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Bioorganic & Medicinal Chemistry Letters

Sreekanth Thota, Daniel A Rodrigues, Pedro de Sena Murteira Pinheiro, Lídia M Lima, Carlos A M Fraga, Eliezer J Barreiro
Over the last two decades, N-acylhydrazone (NAH) has been proven to be a very versatile and promising motif in drug design and medicinal chemistry. Herein, we discuss the current and future challenges in the emergence of bioactive NAH-based scaffolds and to developing strategies to overcome the failures in drug discovery. The NAH-related approved drugs nitrofurazone, nitrofurantoin, carbazochrome, testosterone 17-enanthate 3-benzilic acid hydrazine, nifuroxazide, dantrolene, and azumolene are already used as therapeutics in various countries...
July 9, 2018: Bioorganic & Medicinal Chemistry Letters
Apeng Wang, Guocheng Huang, Bin Wang, Kai Lv, Hongjian Wang, Zeyu Tao, Mingliang Liu, Huiyuan Guo, Yu Lu
We report herein the design, synthesis and antimycobacterial activity of 3,5-dinitrobenzamide derivatives containing fused ring moieties. Results reveal that many of the target compounds have considerable in vitro antitubercular activity. Especially, N-((2-(4-fluorophenyl)/N-((2-(3-fluorobenzyl)-1,2,3,4-tetrahydroisoquilin-6-yl)methyl)-3,5-dinitrobenzamides 18a and 20e exhibit potent MIC values of 0.056-0.078 μg/mL against both drug-sensitive Mycobacterium tuberculosis (MTB) H37Rv strain and two clinically isolated multidrug-resistant MTB (MDR-MTB) strains, opening a new direction for further SAR studies...
July 7, 2018: Bioorganic & Medicinal Chemistry Letters
Hiroyuki Kimura, Saki Yamauchi, Hidekazu Kawashima, Kenji Arimitsu, Yusuke Yagi, Yuji Nakamoto, Kaori Togashi, Masahiro Ono, Hideo Saji
The tripeptide formyl-Met-Leu-Phe (fMLF) is a prototype of N-formylated chemotactic peptides for neutrophils owing to its ability to bind and activate the G protein-coupled formyl peptide receptor (FPR). Here, we developed an 18 F-labeled fMLF derivative targeting FPR as a positron emission tomography (PET) imaging probe for bacterial infections. The study demonstrates that the fMLF derivative fMLFXYk(FB)k (X = Nle) has a high affinity for FPR (Ki = 0.62 ± 0.13 nM). The radiochemical yield and purity of [18 F]fMLFXYk(FB)k were 16% and >96%, respectively...
July 6, 2018: Bioorganic & Medicinal Chemistry Letters
Yaping Huang, Geng Sun, Pengfei Wang, Rui Shi, Yanchun Zhang, Xiaoan Wen, Hongbin Sun, Caiping Chen
In this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC50  = 5.2 ± 0.9 μM). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious anticancer activity. Among them, H20 exhibited the most potent activity (IC50  = 2.8 ± 0.4 μM). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death...
July 6, 2018: Bioorganic & Medicinal Chemistry Letters
Kenji Suzuki, Itsuki Nomura, Masayuki Ninomiya, Kaori Tanaka, Mamoru Koketsu
β-Carbolines constitute a vast group of indole alkaloids and exhibit various biological actions. The objective of this study was to investigate the structure-activity relationships of β-carboline derivatives on in vitro inhibitory effects against clinically relevant microorganisms. A series of β-carboline dimers and their N2 -alkylated analogues were therefore prepared and evaluated for their antimicrobial effects. Among these, a dimeric 6-chlorocarboline N2 -benzylated salt exerted potent activity against Staphylococcus aureus at MICs of 0...
July 6, 2018: Bioorganic & Medicinal Chemistry Letters
Wei-Jin Zhu, Jin-Yun Niu, Ru Sun, Yu-Jie Xu, Jian-Feng Ge
In order to improve lysosome targetability of probes, fluorescent probes based on benzo[a]phenoxazine attaching different length oligoethyleneoxy chains were designed and prepared. Probes 2a-c containing N-pyridineium-3-yl exhibited almost ON-OFF near-infrared emission responses at 697-701 nm from pH 2.8 to 7.2, and the calculated pKa values of 2a-c were 4.90, 4.92 and 5.03 respectively. More importantly, fluorescent imaging experiments indicated that probes 2a-c were all lysosome biomarkers for Ges-1 and HeLa cells, which was because the introduction of oligoethyleneoxy groups improved the biocompatibility of probes, so that the probes 2a-c were better transported to lysosomes via the endocytosis pathway of the cells...
