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ACS Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/29152055/correction-to-structure-based-design-of-non-natural-peptidic-macrocyclic-mcl-1-inhibitors
#1
Jeffrey W Johannes, Stephanie Bates, Carl Beigie, Matthew A Belmonte, John Breen, Shenggen Cao, Paolo A Centrella, Matthew A Clark, John W Cuozzo, Christoph E Dumelin, Andrew D Ferguson, Sevan Habeshian, David Hargreaves, Camil Joubran, Steven Kazmirski, Anthony D Keefe, Michelle L Lamb, Haiye Lan, Yunxia Li, Hao Ma, Scott Mlynarski, Martin J Packer, Philip B Rawlins, Daniel W Robbins, Haidong Shen, Eric A Sigel, Holly H Soutter, Nancy Su, Dawn M Troast, Haiyun Wang, Kate F Wickson, Chengyan Wu, Ying Zhang, Qiuying Zhao, Xiaolan Zheng, Alexander W Hird
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00464.].
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152054/structure-optimization-of-aloperine-derivatives-as-hiv-1-entry-inhibitors
#2
Zhao Dang, Hua Xie, Lei Zhu, Qingye Zhang, Zhijun Li, Li Huang, Chin-Ho Chen
As a step toward developing novel anti-HIV agents, we have identified a class of quinolizidines, including aloperine, that inhibit HIV at 1-5 μM by blocking viral entry. In this study, we have optimized the structure of aloperine and derived compounds with markedly improved activity. Our structural optimization has yielded an aloperine derivative 19 with approximately a 15-fold increase in anti-HIV-1 activity. Our mechanism of action study reveals that compound 19 does not inhibit binding of HIV-1 to receptors but arrests the virus from fusion with the membrane...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152053/benzoxaboroles-as-efficient-inhibitors-of-the-%C3%AE-carbonic-anhydrases-from-pathogenic-fungi-activity-and-modeling-study
#3
Alessio Nocentini, Roberta Cadoni, Sonia Del Prete, Clemente Capasso, Pascal Dumy, Paola Gratteri, Claudiu T Supuran, Jean-Yves Winum
A series of 6-substituted benzoxaboroles were investigated as inhibitors of the β-class carbonic anhydrase from three pathogenic fungi (Cryptococcus neoformans, Candida glabrata, and Malassezia globosa). Independently from the nature of the substituents on the phenyl of the urea/thiourea group, all reported derivatives showed nanomolar inhibitory activities against Can2 and CgNce103 vs micromolar inhibition against MgCA. Selectivity over human CA I and CA II was noticed. The observed structure-activity relationship trends have been rationalized by modeling study of selected compounds into the active site of Can2 and MgCA...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152052/discovery-of-thiophene-3-2-d-pyrimidine-derivatives-as-potent-hiv-1-nnrtis-targeting-the-tolerant-region-i-of-nnibp
#4
Dongwei Kang, Xiao Ding, Gaochan Wu, Zhipeng Huo, Zhongxia Zhou, Tong Zhao, Da Feng, Zhao Wang, Ye Tian, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Our previous studies led us to conclude that thiophene[3,2-d]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (J. Med. Chem. 2016, 59, 7991-8007; J. Med. Chem. 2017, 60, 4424-4443). In the present study, we designed and synthesized a series of thiophenepyrimidine derivatives with various substituents in the right wing region of the structure with the aim of developing new interactions with the tolerant region I of the binding pocket of the HIV-1 non-nucleoside reverse transcriptase (NNRTI), and we evaluated their activity against a panel of mutant HIV-1 strains...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152051/%C3%AF-space-screening-of-dermorphin-based-tetrapeptides-through-use-of-constrained-arylazepinone-and-quinolinone-scaffolds
#5
Olivier Van der Poorten, Robin Van Den Hauwe, Emilie Eiselt, Cecilia Betti, Karel Guillemyn, Nga N Chung, François Hallé, Frédéric Bihel, Peter W Schiller, Dirk Tourwé, Philippe Sarret, Louis Gendron, Steven Ballet
Herein, the synthesis of novel conformationally constrained amino acids, 4-amino-8-bromo-2-benzazepin-3-one (8-Br-Aba), 3-amino-3,4-dihydroquinolin-2-one, and regioisomeric 4-amino-naphthoazepinones (1- and 2-Ana), is described. Introduction of these constricted scaffolds into the N-terminal tetrapeptide of dermorphin (i.e., H-Tyr-d-Ala-Phe-Gly-NH2) induced significant shifts in binding affinity, selectivity, and in vitro activity at the μ- and δ-opioid receptors (MOP and DOP, respectively). A reported constrained μ-/δ-opioid lead tetrapeptide H-Dmt-d-Arg-Aba-Gly-NH2 was modified through application of various constrained building blocks to identify optimal spatial orientations in view of activity at the opioid receptors...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152050/consequences-of-depsipeptide-substitution-on-the-clpp-activation-activity-of-antibacterial-acyldepsipeptides
#6
Yangxiong Li, Nathan P Lavey, Jesse A Coker, Jessica E Knobbe, Dat C Truong, Hongtao Yu, Yu-Shan Lin, Susan L Nimmo, Adam S Duerfeldt
