Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16
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The design strategy of selective PTP1B inhibitors over TCPTP ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): XiangQian Li, LiJun Wang, DaYong Shi Protein tyrosine phosphatase 1B (PTP1B) has already been well studied as a highly validated therapeutic target for diabetes and obesity. However, the lack of selectivity limited further studies and clinical applications of PTP1B inhibitors, especially over T-cell protein tyrosine phosphatase (TCPTP). In this review, we enumerate the published specific inhibitors of PTP1B, discuss the structure–activity relationships by analysis of their X-ray structures or docking results, and summarize the characteristic of selectivity related residues and groups. Furthermore, the design strategy of selective PTP1B inhibitors over TCPTP is also proposed. We hope our work could provide an effective way to gain specific PTP1B inhibitors. Graphical abstract image
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Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2 ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Hao Qiang, Weijie Gu, DanDan Huang, Wei Shi, Qianqian Qiu, Yuxuan Dai, Wenlong Huang, Hai Qian The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210nM and 170nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential. Graphical abstract image
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6-Oxooxazolidine–quinazolines as noncovalent inhibitors with the potential to target mutant forms of EGFR ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Jiaan Shao, En Chen, Ke Shu, Wenteng Chen, Guolin Zhang, Yongping Yu Despite the remarkable benefits of gefitinib, the clinical efficacy is eventually diminished due to the acquired point mutations in the EGFR (T790M). To address this unmet medical need, we demonstrated a strategy to prepare a hybrid analogue consisting of the oxooxazolidine ring and the quinazoline scaffold and provided alternative noncovalent inhibitors targeting mutant forms of EGFR. Most of the derivatives displayed moderate to good anti-proliferative activity against gefitinib-resistant NCI-H1975. Some of them exhibited potent EGFR kinase inhibitory activities, especially on EGFRT790M and EGFRL858R kinases. SAR studies led to the identification of a hit 9a that can target both of the most common EGFR mutants: L858R and T790M. Also, 9a displayed weaker inhibitory against cancer cell lines with low level of EGFR expression and good chemical stability under different pH conditions. The work presented herein showed the potential for developing noncovalent inhibitors targeting EGFR mutants. Graphical abstract image
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Arabinoamidine synthesis and its inhibition toward β-glucosidase (sweet almonds) in comparison to a library of galactonoamidines ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Jessica B. Pickens, Susanne Striegler, Qiu-Hua Fan Aiming at the development of potent inhibitors of β-glucosidases, a small library of galactonoamidines and one arabinoamidine derived in analogy were studied as inhibitors of sweet almond β-glucosidase. The five-membered glycon in arabinoamidine was shown to interact with the proton donor in the active site of the retaining enzyme, but not with the nucleophile. By contrast, the corresponding galactonoamidine with a six-membered glycon and identical aglycon interacts with both hydrolysis-promoting amino acids in the active site and inhibits the enzymatic hydrolysis of β-glucosides in the low nanomolar concentration range. While both inhibitors are competitive, their inhibition ability is more than 37,000-fold different. Graphical abstract image
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Pterostilbene-mediated Nrf2 activation: Mechanistic insights on Keap1:Nrf2 interface ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Elango Bhakkiyalakshmi, Kesavan Dineshkumar, Suresh Karthik, Dornadula Sireesh, Waheeta Hopper, Ramasamy Paulmurugan, Kunka Mohanram Ramkumar The discovery of Keap1–Nrf2 protein–protein interaction (PPI) inhibitors has become a promising strategy to develop novel lead molecules against variety of stress. Hence, Keap1–Nrf2 system plays an important role in oxidative/electrophilic stress associated disorders. Our earlier studies identified pterostilbene (PTS), a natural analogue of resveratrol, as a potent Nrf2 activator and Keap1–Nrf2 PPI inhibitor as assessed by luciferase complementation assay. In this study, we further identified the potential of PTS in Nrf2 activation and ARE-driven downstream target genes expression by nuclear translocation experiments and ARE-luciferase reporter assay, respectively. Further, the luciferase complementation assay identified that PTS inhibits Keap1–Nrf2 PPI in both dose and time-dependent manner. Computational studies using molecular docking and dynamic simulation revealed that PTS directly interacts with the basic amino acids of kelch domain of Keap1 and perturb Keap1–Nrf2 interaction pattern. This manuscript not only shows the binding determinants of Keap1–Nrf2 proteins but also provides mechanistic insights on Nrf2 activation potential of PTS. Graphical abstract image
