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Bioorganic & Medicinal Chemistry Letters

Yixian Liao, Yiming Guo, Sumei Li, Lei Wang, Yongmei Tang, Tianmiao Li, Weihao Chen, Guohua Zhong, Gaopeng Song
This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC50 of 0...
March 6, 2018: Bioorganic & Medicinal Chemistry Letters
Hong Jiang, Wen-Jin Zhang, Peng-Hui Li, Jian Wang, Chang-Zhi Dong, Kun Zhang, Hui-Xiong Chen, Zhi-Yun Du
In this study, a series of carbazole-rhodanine conjugates was synthesized and evaluated for their Topoisomerase II inhibition potency as well as cytotoxicity against a panel of four human cancer cell lines. Among these thirteen compounds, 3a, 3b, 3g, and 3h possessed Topoisomerase II inhibition potency at 20 μM. Mechanism study revealed that these compounds may function as Topo II catalytic inhibitors. It was found that the electron-withdrawing groups on the phenyl ring of compounds played an important role on enhancing both enzyme inhibition and cytotoxicity...
March 6, 2018: Bioorganic & Medicinal Chemistry Letters
Asher M Siddiqui, Jitendra A Sattigeri, Kalim Javed, Syed Shafi, M Shamim, Smita Singhal, Zubbair M Malik
Gram-positive bacteria are among the most common human pathogens associated with clinical infections which range from mild skin infections to sepsis. Resistance towards existing class of drugs by Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE) is a growing concern. There is an urgent need to discover new antibiotics which are active against resistant strains of Gram positive bacteria. We report herein a novel class of spiropyrimidinetrione oxazolidinone derivatives as novel antibacterial agents...
March 6, 2018: Bioorganic & Medicinal Chemistry Letters
Jie Zhang, Tatsunori Sasaki, Wei Li, Kazuya Nagata, Koji Higai, Feng Feng, Jian Wang, Maosheng Cheng, Kazuo Koike
Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes, obesity, and cancer. Ten caffeoylquinic acid derivatives (1-10) from leaves of Artemisia princeps Pamp. (Asteraceae) were identified as natural PTP1B inhibitors. Among them, chlorogenic acid (3) showed the most potent inhibitory activity (IC50 11.1 μM). Compound 3 was demonstrated to be a noncompetitive inhibitor by a kinetic analysis. Molecular docking simulation suggested that compound 3 bound to the allosteric site of PTP1B...
March 6, 2018: Bioorganic & Medicinal Chemistry Letters
Boshi Huang, Xinhao Liu, Ye Tian, Dongwei Kang, Zhongxia Zhou, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
In the present work, we described the synthesis, antiviral profiles and metabolic stability in human plasma of compound 6, a potential carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound 6 was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at nano- and submicromolar concentrations, respectively. Moreover, it displayed potent HIV-1 reverse transcriptase inhibitory activity (IC50  = 0.264 μM). Further stability test in human plasma showed that 6 could release its active form RDEA427 in a linearly time-independent manner, possibly acting as a potential prodrug...
March 5, 2018: Bioorganic & Medicinal Chemistry Letters
Muneaki Motomura, Hideaki Ichihara, Yoko Matsumoto
Negatively charged phosphatidylserine (PS) and sialic acid-containing glycosphingolipids (GM1) were observed to be over represented on the cell membranes of pancreatic cancer cells (BxPC-3) as opposed to normal pancreatic cells. Cationic liposomes (CL) were also found to selectively accumulate into the negatively charged cell membranes of BxPC-3 cells and inhibited their growth but have no effect on the viability of normal pancreatic cells. CL induced apoptosis in BxPC-3 cells via activation of caspase-3, -8, and -9 and mitochondrial events and inhibited tumor enlargement in xenograft mouse models of pancreatic cancer...
March 5, 2018: Bioorganic & Medicinal Chemistry Letters
Lianbin Yao, Sten Ohlson, Brian W Dymock
Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90)...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Richard J Steel, Maria A O'Connell, Mark Searcey
The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the β-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl-bridging group to constrain the peptides, coupled with a glutamic acid to proline replacement leads to a new peptide with a Ki of 6...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Rémi Patouret, Christelle Doebelin, Ruben D Garcia-Ordonez, Mi Ra Chang, Claudia Ruiz, Michael D Cameron, Patrick R Griffin, Theodore M Kamenecka
Crystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORβ, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORβ and RORγ inverse agonist with no activity towards RORα (Fig. 1). To our knowledge, this is one of only two small molecule RORβ inverse agonists identified in the primary literature from a tractable chemical series and represents an ideal starting point from which to design RORβ-selective modulators...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Aleksandra Pawlak, Witold Gładkowski, Justyna Kutkowska, Marcelina Mazur, Bożena Obmińska-Mrukowicz, Andrzej Rapak
For many years, studies focused on developing new natural or synthetic compounds with antineoplastic activity have attracted the attention of researchers. An interesting group of such compounds seem to be those with both lactone moiety and an aromatic ring which, in addition to antimicrobial or antiviral activity, also exhibit antitumor properties. The study shows antitumor activity of two enantiomeric trans isomers of 5-(1-iodoethyl)-4-(2',5'-dimethylphenyl)dihydrofuran-2-one. Our aim was to determine their antitumor activity manifested as an ability to induce apoptosis in selected canine cancer cell lines as well as to evaluate differences in their strength depending on the configuration of their stereogenic centers...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Saleha Banu, Rajitha Bollu, Mohammad Naseema, P Mary Gomedhika, Lingaiah Nagarapu, K Sirisha, C Ganesh Kumar, Shravan Kumar Gundasw
A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by1 H NMR,13 C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ)...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Gee-Hong Kuo, Micheal D Gaul, Yin Liang, June Z Xu, Fuyong Du, Pamela Hornby, Guozhang Xu, Jenson Qi, Nathaniel Wallace, Seunghun Lee, Eugene Grant, William V Murray, Keith Demarest
Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50  = 45 nM), and excellent potency at SGLT2 (IC50  = 1 nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F = 78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24 h...
