29274-35-9Relevant academic research and scientific papers
Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria
Workman, Sean D.,Day, Jonathan,Farha, Maya A.,El Zahed, Sara S.,Bon, Chris,Brown, Eric D.,Organ, Michael G.,Strynadka, Natalie C. J.
supporting information, p. 13540 - 13550 (2021/09/20)
The polyprenyl lipid undecaprenyl phosphate (C55P) is the universal carrier lipid for the biosynthesis of bacterial cell wall polymers. C55P is synthesized in its pyrophosphate form by undecaprenyl pyrophosphate synthase (UppS), an essentialcis-prenyltransferase that is an attractive target for antibiotic development. We previously identified a compound (MAC-0547630) that showed promise as a novel class of inhibitor and an ability to potentiate β-lactam antibiotics. Here, we provide a structural model for MAC-0547630’s inhibition of UppS and a structural rationale for its enhanced effect on UppS fromBacillus subtilisversusStaphylococcus aureus. We also describe the synthesis of a MAC-0547630 derivative (JPD447), show that it too can potentiate β-lactam antibiotics, and provide a structural rationale for its improved potentiation. Finally, we present an improved structural model of clomiphene’s inhibition of UppS. Taken together, our data provide a foundation for structure-guided drug design of more potent UppS inhibitors in the future.
SPIRO COMPOUNDS AS GLYCOSIDASE INHIBITORS
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Page/Page column 119, (2020/03/15)
Compounds of formula (I) wherein A, R, L, Z, Q1, Q2 and n have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
Development of Highly Potent, Selective, and Cellular Active Triazolo[1,5- a]pyrimidine-Based Inhibitors Targeting the DCN1-UBC12 Protein-Protein Interaction
Wang, Shuai,Zhao, Lijie,Shi, Xiao-Jing,Ding, Lina,Yang, Linlin,Wang, Zhi-Zheng,Shen, Dandan,Tang, Kai,Li, Xiao-Jing,Mamun,Li, Huiju,Yu, Bin,Zheng, Yi-Chao,Wang, Shaomeng,Liu, Hong-Min
, (2019/03/19)
The cullin-RING ubiquitin ligases (CRLs) are responsible for about 20% of cellular protein degradation and regulate diverse cellular processes, and the dysfunction of CRLs is implicated in human diseases. Targeting the CRLs has become an emerging strategy for the treatment of human diseases. Herein, we describe the discovery of a hit compound from our in-house library and further structure-based optimizations, which have enabled the identification of new triazolo[1,5-a]pyrimidine-based inhibitors targeting the DCN1-UBC12 interaction. Compound WS-383 blocks the DCN1-UBC12 interaction (IC50 = 11 nM) reversibly and shows selectivity over selected kinases. WS-383 exhibits cellular target engagement to DCN1 in MGC-803 cells. WS-383 inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27, and NRF2. Collectively, targeting the DCN1-UBC12 interaction would be a viable strategy for selective neddylation inhibition of Cul3/1 and may be of therapeutic potential for disease treatment in which Cul3/1 is dysregulated.
Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization
Candice, Soares De Melo,Feng, Tzu-Shean,Van Der Westhuyzen, Renier,Gessner, Richard K.,Street, Leslie J.,Morgans, Garreth L.,Warner, Digby F.,Moosa, Atica,Naran, Krupa,Lawrence, Nina,Boshoff, Helena I.M.,Barry, Clifton E.,Harris, C. John,Gordon, Richard,Chibale, Kelly
, p. 7240 - 7250 (2015/11/16)
Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with p
Discovery and characterization of a novel 7-aminopyrazolo[1,5-a]pyrimidine analog as a potent hepatitis C virus inhibitor
Hwang, Jong Yeon,Windisch, Marc Peter,Jo, Suyeon,Kim, Keumhyun,Kong, Sunju,Kim, Hyoung Cheul,Kim, Soohyun,Kim, Heeyoung,Lee, Myung Eun,Kim, Youngmi,Choi, Jihyun,Park, Dong-Sik,Park, Eunjung,Kwon, Jeongjin,Nam, Jiyoun,Ahn, Sujin,Cechetto, Jonathan,Kim, Junwon,Liuzzi, Michel,No, Zaesung,Lee, Jinhwa
, p. 7297 - 7301 (2013/02/23)
We describe a novel 7-aminopyrazolo[1,5-a]pyrimidine (7-APP) derivative as a potent hepatitis C virus (HCV) inhibitor. A series of 7-APPs was synthesized and evaluated for inhibitory activity against HCV in different cell culture systems. The synthesis and preliminary structure-activity relationship study of 7-APP are reported.
Synthesis and structure-activity relationship of a new series of potent angiotensin II receptor antagonists: Pyrazolo[1,5-α]pyrimidine derivatives
Shiota, Takeshi,Yamamori, Teruo,Sakai, Katsunori,Kiyokawa, Mitsugu,Honma, Tsunetoshi,Ogawa, Masayoshi,Hayashi, Kunio,Ishizuka, Natsuki,Matsumura, Ken-Ichi,Hara, Mariko,Fujimoto, Masafumi,Kawabata, Tomoji,Nakajima, Shigeyuki
, p. 928 - 938 (2007/10/03)
We have already reported 7-oxo-4,7-dihydropyrazolo[1,5-α]pyrimidine-3- carboxylic acid derivatives, which are potent in vitro angiotensin II (AII) antagonists, but have no oral antihypertensive activity. Removal of the carboxylic acid and replacement of t