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Synthesis and in vitro α-chymotrypsin inhibitory activity of 6-chlorobenzimidazole derivatives ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Hina Siddiqui, Rabia Farooq, Bishnu P. Marasini, Rizwana Malik, Naima Syed, Syed Tarique Moin, Atta-ur-Rahman, M. Iqbal Choudhary A library of benzimidazole derivatives 1–20 were synthesized, and studied for their α-chymotrypsin (α-CT) inhibitory activity in vitro. Kinetics and molecular docking studies were performed to identify the type of inhibition. Compound 1 was found to be a good inhibitor of α-chymotrypsin enzyme (IC50 =14.8±0.1μM, K i =16.4μM), when compared with standard chymostatin (IC50 =5.7±0.13μM). Compounds 2–8, 15, 17, and 18 showed significant inhibitory activities. All the inhibitors were found to be competitive inhibitors, except compound 17, which was a mixed type inhibitor. The substituents (R) in para and ortho positions of phenyl ring B, apparently played a key role in the inhibitory potential of the series. Compounds 1–20 were also studied for their cytotoxicity profile by using 3T3 mouse fibroblast cells and compounds 3, 5, 6, 8, 12–14, 16, 17, 19, and 20 were found to be cytotoxic. Molecular docking was performed on the most active members of the series in comparison to the standard compound, chymostatin, to identify the most likely binding modes. The compounds reported here can serve as templates for further studies for new inhibitors of α-chymotrypsin and other chymotrypsin-like serine proteases enzymes. Graphical abstract image
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Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Barbara Costa, Milind Dangate, Maria Vetro, Giulia Donvito, Luca Gabrielli, Loredana Amigoni, Giuliana Cassinelli, Cinzia Lanzi, Michela Ceriani, Luca De Gioia, Giulia Filippi, Laura Cipolla, Nadia Zaffaroni, Paola Perego, Diego Colombo The serine–threonine protein kinase Akt, also known as protein kinase B, is a key component of the phosphoinositide 3-kinase (PI3K)–Akt–mTOR axis. Deregulated activation of this pathway is frequent in human tumors and Akt-dependent signaling appears to be critical in cell survival. PI3K activation generates 3-phosphorylated phosphatidylinositols that bind Akt pleckstrin homology (PH) domain. The blockage of Akt PH domain/phosphoinositides interaction represents a promising approach to interfere with the oncogenic potential of over-activated Akt. In the present study, phosphatidyl inositol mimics based on a β-glucoside scaffold have been synthesized as Akt inhibitors. The compounds possessed one or two lipophilic moieties of different length at the anomeric position of glucose, and an acidic or basic group at C-6. Docking studies, ELISA Akt inhibition assays, and cellular assays on different cell models highlighted 1-O-octadecanoyl-2-O-β-d-sulfoquinovopyranosyl-sn-glycerol as the best Akt inhibitor among the synthesized compounds, which could be considered as a lead for further optimization in the design of Akt inhibitors. Graphical abstract image
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Functional evaluation of fluorescein-labeled derivatives of a peptide inhibitor of the EGF receptor dimerization ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Kei Toyama, Takaaki Mizuguchi, Wataru Nomura, Hirokazu Tamamura A cyclic decapeptide (1, ), which acts on the extracellular region of the EGF receptor, preventing it from dimerizing, has been developed. Peptide 2, which was labeled with fluorescein at the N-terminus of peptide 1, was synthesized based on structure–activity relationship studies. Peptide 2 essentially retained the inhibitory activity of peptide 1 against the receptor autophosphorylation. Confocal microscopy studies revealed that in carcinoma cells, the fluorescence of peptide 2 was localized inside some vesicles. Treatment of intact cells by peptide 1 in combination with peptide 2 decreased the fluorescence intensity significantly compared to treatment with only peptide 2. These results indicate that peptide 2 competes with peptide 1 for binding to the cellular surface. Six derivatives of peptide 2, in which constituent amino acids, with the exception of two cysteines and proline were randomized, were synthesized and used to treat the cells. Peptides 6 and 9 showed the highest fluorescence intensity in cells. From the results of the EGF receptor autophosphorylation assay, these two derivatives were proven to have higher inhibitory activity than peptide 2, which would therefore be a useful delivery peptide and fluorescent probe to find new inhibitors against the EGF receptor. Peptides 6 and 9 are promising leads for EGF receptor inhibitors. Graphical abstract image
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Anion inhibition profiles of α-, β- and γ-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Sonia Del Prete, Daniela Vullo, Viviana De Luca, Vincenzo Carginale, Pietro di Fonzo, Sameh M. Osman, Zeid AlOthman, Claudiu T. Supuran, Clemente Capasso Among the numerous metalloenzymes known to date, carbonic anhydrase (CA, EC 4.2.1.1) was the first zinc containing one, being discovered decades ago. CA is a hydro-lyase, which catalyzes the following hydration–dehydration reaction: CO2 +H2O⇋HCO3 − +H+. Several CA classes are presently known, including the α-, β-, γ-, δ-, ζ- and η-CAs. In prokaryotes, the existence of genes encoding CAs from at least three classes (α-, β- and γ-class) suggests that these enzymes play a key role in the physiology of these organisms. In many bacteria CAs are essential for the life cycle of microbes and their inhibition leads to growth impairment or growth defects of the pathogen. CAs thus started to be investigated in detail in bacteria, fungi and protozoa with the aim to identify antiinfectives with a novel mechanism of action. Here, we investigated the catalytic activity, biochemical properties and anion inhibition profiles of the three CAs from the bacterial pathogen Vibrio cholera, VchCA, VchCAβ and VchCAγ. The three enzymes are efficient catalysts for CO2 hydration, with k cat values ranging between (3.4−8.23)×105 s−1 and k cat/K M of (4.1−7.0)×107 M−1 s−1. A set of inorganic anions and small molecules was investigated for inhibition of these enzymes. The most potent VchCAγ inhibitors were N,N-diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid and phenylarsonic acid, with K I values ranging between 44 and 91μM. Graphical abstract image