The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gram-positive pathogens. Although newly identified ADEP analogs demonstrate remarkable antibacterial activity against bacterial isolates and in mouse models of bacterial infections, stability issues pertaining to the depsipeptide core remain...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152049/indolylalkyltriphenylphosphonium-analogues-are-membrane-depolarizing-mycobactericidal-agents
#7
Ming Li, Samuel A Nyantakyi, Pooja Gopal, Dinah Binte Aziz, Thomas Dick, Mei-Lin Go
Agents that selectively target the mycobacterial membrane could potentially shorten treatment time for tuberculosis, reduce relapse, and curtail emergence of resistant strains. The lipophilicity and extensive charge-delocalized state of the triphenylphosphonium cation strongly favor accumulation within bacterial membranes. Here, we explored the antimycobacterial activities and membrane-targeting properties of indolylalkyltriphenylphosphonium analogues. The most active analogues preferentially inhibited growth of Mycobacterium tuberculosis H37Rv (MIC50 2-4 μM) and were bactericidal against Mycobacterium bovis BCG (MBC99 3 μM)...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152048/structure-based-design-and-synthesis-of-new-estrane-pyridine-derivatives-as-cytochrome-p450-cyp-1b1-inhibitors
#8
Raphaël Dutour, Francisco Cortés-Benítez, Jenny Roy, Donald Poirier
Inhibition of cytochrome P450 (CYP) 1B1 is a promising therapeutic strategy, as such an inhibitor could modulate the bioactivation of procarcinogens while reducing drug resistance. Based on docking studies, the synthesis of 12 estra-1,3,5(10)-triene derivatives containing a pyridin-3-/4-yl moiety at position C2, C3, or C4 was performed, and we measured their inhibitory activity on CYP1B1 using the ethoxyresorufin-O-deethylase (EROD) assay. The position of the nitrogen atom in the aromatic ring has little influence on their inhibition potency, but compounds with a pyridinyl at C2 of the steroid nucleus are more potent CYP1B1 inhibitors than those with a pyridinyl at C3 or C4...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152047/design-synthesis-and-antibacterial-evaluation-of-oxazolidinones-with-fused-heterocyclic-c-ring-substructure
#9
Mahesh S Deshmukh, Nidhi Jain
A series of novel oxazolidinone antibacterials with diverse fused heteroaryl C-rings bearing hydrogen bond donor and hydrogen bond acceptor functionalities were designed and synthesized. The compound with benzoxazinone C-ring substructure (8c) exhibited superior activity compared to linezolid against a panel of Gram-positive and Gram-negative bacteria. Structural modifications at C5-side chain of 8c resulted in identification of several potent compounds (12a, 12b, 12g, and 12h). Selected compounds 8c and 12a showed very good microsomal stability and no CYP450 liability, thus clearing preliminary safety hurdles...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152046/design-and-synthesis-of-n1-modified-imidazoquinoline-agonists-for-selective-activation-of-toll-like-receptors-7-and-8
#10
Peter Larson, Tamara A Kucaba, Zhengming Xiong, Michael Olin, Thomas S Griffith, David M Ferguson
A series of N1-modified imidazoquinolines were synthesized and screened for Toll-like receptors (TLR) 7 and 8 activities to identify recognition elements that confer high affinity binding and selectivity. These receptors are key targets in the development of immunomodulatory agents that signal the NF-κB mediated transcription of pro-inflammatory chemokines and cytokines. Results are presented showing both TLR7/8 activations are highly correlated to N1-substitution, with TLR8 selectivity achieved through inclusion of an ethyl-, propyl-, or butylamino group at this position...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152045/discovery-of-indolinone-based-multikinase-inhibitors-as-potential-therapeutics-for-idiopathic-pulmonary-fibrosis
#11
Zhenhua Huang, Heran Li, Qian Zhang, Fangzheng Lu, Mei Hong, Zhigang Zhang, Xiaocui Guo, Yuanju Zhu, Sanming Li, Hongzhuo Liu
Idiopathic pulmonary fibrosis (IPF) is a serious and deadly disease for which treatment options are limited. The recent approval of antifibrosis agent nintedanib represents one of the first therapeutic approaches for the treatment of IPF. Here, we report novel indolinone-based multikinase inhibitors that target angiogenesis and fibrosis pathways and may serve as potential therapeutics for IPF. KBP-7018 is a novel, tyrosine kinase-selective inhibitor with potent effects on three fibrotic kinases (c-KIT, PDGFR, and RET)...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152044/structure-based-discovery-of-thiosemicarbazone-metalloproteinase-inhibitors-for-hemorrhage-treatment-in-snakebites
#12
Francis B Ferreira, Thiago M Pereira, Dayane L N Souza, Daiana S Lopes, Vitor Freitas, Veridiana M R Ávila, Arthur E Kümmerle, Carlos Mauricio R Sant'Anna
The venoms of snakes are composed by many toxins, which are responsible for various toxic effects including intense pain, bleeding disorders, and local tissue damage caused by hemorrhage and necrosis. The snake venom metalloproteinases (SVMPs) are proteolytic zinc-dependent enzymes acting in different hemostatic mechanisms. In this work, a structure-based molecular modeling strategy was used for the rational design, by means of a homology 3D model of an SVMP isolated from Bothrops pauloensis venom (BpMP-I), followed by synthesis and in vitro evaluation of new thiosemicarbazones as the first inhibitors of the B...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152043/lysine-specific-demethylase-1-lsd1-inhibitors-as-potential-treatment-for-different-types-of-cancers