July 5, 2018: Bioorganic & Medicinal Chemistry Letters
Alexandria A Oviatt, Jissy A Kuriappan, Elirosa Minniti, Kendra R Vann, Princess Onuorah, Anna Minarini, Marco De Vivo, Neil Osheroff
Etoposide is an anticancer drug that acts by inducing topoisomerase II-mediated DNA cleavage. Despite its wide use, etoposide is associated with some very serious side-effects including the development of treatment-related acute myelogenous leukemias. Etoposide targets both human topoisomerase IIα and IIβ. However, the contributions of the two enzyme isoforms to the therapeutic vs. leukemogenic properties of the drug are unclear. In order to develop an etoposide-based drug with specificity for cancer cells that express an active polyamine transport system, the sugar moiety of the drug has been replaced with a polyamine tail...
July 5, 2018: Bioorganic & Medicinal Chemistry Letters
Ren Sheng, Liu Yang, Yanchun Zhang, Enming Xing, Rui Shi, Xiaoan Wen, Heyao Wang, Hongbin Sun
GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC50  = 93 nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure-activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications...
June 28, 2018: Bioorganic & Medicinal Chemistry Letters
Tatjana Stanojković, Violeta Marković, Ivana Z Matić, Milan P Mladenović, Nina Petrović, Ana Krivokuća, Miloš Petković, Milan D Joksović
A series of 23 novel anthraquinone-chalcone hybrids containing amide function was synthesized and structurally characterized. Sixteen compounds exerted strong cytotoxic activities against K562, Jurkat and HL-60 leukemia cell lines and significantly lower cytotoxic effects against normal MRC-5 cells, indicating very high selectivity in their anticancer action. The compounds 6g, 6u and 6v activate apoptosis in K562 cells through the extrinsic and intrinsic apoptotic pathway. The compound 6e triggered apoptosis in K562 cells only through the extrinsic apoptotic pathway...
June 28, 2018: Bioorganic & Medicinal Chemistry Letters
Arun K Ghosh, Koena Ghosh, Margherita Brindisi, Emma K Lendy, Yu-Chen Yen, Nagaswamy Kumaragurubaran, Xiangping Huang, Jordan Tang, Andrew D Mesecar
We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 Ki value of 10.9 nM and EC50 of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 Å resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature...
June 26, 2018: Bioorganic & Medicinal Chemistry Letters
Huai Gao, Craig Marhefka, Marc D Jacobs, Jingrong Cao, Upul K Bandarage, Jeremy Green
Solubilizing groups have been frequently appended to kinase inhibitor drug molecules when solubility is insufficient for pharmaceutical development. Such groups are usually located at substitution sites that have minimal impact on target activity. In this report we describe the incorporation of solubilizing groups in a class of Rho kinase (ROCK) inhibitors that not only confer improved solubility, but also enhance target potency and selectivity against a closely related kinase, PKA.
June 21, 2018: Bioorganic & Medicinal Chemistry Letters
Mateusz Psurski, Łukasz Janczewski, Marta Świtalska, Anna Gajda, Tomasz M Goszczyński, Jarosław Ciekot, Łukasz Winiarski, Józef Oleksyszyn, Joanna Wietrzyk, Tadeusz Gajda
A series of phosphonates, phosphinates and phosphine oxides isothiocyanate-derived mercapturic acids were synthesized. A temperature dependence dynamic proton decoupled 31 P NMR studies indicated that in most cases the compounds were obtained as a mixture of rotamers. Moreover, biologically relevant reversibility of mercapturic acids synthesis from the parental isothiocyanates was confirmed. All compounds were evaluated ashighly active antiproliferative agents in vitro in human colon cancer cell lines (LoVo and its doxorubicin-resistant subline LoVo/DX)...
June 20, 2018: Bioorganic & Medicinal Chemistry Letters
Darren W Engers, Sean R Bollinger, Julie L Engers, Joseph D Panarese, Megan M Breiner, Alison Gregro, Anna L Blobaum, Joanne J Bronson, Yong-Jin Wu, John E Macor, Alice L Rodriguez, Rocio Zamorano, P Jeffrey Conn, Craig W Lindsley, Colleen M Niswender, Corey R Hopkins
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds...