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Design, synthesis, and anticancer activity of C8-substituted-4′-thionucleosides as potential HSP90 inhibitors ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Shuhao Qu, Varughese A. Mulamoottil, Akshata Nayak, Seungyeon Ryu, Xiyan Hou, Jayoung Song, Jinha Yu, Pramod K. Sahu, Long Xuan Zhao, Sun Choi, Sang Kook Lee, Lak Shin Jeong A series of C8-substituted-4′-thioadenosine analogs 3a–3g, 15, and 17 and their truncated derivatives 4a–4j, 23–25, and 27 have been successfully synthesized from d-ribose and d-mannose, respectively, employing Pummerer type or Vorbrüggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100μM. However, the 8-iodo derivatives 15, 17, and 27 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity. Graphical abstract image
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Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Arwin J. Brouwer, Natalia Herrero Álvarez, Adriano Ciaffoni, Helmus van de Langemheen, Rob M.J. Liskamp The success of inhibition of the proteasome by formation of covalent bonds is a major victory over the long held-view that this would lead to binding the wrong targets and undoubtedly lead to toxicity. Great challenges are now found in uncovering ensembles of new moieties capable of forming long lasting ties. We have introduced peptido sulfonyl fluorides for this purpose. Tuning the reactivity of this electrophilic trap may be crucial for modulating the biological action. Here we describe incorporation of a vinyl moiety into a peptido sulfonyl fluoride backbone, which should lead to a combined attack of the proteasome active site threonine on the double bond and the sulfonyl fluoride. Although this led to strong proteasome inhibitors, in vitro studies did not unambiguously demonstrate the formation of the proposed seven-membered ring structure. Possibly, formation of a seven-membered covalent adduct with the proteosomal active site threonine can only be achieved within the context of the enzyme. Nevertheless, this dual warhead concept may provide exclusive possibilities for duration and selectivity of proteasome inhibition. Graphical abstract image
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Discovery of a 2-hydroxyacetophenone derivative as an outstanding linker to enhance potency and β-selectivity of liver X receptor agonist ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Minoru Koura, Yuki Yamaguchi, Sayaka Kurobuchi, Hisashi Sumida, Yuichiro Watanabe, Takashi Enomoto, Takayuki Matsuda, Ayumu Okuda, Tomoaki Koshizawa, Yuki Matsumoto, Kimiyuki Shibuya Our research found that the 2-hydroxyacetophenone derivative is an outstanding linker between the 1,1-bistrifluoromethylcarbinol moiety and the imidazolidine-2,4-dione moiety to enhance the potency and β-selectivity of liver X receptor (LXR) agonist in our head-to-tail molecular design. The incorporation of this linker is 20-fold more potent than our previous compound (2) for LXR β agonistic activity (EC50) in a GAL-4 luciferase assay. Furthermore, we also identified 5-[5-(1-methylethoxy)pyridyl-2-yl]-5-methylimidazoline-2,4-dione (54), which lowers the lipophilicity of 2-hydroxyacetophenone derivative. We revealed that a combination of our newly developed linker and hydantoin (54) plays a pivotal role in improving the potency and selectivity of LXRβ. The optically separated (−)-56 increases high-density lipoprotein cholesterol levels without elevating plasma triglyceride levels and results in a decrease of the lipid accumulation area in the aortic arch in a high-fat- and cholesterol-fed low-density lipoprotein receptor knock-out mice. In this manuscript, we report that (−)-56 is a highly potent and β-selective LXR agonist for use in the treatment of atherosclerosis. Graphical abstract image
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Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Masato Yoshikawa, Takenori Hitaka, Tomoaki Hasui, Makoto Fushimi, Jun Kunitomo, Hironori Kokubo, Hideyuki Oki, Kosuke Nakashima, Takahiko Taniguchi Utilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50 =0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50 =>10,000nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs. Graphical abstract image
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Bacterial Peptide deformylase inhibition of cyano substituted biaryl analogs: Synthesis, in vitro biological evaluation, molecular docking study and in silico ADME prediction ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Firoz A. Kalam Khan, Rajendra H. Patil, Devanand B. Shinde, Jaiprakash N. Sangshetti Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a–m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC50 value=13.16μM), 5d (IC50 value=15.66μM) and 5j (IC50 value=19.16μM) had shown good PDF inhibition activity. The compounds 5a (MIC range=11.00–15.83μg/mL), 5b (MIC range=23.75–28.50μg/mL) and 5j (MIC range=7.66–16.91μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range=25–50μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(a–m) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates. Graphical abstract image