#13
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152042/selective-inhibitors-of-phosphodiesterase-4b-pde-4b-may-provide-a-better-treatment-for-cns-metabolic-autoimmune-and-inflammatory-diseases
#14
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29152041/selective-estrogen-receptor-degraders-serds-a-promising-treatment-to-overcome-resistance-to-endocrine-therapy-in-er%C3%AE-positive-breast-cancer
#15
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29057062/discovery-of-mechanism-based-inactivators-for-human-pancreatic-carboxypeptidase-a-from-a-focused-synthetic-library
#16
Sebastián A Testero, Carla Granados, Daniel Fernández, Pablo Gallego, Giovanni Covaleda, David Reverter, Josep Vendrell, Francesc X Avilés, Irantzu Pallarès, Shahriar Mobashery
Metallocarboxypeptidases (MCPs) are involved in many biological processes such as fibrinolysis or inflammation, development, Alzheimer's disease, and various types of cancer. We describe the synthesis and kinetic characterization of a focused library of 22 thiirane- and oxirane-based potential mechanism-based inhibitors, which led to discovery of an inhibitor for the human pro-carboxypeptidase A1. Our structural analyses show that the thiirane-based small-molecule inhibitor penetrates the barrier of the pro-domain to bind within the active site...
October 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29057061/discovery-and-evaluation-of-clinical-candidate-idh305-a-brain-penetrant-mutant-idh1-inhibitor
#17
Young Shin Cho, Julian R Levell, Gang Liu, Thomas Caferro, James Sutton, Cynthia M Shafer, Abran Costales, James R Manning, Qian Zhao, Martin Sendzik, Michael Shultz, Gregg Chenail, Julia Dooley, Brian Villalba, Ali Farsidjani, Jinyun Chen, Raviraj Kulathila, Xiaoling Xie, Stephanie Dodd, Ty Gould, Guiqing Liang, Tycho Heimbach, Kelly Slocum, Brant Firestone, Minying Pu, Raymond Pagliarini, Joseph D Growney
Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg(132). Having identified an allosteric, induced pocket of IDH1(R132H), we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents...
October 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29057060/discovery-of-vu6005649-a-cns-penetrant-mglu7-8-receptor-pam-derived-from-a-series-of-pyrazolo-1-5-a-pyrimidines
#18
Masahito Abe, Mabel Seto, Rocco G Gogliotti, Matthew T Loch, Katrina A Bollinger, Sichen Chang, Eileen M Engelberg, Vincent B Luscombe, Joel M Harp, Michael Bubser, Darren W Engers, Carrie K Jones, Alice L Rodriguez, Anna L Blobaum, P Jeffrey Conn, Colleen M Niswender, Craig W Lindsley
Herein, we report the structure-activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.
October 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29057059/lucky-switcheroo-dramatic-potency-and-selectivity-improvement-of-imidazoline-inhibitors-of-human-carbonic-anhydrase-vii
#19
Stanislav Kalinin, Stanislav Kopylov, Tiziano Tuccinardi, Alexander Sapegin, Dmitry Dar'in, Andrea Angeli, Claudiu T Supuran, Mikhail Krasavin
A substantial improvement of potency and selectivity of imidazoline-based inhibitors of hCA VII (a promising target for the treatment of seizures and neuropathic pain) was achieved by simply switching the position of the benzenesulfonamide moiety from N(1) (as in the earlier reported series) to C(2). Selectivity indices vs the off-target isoforms (hCA I, I, I and IV) greater than 100 were reached, which is exceedingly rare for hCA VII inhibitors. The drastic profile improvement of the new series has been rationalized by an additional hydrogen bonding with the nonconserved Q69 residue in the active site of hCA VII (absent in the other three isoforms studied), which also results in a favorable accommodation of the inhibitor's lipophilic periphery in the nearby hydrophobic pocket...
October 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29057058/addressing-the-metabolic-stability-of-antituberculars-through-machine-learning
#20
Thomas P Stratton, Alexander L Perryman, Catherine Vilchèze, Riccardo Russo, Shao-Gang Li, Jimmy S Patel, Eric Singleton, Sean Ekins, Nancy Connell, William R Jacobs, Joel S Freundlich
We present the first prospective application of our mouse liver microsomal (MLM) stability Bayesian model. CD117, an antitubercular thienopyrimidine tool compound that suffers from metabolic instability (MLM t1/2 < 1 min), was utilized to assess the predictive power of our new MLM stability model. The S-substituent was removed, a set of commercial reagents was utilized to construct a virtual library of 411 analogues, and our MLM stability model was applied to prioritize 13 analogues for synthesis and biological profiling...
October 12, 2017: ACS Medicinal Chemistry Letters
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