June 19, 2018: Bioorganic & Medicinal Chemistry Letters
Adriano Aloisi, Adrien Franchet, Dominique Ferrandon, Alberto Bianco, Cécilia Ménard-Moyon
Fipronil is a phenyl pyrazole molecule widely used across the world as both insecticide and veterinary drug. The main goal of this work was to synthesize a fluorescently labeled fipronil derivative for cellular imaging without affecting its intrinsic properties. We selected fluorescein as fluorescent probe and we investigated different strategies for stable chemical ligation between both entities, such as thiourea and direct peptide bond. While thiourea bond displayed low stability, direct peptide bond was difficult to achieve due to problems of steric hindrance...
June 19, 2018: Bioorganic & Medicinal Chemistry Letters
Lianbin Yao, Pondy Murugappan Ramanujulu, Anders Poulsen, Sten Ohlson, Brian W Dymock
Inhibition of more than one pathway in a cancer cell with a single molecule could result in better therapies with less complex dosing regimens. In this work multi-component ligands have been prepared by joining together key pharmacophores of two different enzyme inhibitors in a way which increases potency against the individual pathways. Selective JAK1/2 inhibitor, ruxolitinib (3), and pan-HDAC inhibitor vorinostat (4) were linked together by a single nitrogen atom to create a new series of compounds with very potent JAK2 and HDAC6 inhibition with selectivity against HDAC1...
June 19, 2018: Bioorganic & Medicinal Chemistry Letters
Atsushi Ogawa, Yuta Murashige, Hajime Takahashi
We have found that OFF-riboswitches that ligand-dependently downregulate the canonical translation in a higher eukaryotic expression system (wheat germ extract) can be easily created by inserting a single aptamer into the 5' untranslated region (UTR) of mRNA, even if its ligand is as small as theophylline. The key is the position of the inserted aptamer: the 5' end (+0 position) is much better than other positions for inhibiting canonical translation with the aptamer-ligand complex. The data showed that ribosome loading is suppressed by a rigid structure in the 5' end, and this suppression is dependent on the structure's stability but not on its size...
June 19, 2018: Bioorganic & Medicinal Chemistry Letters
Gaëtan Maertens, Oscar M Saavedra, Vito Vece, Miguel A Vilchis Reyes, Sofiane Hocine, Esat Öney, Bertrand Goument, Olivier Mirguet, Arnaud Le Tiran, Philippe Gloanec, Stephen Hanessian
We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.
June 19, 2018: Bioorganic & Medicinal Chemistry Letters
Zhe-Hui Zhao, Xiao-Xi Zhang, Long-Long Jin, Shuang Yang, Ping-Sheng Lei
A series of quinoylalkyl side chains was designed and synthesized, followed by introduction into ketolides by coupling with building block 6 or 32. The corresponding targets 7a-n, 33b, and 33e were tested for their in vitro activities against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed a similar antibacterial spectrum and comparable activity to telithromycin. Among them, two C2-F ketolides, compounds 33b and 33e, displayed excellent activities against macrolide-sensitive and macrolide-resistant pathogens...
June 19, 2018: Bioorganic & Medicinal Chemistry Letters
Masakazu Atobe, Kenji Naganuma, Masashi Kawanishi, Takahiko Hayashi, Hiroko Suzuki, Masahiro Nishida, Hirokazu Arai
We describe a medicinal chemistry approach to the discovery of a novel EP1 antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP1 receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies...
June 19, 2018: Bioorganic & Medicinal Chemistry Letters
Manoj Manickam, Pulla Reddy Boggu, Thanigaimalai Pillaiyar, Niti Sharma, Hitesh B Jalani, Eeda Venkateswararao, Sang-Hun Jung
To explore novel cardiac myosin activator, a series of diphenylalkyl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles have been prepared and tested for cardiac myosin ATPase activation in vitro. In all cases, three carbon spacer between the oxadiazole core and one of the phenyl ring was considered crucial. In case of 1,3,4-oxadiazole, zero to two carbon spacer between oxadiazole core and other phenyl ring are favorable. Phenyl ring can be replaced by cyclohexyl moiety. In case of 1,2,4-oxadiazole, zero or one carbon spacer between the oxadiazole and other phenyl ring are favorable...
June 18, 2018: Bioorganic & Medicinal Chemistry Letters
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