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Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Edward Ofori, Xue Y. Zhu, Jagan R. Etukala, Kwakye Peprah, Kamanski R. Jordan, Adia A. Adkins, Barbara A. Bricker, Hye J. Kang, Xi-Ping Huang, Bryan L. Roth, Seth Y. Ablordeppey 5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin. Graphical abstract image
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Discovery of 3-benzyl-1,3-benzoxazine-2,4-dione analogues as allosteric mitogen-activated kinase kinase (MEK) inhibitors and anti-enterovirus 71 (EV71) agents ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Jing Sun, Yan Niu, Chao Wang, Hao Zhang, Bingyu Xie, Fengrong Xu, Hongwei Jin, Yihong Peng, Lei Liang, Ping Xu Enterovirus 71 (EV71) is a kind of RNA virus and one of the two causes of Hand, foot and mouth disease (HFMD). Inhibitors that target key components of Ras/Raf/MEK/ERK pathway in host cells could impair replication of EV71. A series of 3-benzyl-1,3-benzoxazine-2,4-diones were designed from a specific MEK inhibitor G8935, by replacing the double bond between C3 and C4 within the coumarin scaffold with amide bond. One compound (9f) showed submicromolar inhibitory activity among the 12 derivatives. Further optimization on 9f led to two active compounds (9k and 9m) with nanomolar bioactivities (55nM and 60nM). The results of enzymatic assays also demonstrated that this series of compounds were allosteric inhibitors of unphosphorylated MEK1. The binding mode of compound 9k was predicted by molecular dynamic simulation and the key interactions were same as published MEK1/2 allosteric inhibitors. In the cell-based assays, compounds 9k and 9m could effectively suppress the ERK1/2 pathway, expression of EV71 VP1, and EV71 induced cytopathic effect (CPE) in rhabdomyosarcoma (RD) cells. Graphical abstract image
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Synthesis and biological evaluation of new [1,2,4]triazolo[4,3-a]pyridine derivatives as potential c-Met inhibitors ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Junjun Zhao, Lei Fang, Xiaobing Zhang, Yan Liang, Shaohua Gou A series of [1,2,4]triazolo[4,3-a]pyrazine derivatives (4a–4i) were designed, synthesized and evaluated for their c-Met kinase inhibition and antitumor activity against SNU5 gastric cell line in vitro. Among these compounds, 4d was found to show the highest activity against c-Met and high selectivity against the tumor cells which are believed to be dependent on the c-Met oncogene amplification, because 4d selectively inhibited c-Met while had no effect on other 59 kinases. In vivo efficacy study on human gastric (MKN-45) and human non-small cell lung (NCI-H1993) tumor xenograft in nude mouse demonstrated that 4d·CH3SO3H had a better inhibiting activity than SGX-523 in a dose-dependent manner. When tested in mice, compound 4d·CH3SO3H was found to have biological half-lives and plasma exposure values higher than those of JNJ-38877605, and its long-term toxicity and acute toxicity turned out to be acceptable, all of which indicates that 4d·CH3SO3H is a desirable drug candidate. Graphical abstract image
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Development of novel NK3 receptor antagonists with reduced environmental impact ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Koki Yamamoto, Shiho Okazaki, Hiroaki Ohno, Fuko Matsuda, Satoshi Ohkura, Kei-ichiro Maeda, Nobutaka Fujii, Shinya Oishi The neurokinin B (NKB)–neurokinin-3 receptor (NK3R) signaling positively regulates the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. The NK3R-selective antagonists may suppress the reproductive functions of mammals. For development of novel NK3R antagonists with reduced environmental toxicity, a structure–activity relationship study of an NK3R antagonist, talnetant, was carried out. Among several talnetant derivatives with labile functional groups in the natural environment, 3-mercaptoquinoline 2f exhibited a comparable biological activity to that of the parent talnetant. Additionally, compound 2f was converted into the disulfide 3f or isothiazolone 8 by air-oxidation, both of which showed no binding affinity to NK3R. Graphical abstract image
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Toward discovery of mutant EGFR inhibitors; Design, synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Samar Mowafy, A. Galanis, Zainab M. Doctor, Raymond M. Paranal, Deena S. Lasheen, Nahla A. Farag, Pasi A. Jänne, Khaled A.M. Abouzid A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC50 values in the low nanomolar range (<0.495–9.05nM) and displayed more potent cytotoxic effect in BaF/3 expressing EGFR WT than reference compound gefitinib. The anti-proliferative effect of all synthesized compounds against gefitinib insensitive double mutant cell lines Ba/F3 expressing Del19/T790M and Ba/F3 expressing L858R/T790M were assayed. Compounds 4d, 6f, 7e showed significant inhibition (IC50 =1.76–2.38μM) in these mutant lines and significant Her2 enzyme inhibition (IC50 =19.2–40.6nM) compared to lapatinib (60.1nM). The Binding mode of compounds 6d, 6f, 7a, 7b and 8b were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds 6f and 7e showed about eight and three folds respectively greater potency than gefitinib. Our structure–activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing inhibitors against wild type and mutant EGFR. Graphical abstract image