March 1, 2018: Bioorganic & Medicinal Chemistry Letters
Nagarajan Muthukaman, Sanjay Deshmukh, Macchindra Tambe, Dnyandeo Pisal, Shital Tondlekar, Mahamadhanif Shaikh, Neelam Sarode, Vidya G Kattige, Pooja Sawant, Monali Pisat, Vikas Karande, Srinivasa Honnegowda, Abhay Kulkarni, Dayanidhi Behera, Satyawan B Jadhav, Ramchandra R Sangana, Girish S Gudi, Neelima Khairatkar-Joshi, Laxmikant A Gharat
In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases...
February 28, 2018: Bioorganic & Medicinal Chemistry Letters
Alexander Q Cusumano, Joshua G Pierce
Herein, we report the synthesis and evaluation of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones as antibacterial agents against methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE). Lead compound 38 showed minimum inhibitory concentrations (MICs) of 8 and 4 μg/mL against MRSA and MRSE, respectively. Furthermore, compound 38 displayed a MIC of 8-16 μg/mL against linezolid-resistant MRSA. These molecules, previously underexplored as antibacterial agents, serve as a new scaffold for antimicrobial development...
February 27, 2018: Bioorganic & Medicinal Chemistry Letters
Young-Mi Kim, Jongmin Ahn, Hee-Sung Chae, Young Hee Choi, Jinwoong Kim, Young-Won Chin
As part of our ongoing search for anti-inflammatory compounds from higher plants, we isolated and elucidated two new diterpenoid glycosides, kansuingol A (1) and kansuingol B (2), from the roots of Euphorbia kansui. These structures were elucidated by extensive spectroscopic methods such as NMR and MS. Compounds were assessed for their IL-6 production inhibitory activity in PMA + A23187-stimulated HMC-1 cells. As a result, compounds 1 and 2 exerted inhibitory activities in the production of IL-6 with IC50 values of 2...
February 27, 2018: Bioorganic & Medicinal Chemistry Letters
Okiemute Rosa Johnson-Ajinwo, Imran Ullah, Haddijatou Mbye, Alan Richardson, Paul Horrocks, Wen-Wu Li
Thymoquinone (TQ), 2-isopropyl-5-methyl-1,4-benzoquinone, a natural product isolated from Nigella sativa L., has previously been demonstrated to exhibit antiproliferative activity in vitro against a range of cancers as well as the human malarial parasite Plasmodium falciparum. We describe here the synthesis of a series of analogues of TQ that explore the potential for nitrogen-substitution to this scaffold, or reduction to a hydroquinone scaffold, in increasing the potency of this antiproliferative activity against ovarian cancer cell lines and P...
February 27, 2018: Bioorganic & Medicinal Chemistry Letters
Zilun Hu, Cailan Wang, Wei Han, Karen A Rossi, Jeffrey M Bozarth, Yiming Wu, Steven Sheriff, Joseph E Myers, Joseph M Luettgen, Dietmar A Seiffert, Ruth R Wexler, Mimi L Quan
Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability.
February 27, 2018: Bioorganic & Medicinal Chemistry Letters
Daniel Pettersen, Ola Fjellström
Proprotein convertase subtilisin kexin like type 9 (PCSK9) has since its discovery been a key protein target for the modulation of LDL cholesterol. The interest in PCSK9 has grown even more with the positive clinical trial outcomes in cardiovascular disease recently reported for two PCSK9 antibodies. Currently, there are no PCSK9 small molecule programs active in clinical development. However, there has been a steady increase in publications and patent applications within the PCSK9 small molecule field. This digest will provide a summary of small molecule and peptide PCSK9 modulators reported both in scientific journals and in patent applications, most of them originating from the last 3-4 years...
February 26, 2018: Bioorganic & Medicinal Chemistry Letters
Mehdi Rajabi, Murat Yalcin, Shaker A Mousa
In the angiogenesis process, integrins, which are members of a family of cell surface transmembrane receptors, play a critical role particularly in blood vessel formation and the local release of vascular growth factors. Thyroid hormones such as l-thyroxine (T4 ) and 3,5,3'-triiodo-l-thyronine (T3 ) promote angiogenesis and tumor cell proliferation via integrin αvβ3 receptor. At or near an arginine-glycine-aspartate (RGD) recognition site on the binding pocket of integrin αv β3 , tetraiodothyroacetic acid (tetrac, a deaminated derivative of T4 ) is a thyrointegrin receptor antagonist and blocks the actions of T3 and T4 as well as different growth factors-mediated angiogenesis...
February 26, 2018: Bioorganic & Medicinal Chemistry Letters
Danny C Lenstra, Abbas H K Al Temimi, Jasmin Mecinović
Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site...
February 24, 2018: Bioorganic & Medicinal Chemistry Letters
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