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ACS Medicinal Chemistry Letters

Andriy Buchynskyy, J Robert Gillespie, Zackary M Herbst, Ranae M Ranade, Frederick S Buckner, Michael H Gelb
A high throughput screening and subsequent hit validation identified compound 1 as an inhibitor of Trypanosoma brucei parasite growth. Extensive structure-activity relationship optimization based on antiparasitic activity led to the highly potent compounds, 1-(4-fluorobenzyl)-3-(4-dimethylamino-3-chlorophenyl)-2-thiohydantoin (68) and 1-(2-chloro-4-fluorobenzyl)-3-(4-dimethylamino-3-methoxyphenyl)-2-thiohydantoin (76), with a T. brucei EC50 of 3 and 2 nM, respectively. This represents >100-fold improvement in potency compared to compound 1...
August 10, 2017: ACS Medicinal Chemistry Letters
Grazia M L Consoli, Ivana Di Bari, Anna R Blanco, Antonia Nostro, Manuela D'Arrigo, Venerando Pistarà, Salvatore Sortino
The role of nitric oxide (NO) as an antimicrobial and anticancer agent continues to stimulate the search of compounds generating NO in a controlled fashion. Photochemical generators of NO are particularly appealing due to the accurate spatiotemporal control that light-triggering offers. This contribution reports a novel molecular construct in which multiple units of 3-(trifluoromethyl)-4-nitrobenzenamine NO photodonor are clustered and spatially organized by covalent linkage to a calix[4]arene scaffold bearing two quaternary ammonium groups at the lower rim...
August 10, 2017: ACS Medicinal Chemistry Letters
Chengbin Yang, Xi Zhang, Yi Wang, Yongtai Yang, Xiaofeng Liu, Mingli Deng, Yu Jia, Yun Ling, Ling-Hua Meng, Yaming Zhou
The phosphoinositide 3-kinase (PI3K) inhibitors potently inhibit the signaling pathway of PI3K/AKT/mTOR, which provides a promising new approach for the molecularly targeted cancer therapy. In this work, a novel series of 7-azaindole scaffold derivatives was discovered by the fragment-based growing strategy. The structure-activity relationship profiles identified that the 7-azaindole scaffold derivatives exhibit potent activity against PI3K at molecular and cellular levels as well as cell proliferation in a panel of human tumor cells...
August 10, 2017: ACS Medicinal Chemistry Letters
Young K Chen, Tiziana Bonaldi, Alessandro Cuomo, Joselyn R Del Rosario, David J Hosfield, Toufike Kanouni, Shih-Chu Kao, Chon Lai, Neethan A Lobo, Jennifer Matuszkiewicz, Andrew McGeehan, Shawn M O'Connell, Lihong Shi, Jeffrey A Stafford, Ryan K Stansfield, James M Veal, Michael S Weiss, Natalie Y Yuen, Michael B Wallace
Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models...
August 10, 2017: ACS Medicinal Chemistry Letters
Pierrik Lassalas, Killian Oukoloff, Vishruti Makani, Michael James, Van Tran, Yuemang Yao, Longchuan Huang, Krishna Vijayendran, Ludovica Monti, John Q Trojanowski, Virginia M-Y Lee, Marisa C Kozlowski, Amos B Smith, Kurt R Brunden, Carlo Ballatore
The oxetane ring serves as an isostere of the carbonyl moiety, suggesting that oxetan-3-ol may be considered as a potential surrogate of the carboxylic acid functional group. To investigate this structural unit, as well as thietan-3-ol and the corresponding sulfoxide and sulfone derivatives, as potential carboxylic acid bioisosteres, a set of model compounds has been designed, synthesized, and evaluated for physicochemical properties. Similar derivatives of the cyclooxygenase inhibitor, ibuprofen, were also synthesized and evaluated for inhibition of eicosanoid biosynthesis in vitro...