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Systematic N-methylation of oxytocin: Impact on pharmacology and intramolecular hydrogen bonding network ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Simone Sciabola, Gilles H. Goetz, Guoyun Bai, Bruce N. Rogers, David L. Gray, Allen Duplantier, Kari R. Fonseca, Michelle A. Vanase-Frawley, Natasha M. Kablaoui Oxytocin (OT) is a peptide hormone agonist of the OT receptor (OTR) that plays an important role in social behaviors such as pair bonding, maternal bonding and trust. The pharmaceutical development of OT as an oral peptide therapeutic has been hindered historically by its unfavorable physicochemical properties, including molecular weight, polarity and number of hydrogen bond donors, which determines poor cell permeability. Here we describe the first systematic study of single and multiple N-methylations of OT and their effect on physicochemical properties as well as potency at the OT receptor. The agonist EC50 and percent effect for OTR are reported and show that most N-methylations are tolerated but with some loss in potency compared to OT. The effect of N-methylation on exposed polarity is assessed through the EPSA chromatographic method and the results validated against NMR temperature coefficient experiments and the determination of NMR solution structures. We found that backbone methylation of residues not involved in IMHB and removal of the N-terminal amine can significantly reduce the exposed polarity of peptides, and yet retain a significant OTR agonist activity. The results of this study also expose the potential challenge of using the N-methylation strategy for the OT system; while exposed polarity is reduced, in some cases backbone methylation produces a significant conformational change that compromises agonist activity. The data presented provides useful insights on the SAR of OT and suggests future design strategies that can be used to develop more permeable OTR agonists based on the OT framework. Graphical abstract image
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Identification of anticancer agents based on the thieno[2,3-b]pyridine and 1H-pyrazole molecular scaffolds ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Chatchakorn Eurtivong, Inga Reynisdóttir, Stephanie Kuczma, Daniel P. Furkert, Margaret A. Brimble, Jóhannes Reynisson Structural similarity search of commercially available analogues of thieno[2,3-b]pyridine and 1H-pyrazole derivatives, known anticancer agents, resulted in 717 hits. These were docked into the phosphoinositide specific-phospholipase C (PLC) binding pocket, the putative target of the compounds, to further focus the selection. Thirteen derivatives of the thieno[2,3-b]pyridines were identified and tested against the NCI60 panel of human tumour cell lines. The most active derivative 1 was most potent against the MDA-MB-435 melanoma cell line with GI50 at 30nM. Also, it was found that a piperidine moiety is tolerated on the thieno[2,3-b]pyridine scaffold with GI50 =296nM (MDA-MB-435) for derivative 10 considerably expanding the structure activity relationship for the series. For the 1H-pyrazoles four derivatives were identified using the in silico approach and additionally ten were synthesised with various substituents on the phenyl moiety to extend the structural activity relationship but only modest anticancer activity was found. Graphical abstract image
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Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Hassan M. Faidallah, Siva S. Panda, Juan C. Serrano, Adel S. Girgis, Khalid A. Khan, Khalid A. Alamry, Tanya Therathanakorn, Marvin J. Meyers, Francis M. Sverdrup, Christopher S. Eickhoff, Stephen G. Getchell, Alan R. Katritzky Click chemistry technique led to novel 1,2,3-triazole-quinine conjugates 8a–g, 10a–o, 11a–h and 13 utilizing benzotriazole-mediated synthetic approach with excellent yields. Some of the synthesized analogs (11a, 11d–h) exhibited antimalarial properties against Plasmodium falciparum strain 3D7 with potency higher than that of quinine (standard reference used) through in vitro standard procedure bio-assay. Statistically significant BMLR-QSAR model describes the bio-properties, validates the observed biological observations and identifies the most important parameters governing bio-activity. Graphical abstract image
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Molecular similarity guided optimization of novel Nrf2 activators with 1,2,4-oxadiazole core ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Li-Li Xu, Xian Zhang, Zheng-Yu Jiang, Qi-Dong You DDO-7204 is a novel Nrf2 activator first identified through screening of in-house database by ARE-luciferase reporter gene assay. To further optimize this kind of Nrf2 activators efficiently, the hit-based substructure search was applied to screen the Specs database virtually. DDO-7204 contains three rings of A, B, C. SAR results showed that: for ring A, the cyclane substituent is beneficial for ARE inductivity. Enhanced flexibility of linker between ring A and ring B is not preferable for the Nrf2 activity. Ring A replaced by heterocyclic aromatic is beneficial for the Nrf2 activity. The resulting compound 7 was more potent than DDO-7204. Compound 7 can induce Nrf2 translocation into nuclear not only in HCT116 cells, but also in three normal cells such as L02, NCM460 and PC12 cells. The Nrf2-regualted genes, γ-GCS, NQO1 and HO-1, were up-regulated at a concentration-dependent manner. In addition, compound 7 showed cytoprotective effects on the three normal cells against the damage of H2O2. Graphical abstract image
