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Bioorganic & Medicinal Chemistry Letters

Sarka Pospisilova, Hana Michnova, Tereza Kauerova, Karel Pauk, Peter Kollar, Jarmila Vinsova, Ales Imramovsky, Alois Cizek, Josef Jampilek
A series of 13 salicylamide derivatives was assessed for antibacterial activity against three isolates of vancomycin-resistant Enterococcus faecalis (VRE) and Enterococcus faecalis ATCC 29212 as a quality standard. The minimum inhibitory concentration was determined by the broth microdilution method with subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The growth kinetics was established by the time-kill assay. Ampicillin, ciprofloxacin, tetracycline and vancomycin were used as the reference antibacterial drugs...
May 14, 2018: Bioorganic & Medicinal Chemistry Letters
Rajack Abdul, Taraka Ramji Moturu, J Jeson Babu, K Aruna Lakshmi
No abstract text is available yet for this article.
May 14, 2018: Bioorganic & Medicinal Chemistry Letters
Ning Li, Li-Jun Wang, Bo Jiang, Shu-Ju Guo, Xiang-Qian Li, Xue-Chun Chen, Jiao Luo, Chao Li, Yi Wang, Da-Yong Shi
A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC50 values of 64.47 nM, 188.7 nM and 65.36 nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure-activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes...
May 14, 2018: Bioorganic & Medicinal Chemistry Letters
Bini Mathew, Timothy S Snowden, Michele C Connelly, R Kiplin Guy, Robert C Reynolds
Non-steroidal anti-inflammatory drugs (NSAIDs) have a variety of potential indications that include management of pain and inflammation as well as chemoprevention and/or treatment of cancer. Furthermore, a specific form of ibuprofen, dexibuprofen or the S-(+) form, shows interesting neurological activities and has been proposed for the treatment of Alzheimer's disease. In a continuation of our work probing the anticancer activity of small sulindac libraries, we have prepared and screened a small diversity library of α-methyl substituted sulindac amides in the profen class...
May 10, 2018: Bioorganic & Medicinal Chemistry Letters
Matthew W Martin, Jennifer Y Lee, David R Lancia, Pui Yee Ng, Bingsong Han, Jennifer R Thomason, Maureen S Lynes, C Gary Marshall, Chiara Conti, Alan Collis, Monica Alvarez Morales, Kshama Doshi, Aleksandra Rudnitskaya, Lili Yao, Xiaozhang Zheng
N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.
May 9, 2018: Bioorganic & Medicinal Chemistry Letters
Yulong Xu, Xicheng Yang, Yiyi Chen, Hao Chen, Huijiao Sun, Wei Li, Qiong Xie, Linqian Yu, Liming Shao
A series of structurally novel proteasome inhibitors 1-12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC50  = 9.7 nM) to bortezomib (IC50  = 8.3 nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization.
May 9, 2018: Bioorganic & Medicinal Chemistry Letters
Achim Schlapbach, Laszlo Revesz, Carole Pissot Soldermann, Thomas Zoller, Catherine H Régnier, Frédéric Bornancin, Thomas Radimerski, Jutta Blank, Ansgar Schuffenhauer, Martin Renatus, Paulus Erbel, Samu Melkko, Richard Heng, Oliver Simic, Ralf Endres, Markus Wartmann, Jean Quancard
Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage...
May 9, 2018: Bioorganic & Medicinal Chemistry Letters
Junsuke Hayashi, Misa Nishigaki, Yosuke Ochi, Shun-Ichi Wada, Fumito Wada, Osamu Nakagawa, Satoshi Obika, Mariko Harada-Shiba, Hidehito Urata
Small interfering RNAs (siRNAs) are an active agent to induce gene silencing and they have been studied for becoming a biological and therapeutic tool. Various 2'-O-modified RNAs have been extensively studied to improve the nuclease resistance. However, the 2'-O-modified siRNA activities were often decreased by modification, since the bulky 2'-O-modifications inhibit to form a RNA-induced silencing complex (RISC). We developed novel prodrug-type 2'-O-methyldithiomethyl (MDTM) siRNA, which is converted into natural siRNA in an intracellular reducing environment...
May 8, 2018: Bioorganic & Medicinal Chemistry Letters
Killian Oukoloff, Jane Kovalevich, Anne-Sophie Cornec, Yuemang Yao, Zachary A Owyang, Michael James, John Q Trojanowski, Virginia M-Y Lee, Amos B Smith, Kurt R Brunden, Carlo Ballatore
The [1,2,4]triazolo[1,5-a]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that different analogues may exhibit different binding modes within the same site or possibly interact with tubulin/MTs at alternative binding sites...
May 5, 2018: Bioorganic & Medicinal Chemistry Letters
Jeanette L Bertron, Hyekyung P Cho, Pedro M Garcia-Barrantes, Joseph D Panarese, James M Salovich, Kellie D Nance, Darren W Engers, Jerri M Rook, Anna L Blobaum, Colleen M Niswender, Shaun R Stauffer, P Jeffrey Conn, Craig W Lindsley
This letter describes the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties)...
May 5, 2018: Bioorganic & Medicinal Chemistry Letters
Shohei Utsumi, Kousuke Sato, Satoshi Ichikawa
DNA cytosine-5 methyltransferase (DNMT) catalyzes methylation at the C5 position of cytosine in the CpG sequence in double stranded DNA to give 5-methylCpG (mCpG) in the epigenetic regulation step in human cells. The entire reaction mechanism of DNMT is divided into six steps, which are scanning, recognition, flipping, loop locking, methylation, and releasing. The methylation and releasing mechanism are well-investigated; however, few reports are known about other reaction steps. To obtain insight into the reaction mechanism, we planned the incorporation of acyclic nucleosides, which make it easy to flip out the target nucleobase, into oligodeoxynucleotides (ODNs) and investigated the interaction between the ODN and DNMT...
