield-and-high-purity-amide-bond-formation-using-dmtmm-pf-6-for-dna-encoded-libraries
#19
JOURNAL ARTICLE
Takumi Hosozawa, Masatoshi Niwa, Hisayuki Takeuchi, Takehiko Inohana, Kaori Okumura, Shin Itoh
In this study, we report on the ability of DMTMM PF6 to improve the amidation reaction. The on-DNA amidation reaction using DMTMM PF6 demonstrates higher conversion rates than those using HATU or DMTMM Cl, particularly with challenging sterically hindered amines and carboxylic acids. The developed method enables the expansion of available building blocks and the efficient synthesis of high-purity DNA-encoded libraries.
June 30, 2024: Bioorganic & Medicinal Chemistry Letters
https://read.qxmd.com/read/38950758/the-search-for-pyruvate-kinase-r-activators-from-a-hts-screening-hit-via-an-impurity-to-the-discovery-of-a-lead-series
#20
JOURNAL ARTICLE
Chul Yu, Lina Quattrocchio Setti, Shahul Nilar, Zhe Li, Ming Yu, James Partridge, Rebeca Choy, Vincent Siu, Steven Strutt, Richard Zang, Peter Rademacher, Soheila Bahmanjah, Yekaterina Myslovaty, Manuel Zancanella
Pyruvate kinase (PK) is an essential component of cellular metabolism, converting ADP and phosphoenolpyruvate (PEP) to pyruvate in the final step of glycolysis. Of the four unique isoforms of pyruvate kinase, R (PKR) is expressed exclusively in red blood cells and is a tetrameric enzyme that depends on fructose-1,6-bisphosphate (FBP) for activation. PKR deficiency leads to hemolysis of red blood cells resulting in anemia. Activation of PKR in both sickle cell disease and beta-thalassemia patients could lead to improved red blood cell fitness and survival...
June 29, 2024: Bioorganic & Medicinal Chemistry Letters
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