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Microwave assisted synthesis of novel acridine–acetazolamide conjugates and investigation of their inhibition effects on human carbonic anhydrase isoforms hCA I, II, IV and VII ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Ramazan Ulus, Burak Aday, Muhammet Tanç, Claudiu T. Supuran, Muharrem Kaya 4-Amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide was condensed with cyclic-1,3-diketones (dimedone and cyclohexane-1,3-dione) and aromatic aldehydes under microwave irradiation, leading to a series of acridine–acetazolamide conjugates. The new compounds were investigated as inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), and more precisely cytosolic isoforms hCA I, II, VII and membrane-bound one hCA IV. All investigated isoforms were inhibited in low micromolar and nanomolar range by the new compounds. hCA IV and VII were inhibited with KIs in the range of 29.7–708.8nM (hCA IV), and of 1.3–90.7nM (hCA VII). For hCA I and II the KIs were in the range of 6.7–335.2nM (hCA I) and of 0.5–55.4nM (hCA II). The structure–activity relationships (SAR) for the inhibition of these isoforms with the acridine–acetazolamide conjugates reported here were delineated. Graphical abstract image
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Combined dual effect of modulation of human neutrophils’ oxidative burst and inhibition of colon cancer cells proliferation by hydroxycinnamic acid derivatives ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Elisiário J. Tavares-da-Silva, Carla L. Varela, Ana S. Pires, João C. Encarnação, Ana M. Abrantes, Maria F. Botelho, Rui A. Carvalho, Carina Proença, Marisa Freitas, Eduarda Fernandes, Fernanda M.F. Roleira Colon cancer is one of the most incident cancers in the Western World. While both genetic and epigenetic factors may contribute to the development of colon cancer, it is known that chronic inflammation associated to excessive production of reactive oxygen and nitrogen species by phagocytes may ultimately initiate the multistep process of colon cancer development. Phenolic compounds, which reveal antioxidant and antiproliferative activities in colon cancer cells, can be a good approach to surpass this problem. In this work, hydroxycinnamic amides and the respective acid precursors were tested in vitro for their capacity to modulate human neutrophils’ oxidative burst and simultaneously to inhibit growth of colon cancer cells. A phenolic amide derivative, caffeic acid hexylamide (CAHA) (4) was found to be the most active compound in both assays, inhibiting human neutrophils’ oxidative burst, restraining the inflammatory process, inhibiting growth of colon cancer cells and triggering mitochondrial dysfunction that leads cancer cells to apoptosis. Altogether, these achievements can contribute to the understanding of the relationship between antioxidant and anticancer activities and based on the structure–activity relationships (SAR) established can be the starting point to find more effective phenolic compounds as anticancer agents. Graphical abstract image
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Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Martin Sweeney, Robert Coyle, Paul Kavanagh, Andrey A. Berezin, Daniele Lo Re, Georgia A. Zissimou, Panayiotis A. Koutentis, Michael P. Carty, Fawaz Aldabbagh The thioredoxin (Trx)–thioredoxin reductase (TrxR) system plays a key role in maintaining the cellular redox balance with Trx being over-expressed in a number of cancers. Inhibition of TrxR is an important strategy for anti-cancer drug discovery. The natural product pleurotin is a well-known irreversible inhibitor of TrxR. The cytotoxicity data for benzo[1,2,4]triazin-7-ones showed very strong correlation (Pearson correlation coefficients ∼0.8) to pleurotin using National Cancer Institute COMPARE analysis. A new 3-CF3 substituted benzo[1,2,4]triazin-7-one gave submicromolar inhibition of TrxR, although the parent compound 1,3-diphenylbenzo[1,2,4]triazin-7-one was more cytotoxic against cancer cell lines. Benzo[1,2,4]triazin-7-ones exhibited different types of reversible inhibition of TrxR, and cyclic voltammetry showed characteristic quasi-reversible redox processes. Cell viability studies indicated strong dependence of cytotoxicity on substitution at the 6-position of the 1,3-diphenylbenzo[1,2,4]triazin-7-one ring. Graphical abstract image
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Synthesis and evaluation of antioxidant phenolic diaryl hydrazones as potent antiangiogenic agents in atherosclerosis ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Corinne Vanucci-Bacqué, Caroline Camare, Chantal Carayon, Corinne Bernis, Michel Baltas, Anne Nègre-Salvayre, Florence Bedos-Belval A series of bis-hydrazones derived from diaryl and diaryl ether hydroxybenzaldehyde frames 1 and 2 have been synthesized as potential antioxidant and antiangiogenic agents, two properties required to limit atherogenesis and cardiovascular events. These compounds were evaluated for their ability to neutralize free radical formation, to block endothelial cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS), an essential step in atherogenesis, and subsequent toxicity, to prevent angiogenesis evoked by low oxidized LDL concentration (monitored by the formation of capillary tubes on Matrigel) and to inhibit intracellular ROS increase involved in the angiogenic signaling. A structure/activity study has been carried out and finally allowed to select the phenolic diaryl ether hydralazine derivative 2a, sharing all these protective properties, as a promising hit for further development. Graphical abstract image