May 5, 2018: Bioorganic & Medicinal Chemistry Letters
Yuan Shi, Mary Mader
A recent review of kinase inhibitors in clinical trials for brain cancer noted differences in the properties of these compounds relative to the mean property parameters associated with drugs marketed for CNS-associated conditions. However, many of these kinase drugs arose from opportunistic observations of brain activity, rather than design or flow schemes focused on optimizing CNS penetration. Thus, this digest examines kinase inhibitors that have been developed specifically for neurodegenerative indications such as Alzheimer's or Parkinson's disease, and considers design, flow scheme, and the physicochemical properties associated with compounds that have demonstrated brain penetrance...
May 4, 2018: Bioorganic & Medicinal Chemistry Letters
Kousei Shimada, Yasuo Ohata, Jun Kobayashi, Yoshiyuki Onishi, Asuka Kawamura, Yuki Domon, Naohisa Arakawa, Tatsuya Inoue, Yutaka Kitano, Fumihiko Matsuda, Yuki Abe, Tsuneo Deguchi
We identified novel (3R, 5S)-3-aminomethyl-5-methanesulfanyl hexanoic acid (5a: DS75091588) and (3R, 5S)-3-aminomethyl-5-ethanesulfanyl hexanoic acid (6a: DS18430756) as sulfur-containing γ-amino acid derivatives that were useful for the treatment of neuropathic pain. These two compounds exhibited a potent analgesic effect in animal models of both type I diabetes and type II diabetes, and good pharmacokinetics.
May 4, 2018: Bioorganic & Medicinal Chemistry Letters
Christian Breuer, Carina Lemke, Janina Schmitz, Ulrike Bartz, Michael Gütschow
A series of inhibitors targeting human cathepsins have been designed and synthesized following a combinatorial approach. The compounds bear an α,β-unsaturated phenyl vinyl sulfone or ethyl acrylate warhead and a peptidomimetic portion aligned to the non-primed binding region. Biochemical evaluation toward four human cathepsins was carried out and the kinetic characterization confirmed an irreversible mode of inhibition. Compound 6c combining the most advantageous building blocks for cathepsin S inhibition was identified as a potent cathepsin S inactivator exhibiting a second-order rate constant of 30600 M-1  s-1 ...
May 4, 2018: Bioorganic & Medicinal Chemistry Letters
Cheng Lu, Yan Yin, Fanli Meng, Yongbin Dun, Keke Pei, Chenlu Wang, Xu Xu, Fanhong Wu
Neuraminidase has been considered as an important target for designing agents against influenza viruses. In a discovery of anti-influenza agents with epigoitrin as the initial lead compound, a series of 1-amino-2-alkanols were synthesized and biologically evaluated. The in vitro evaluation indicated that (E)-1-amino-4-phenylbut-3-en-2-ol (C1) had better inhibitory activities than 2-amino-1-arylethan-1-ol derivatives. To our surprise, sulfonation of C1 with 4-methoxybenzenesulfonyl chloride afforded more active inhibitor II with up to 6...
May 4, 2018: Bioorganic & Medicinal Chemistry Letters
Xiaoyu Zhao, Bin Sun, Hongbo Zheng, Jun Liu, Lilin Qian, Xiaoning Wang, Hongxiang Lou
The sodium glucose co-transporter 2 (SGLT2) was considered as an important target for the treatment of type 2 diabetes mellitus in recent years. This report describes the design and synthesis of a series of novel SGLT2 inhibitors (11a-17a) as well as their dehydrate dihydrofuran derivatives (11b-17b), which were prepared by Mitsunobu reaction. Their SGLT2 inhibitory activity was also evaluated, and 16a and 17a were found to be the most potent compounds with IC50 values of 0.63 and 0.81 nM, respectively. However, all the dehydrate derivatives lose the SGLT2 inhibitory activity, with inhibition percentage no more than 66...
May 3, 2018: Bioorganic & Medicinal Chemistry Letters
Siem Jakob Veenstra, Heinrich Rueeger, Markus Voegtle, Rainer Lueoend, Philipp Holzer, Konstanze Hurth, Marina Tintelnot-Blomley, Mathias Frederiksen, Jean-Michel Rondeau, Laura Jacobson, Matthias Staufenbiel, Ulf Neumann, Rainer Machauer
New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied...
May 3, 2018: Bioorganic & Medicinal Chemistry Letters
Jacob Holechek, Robert Lease, Ann-Gerd Thorsell, Tobias Karlberg, Caitlin McCadden, Ryan Grant, Abby Keen, Evan Callahan, Herwig Schüler, Dana Ferraris
A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with ∼15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members...
May 3, 2018: Bioorganic & Medicinal Chemistry Letters
Michael J Bird, Anthony P Silvestri, Philip E Dawson
The benzimidazole moiety is a ubiquitous pharmacophore present in numerous anthelmintic, antibacterial, antiviral, antineoplastic, and antifungal drugs. While the polypharmacology of this heterocycle has spurred the development of numerous solution-phase syntheses, only a handful of disparate and inefficient methods detailing its synthesis on-resin have been reported. Here we report the concise and expedient syntheses of internal and C-terminal peptidic benzimidazoles - an emerging class of peptide deformylase (PDF)-inhibiting antimicrobials...
May 3, 2018: Bioorganic & Medicinal Chemistry Letters
Peter Choi, Katsuya Noguchi, Munetaka Ishiyama, William A Denny, Jiney Jose
This communication details the synthesis, evaluation of photophysical properties, and cellular imaging studies of cyanine chromophore based fluorescent dye 1 as a selective imaging agent for mitochondria.
May 3, 2018: Bioorganic & Medicinal Chemistry Letters
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