August 10, 2017: ACS Medicinal Chemistry Letters
Azzurra Stefanucci, Alfonso Carotenuto, Giorgia Macedonio, Ettore Novellino, Stefano Pieretti, Francesca Marzoli, Edina Szűcs, Anna I Erdei, Ferenc Zádor, Sándor Benyhe, Adriano Mollica
In this work we enhanced the ring lipophilicity of biphalin introducing a xylene moiety, thus obtaining three cyclic regioisomers. Novel compounds have similar in vitro activity as the parent compound, but one of these (6a) shows a remarkable increase of in vivo antinociceptive effect. Nociception tests have disclosed its significant high potency and the more prolonged effect in eliciting analgesia, higher than that of biphalin and of the disulfide-bridge-containing analogue (7).
August 10, 2017: ACS Medicinal Chemistry Letters
John C Lainson, Seth M Daly, Kathleen Triplett, Stephen Albert Johnston, Pamela R Hall, Chris W Diehnelt
One proposed solution to the crisis of antimicrobial resistant (AMR) infections is the development of molecules that potentiate the activity of antibiotics for AMR bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Rather than develop broad spectrum compounds, we developed a peptide that could potentiate the activity of a narrow spectrum antibiotic, oxacillin. In this way, the combination treatment could narrowly target the resistant pathogen and limit impact on host flora. We developed a peptide, ASU014, composed of a S...
August 10, 2017: ACS Medicinal Chemistry Letters
David S Millan, Katherine J Kayser-Bricker, Matthew W Martin, Adam C Talbot, Shawn E R Schiller, Torsten Herbertz, Grace L Williams, George P Luke, Stephen Hubbs, Monica A Alvarez Morales, Daniel Cardillo, Paul Troccolo, Rachel L Mendes, Crystal McKinnon
A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability...
August 10, 2017: ACS Medicinal Chemistry Letters
Peng Li, Jun Yu, Fei Hao, Haiying He, Xuyang Shi, Jiao Hu, Li Wang, Chunyan Du, Xiao Zhang, Ya Sun, Fusen Lin, Zhengxian Gu, Deming Xu, Xinsheng Chen, Liang Shen, Guoping Hu, Jian Li, Shuhui Chen, Wei Xiao, Zhenzhong Wang, Qingming Guo, Xiujuan Chang, Xuyang Tian, Tianwei Lin
Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease (HFMD), which can spread its infections to the central nervous and other systems with severe consequences. The viral caspid protein VP1 is a well-known target for antiviral efficacy because its occupancy by suitable compounds could stabilize the virus capsid, thus preventing uncoating of virus for RNA release. In this Letter, design, synthesis, and biological evaluation of novel anti-EV71 agents (aminopyridyl 1,2,5-thiadiazolidine 1,1-dioxides) are described...
August 10, 2017: ACS Medicinal Chemistry Letters
Sujay Basu, Dinesh A Barawkar, Vidya Ramdas, Minakshi Naykodi, Yogesh D Shejul, Meena Patel, Sachin Thorat, Anil Panmand, K Kashinath, Rajesh Bonagiri, Vandna Prasad, Ganesh Bhat, Azfar Quraishi, Sumit Chaudhary, Amol Magdum, Ashwinkumar V Meru, Indraneel Ghosh, Ravi K Bhamidipati, Amol A Raje, Vamsi L M Madgula, Siddhartha De, Sreekanth R Rouduri, Venkata P Palle, Anita Chugh, Narayanan Hariharan, Kasim A Mookhtiar
Adenosine A2A receptor (A2AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonism of the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33...
August 10, 2017: ACS Medicinal Chemistry Letters
Dong Lu, Juan Yan, Lang Wang, Hongchun Liu, Limin Zeng, Minmin Zhang, Wenwen Duan, Yinchun Ji, Jingchen Cao, Meiyu Geng, Aijun Shen, Youhong Hu
Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, 2m, inhibited c-Met kinase and HDAC1, with IC50 values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide...
August 10, 2017: ACS Medicinal Chemistry Letters
Taha Y Taha, Shaimaa M Aboukhatwa, Rachel C Knopp, Naohiko Ikegaki, Hazem Abdelkarim, Jayaprakash Neerasa, Yunlong Lu, Raghupathi Neelarapu, Thomas W Hanigan, Gregory R J Thatcher, Pavel A Petukhov
Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively...