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Synthesis, photophysical properties of triazolyl-donor/acceptor chromophores decorated unnatural amino acids: Incorporation of a pair into Leu-enkephalin peptide and application of triazolylperylene amino acid in sensing BSA ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Subhendu Sekhar Bag, Subhashis Jana, Manoj Kumar Pradhan The research in the field of design and synthesis of unnatural amino acids is growing at a fast space for the increasing demand of proteins of potential therapeutics and many other diversified novel functional applications. Thus, we report herein the design and synthesis of microenvironment sensitive fluorescent triazolyl unnatural amino acids (UNAA) decorated with donor and/or acceptor aromatic chromophores via click chemistry. The synthesized fluorescent amino acids show interesting solvatochromic characteristic and/or intramolecular charge transfer (ICT) feature as is revealed from the UV–visible, fluorescence photophysical properties and DFT/TDDFT calculation. HOMO–LUMO distribution shows that the emissive states of some of the amino acids are characterized with more significant electron redistribution between the triazolyl moiety and the aromatic chromophores linked to it leading to modulated emission property. A pair of donor–acceptor amino acid shows interesting photophysical interaction property indicating a FRET quenching event. Furthermore, one of the amino acid, triazolyl-perylene amino acid, has been exploited for studying interaction with BSA and found that it is able to sense BSA with an enhancement of fluorescence intensity. Finally, we incorporated a pair of donor/acceptor amino acids into a Leu-enkephalin analogue pentapeptide which was found to adopt predominantly type II β-turn conformation. We envisage that our investigation is of importance for the development of new fluorescent donor–acceptor unnatural amino acids a pair of which can be exploited for generating fluorescent peptidomimetic probe of interesting photophysical property for applications in studying peptide–protein interaction. Graphical abstract image
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A sulfanyl-PEG derivative of relaxin-like peptide utilizable for the conjugation with KLH and the antibody production ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Hidekazu Katayama, Masatoshi Mita A small peptide–keyhole limpet hemocyanin (KLH) conjugate is generally used as an antigen for producing specific antibodies. However, preparation of a disulfide-rich heterodimeric peptide–KLH conjugates is difficult. In this study, we developed a novel method for preparation of the conjugate, and applied it to the production of specific antibodies against the relaxin-like gonad-stimulating peptide (RGP) from the starfish. In this method, a sulfanyl group necessary for the conjugation with KLH was site-specifically introduced to the peptide after regioselective disulfide bond formation reactions. Using the conjugate, we could obtain specific antibodies with a high antibody titer. This method might also be useful for the production of antibodies against other heterodimeric peptides with disulfide cross-linkages, such as vertebrate relaxins. Graphical abstract image
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Sequence-specific DNA binding by long hairpin pyrrole–imidazole polyamides containing an 8-amino-3,6-dioxaoctanoic acid unit ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Yoshito Sawatani, Gengo Kashiwazaki, Anandhakumar Chandran, Sefan Asamitsu, Chuanxin Guo, Shinsuke Sato, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama With the aim of improving aqueous solubility, we designed and synthesized five N-methylpyrrole (Py)–N-methylimidazole (Im) polyamides capable of recognizing 9-bp sequences. Their DNA-binding affinities and sequence specificities were evaluated by SPR and Bind-n-Seq analyses. The design of polyamide 1 was based on a conventional model, with three consecutive Py or Im rings separated by a β-alanine to match the curvature and twist of long DNA helices. Polyamides 2 and 3 contained an 8-amino-3,6-dioxaoctanoic acid (AO) unit, which has previously only been used as a linker within linear Py–Im polyamides or between Py–Im hairpin motifs for tandem hairpin. It is demonstrated herein that AO also functions as a linker element that can extend to 2-bp in hairpin motifs. Notably, although the AO-containing unit can fail to bind the expected sequence, polyamide 4, which has two AO units facing each other in a hairpin form, successfully showed the expected motif and a K D value of 16nM was recorded. Polyamide 5, containing a β-alanine–β-alanine unit instead of the AO of polyamide 2, was synthesized for comparison. The aqueous solubilities and nuclear localization of three of the polyamides were also examined. The results suggest the possibility of applying the AO unit in the core of Py–Im polyamide compounds. Graphical abstract image