August 10, 2017: ACS Medicinal Chemistry Letters
Jessica E Wynn, Wenyu Zhang, Joseph O Falkinham, Webster L Santos
The emergence of microbial resistance presents a challenge in the development of next generation therapeutics. Herein, we report the discovery of branched peptides decorated with acridine and boronic acid moieties with potent antimicrobial activity. The results revealed minimal inhibitory concentrations (MICs) as low as 1 μg/mL against Staphylococcus aureus, Candida albicans, and Escherichia coli. These peptides were nonhemolytic, and significantly inhibited growth of C. albicans in suspension and biofilm formation...
August 10, 2017: ACS Medicinal Chemistry Letters
Luladey Ayalew, Jessica Acuna, Selina F Urfano, Cristobal Morfin, Anthony Sablan, Myungeun Oh, Alicia Gamboa, Katarzyna Slowinska
Paclitaxel (PTX) is one of the most potent cancer drugs; however, its low solubility and strong systemic side effects limit its clinical applications. To overcome these issues, new drug formulations and chemical modifications have been proposed. In this study, we present conjugation of PTX to hybrid collagen-cell penetrating peptide (COL-CPP) carriers. The peptide carrier is highly soluble and utilizes a unique stabilization strategy: folding into a triple helix. Here, we report the formation of PTX-COL-CPP prodrug that has similar drug potency as free PTX when tested in Jurkat (human T lymphocyte of acute T cell leukemia) cells but not in A549 (human epithelial of lung carcinoma) cells...
August 10, 2017: ACS Medicinal Chemistry Letters
Marcian E Van Dort, Stefanie Galbán, Charles A Nino, Hao Hong, April A Apfelbaum, Gary D Luker, Greg M Thurber, Lydia Atangcho, Cagri G Besirli, Brian D Ross
The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168), which displays improved MEK1 and PI3K isoform inhibition, is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8-, 2.7-, 23-, and 2.5-fold improved inhibition toward the PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ isoforms, respectively, as compared to a previous lead compound (4; ST-162) in in vitro enzymatic inhibition assays. ST-168 demonstrated superior tumoricidal efficacy over ST-162 in an A375 melanoma spheroid tumor model...
August 10, 2017: ACS Medicinal Chemistry Letters
Marc A Giulianotti, Brian A Vesely, Ala Azhari, Ashley Souza, Travis LaVoi, Richard A Houghten, Dennis E Kyle, James W Leahy
From a screening campaign that included mixture-based libraries containing more than 6 million compounds, a lead series of bis-cyclic guanidines was identified as the most promising. Lead optimization resulted in the identification of potent (IC50 < 500 nM) and selective compounds within this series as well as potent and selective monoguanidines.
August 10, 2017: ACS Medicinal Chemistry Letters
Ankush Kanwar, Benjamin J Eduful, Linda Barbeto, Piero Carletti Bonomo, Andrea Lemus, Brian A Vesely, Tina S Mutka, Ala Azhari, Dennis E Kyle, James W Leahy
We have determined that tetrahydroindazoles such as 1 show potent activity against Leishmania donovani, the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of 1 have previously been explored, we present here our efforts to optimize their activity against L. donovani via the synthesis of novel analogues designed to probe the hydrophobic pocket of the protozoan Hsp90 orthologue, specifically through the auspices of functionalization of an amine embedded into the scaffold.
August 10, 2017: ACS Medicinal Chemistry Letters
Giulia Bianco, Rita Meleddu, Simona Distinto, Filippo Cottiglia, Marco Gaspari, Claudia Melis, Angela Corona, Rossella Angius, Andrea Angeli, Domenico Taverna, Stefano Alcaro, Janis Leitans, Andris Kazaks, Kaspars Tars, Claudiu T Supuran, Elias Maccioni
A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racemic mixture led to the isolation of the levorotatory eutomer exhibiting an increase of hCA XII inhibition potency and selectivity with respect to hCA II. Computational studies corroborated these data...
August 10, 2017: ACS Medicinal Chemistry Letters
Gerard Rosse
No abstract text is available yet for this article.
August 10, 2017: ACS Medicinal Chemistry Letters
Gerard Rosse
No abstract text is available yet for this article.
August 10, 2017: ACS Medicinal Chemistry Letters
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