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N-Nitrosulfonamides: A new chemotype for carbonic anhydrase inhibition ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Alessio Nocentini, Daniela Vullo, Gianluca Bartolucci, Claudiu T. Supuran A series of N 1-substituted aromatic sulfonamides was obtained by applying a selective sulfonamide nitration synthetic strategy leading to Ar-SO2NHNO2 derivatives which were investigated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Two human (h) hCA isoforms, the cytosolic hCA II and the transmembrane hCA IX, in addition to the fungal enzyme from Malassezia globosa, MgCA, were included in the study. Most of the new compounds reported selectively inhibited hCA IX over hCA II and at the same time showed effective MgCA inhibitory properties, with K Is ranging between 0.22 and 8.09μM. The N-nitro sulfonamides are a new chemotype with CA inhibitory effects. As hCA IX was recently validated as antitumor/antimetastatic drug target, its selective inhibition could be exploited for interesting biomedical applications. Moreover, due to the effective MgCAs inhibitory properties of the N-nitro sulfonamides, of considerable interest in the cosmetics field as potential anti-dandruff agents, the N-nitro sulfonamides may be considered as interesting leads for the design of more efficient compounds targeting fungal enzymes. Graphical abstract image
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Synthesis and evaluation of copper-64 labeled benzofuran derivatives targeting β-amyloid aggregates ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Hiroyuki Watanabe, Azusa Kawasaki, Kohei Sano, Masahiro Ono, Hideo Saji In vivo imaging of β-amyloid (Aβ) aggregates consisting of Aβ(1–40) and Aβ(1–42) peptides by positron emission tomography (PET) contributes to the diagnosis and therapy for Alzheimer’s disease (AD). Because 64Cu (t 1/2 =12.7h) is a radionuclide for PET with a longer physical half-life than 11C (t 1/2 =20min) and 18F (t 1/2 =110min), it is an attractive radionuclide for the development of Aβ imaging probes that are suitable for routine use. In the present study, we designed and synthesized two novel 64Cu labeled benzofuran derivatives and evaluated their utility as PET imaging probes for Aβ aggregates. In an in vitro binding assay, 6 and 8 showed binding affinity for Aβ(1–42) aggregates with a K i value of 33 and 243nM, respectively. In addition, these probes bound to Aβ plaques deposited in the brain of an AD model mouse in vitro. In a biodistribution experiment using normal mice, these probes showed low brain uptake (0.33% and 0.36% ID/g) at 2min post-injection. Although refinement to enhance brain uptake is needed, [64Cu]6 and [64Cu]8 demonstrated the feasibility of developing novel PET probes for imaging Aβ aggregates. Graphical abstract image
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Dihydropyrimidones: As novel class of β-glucuronidase inhibitors ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Farman Ali, Khalid Mohammed Khan, Uzma Salar, Sarosh Iqbal, Muhammad Taha, Nor Hadiani Ismail, Shahnaz Perveen, Abdul Wadood, Mehreen Ghufran, Basharat Ali Dihydropyrimidones 1–37 were synthesized via a ‘one-pot’ three component reaction according to well-known Biginelli reaction by utilizing Cu(NO3)2·3H2O as catalyst, and screened for their in vitro β-glucuronidase inhibitory activity. It is worth mentioning that amongst the active molecules, compounds 8 (IC50 =28.16±.056μM), 9 (IC50 =18.16±0.41μM), 10 (IC50 =22.14±0.43μM), 13 (IC50 =34.16±0.65μM), 14 (IC50 =17.60±0.35μM), 15 (IC50 =15.19±0.30μM), 16 (IC50 =27.16±0.48μM), 17 (IC50 =48.16±1.06μM), 22 (IC50 =40.16±0.85μM), 23 (IC50 =44.16±0.86μM), 24 (IC50 =47.16±0.92μM), 25 (IC50 =18.19±0.34μM), 26 (IC50 =33.14±0.68μM), 27 (IC50 =44.16±0.94μM), 28 (IC50 =24.16±0.50μM), 29 (IC50 =34.24±0.47μM), 31 (IC50 =14.11±0.21μM) and 32 (IC50 =9.38±0.15μM) found to be more potent than the standard d-saccharic acid 1,4-lactone (IC50 =48.4±1.25μM). Molecular docking study was conducted to establish the structure–activity relationship (SAR) which demonstrated that a number of structural features of dihydropyrimidone derivatives were involved to exhibit the inhibitory potential. All compounds were characterized by spectroscopic techniques such as 1H, 13C NMR, EIMS and HREI-MS. Graphical abstract image
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Bistacrine derivatives as new potent antimalarials ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Ines Schmidt, Gabriele Pradel, Ludmilla Sologub, Alexandra Golzmann, Che J. Ngwa, Anna Kucharski, Tanja Schirmeister, Ulrike Holzgrabe Linking two tacrine molecules results in a tremendous increase of activity against Plasmodia in comparison to the monomer. This finding prompted the synthesis of a library of monomeric and dimeric tacrine derivatives in order to derive structure–activity relationships. The most active compounds towards chloroquine sensitive Plasmodium strain 3D7 and chloroquine resistant strain Dd2 show IC50 values in the nanomolar range of concentration, low cytotoxicity and target the cysteine protease falcipain-2, which is essential for parasite growth. Graphical abstract image
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Kinetic and X-ray crystallographic investigations of substituted 2-thio-6-oxo-1,6-dihydropyrimidine–benzenesulfonamides acting as carbonic anhydrase inhibitors ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Daniela Vullo, Claudiu T. Supuran, Andrea Scozzafava, Giuseppina De Simone, Simona Maria Monti, Vincenzo Alterio, Fabrizio Carta Herein we report an in vitro kinetic evaluation against the most relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms (I, II, IX and XII) of a small series of lactate dehydrogenase (LDH, EC 1.1.1.27) inhibitors. All compounds contain a primary sulfonamide zinc-binding group (ZBG) substituted with the 2-thio-6-oxo-1,6-dihydropyrimidine scaffold. By means of X-ray crystallographic experiments we explored the ligand–enzyme binding modes, thus highlighting the contribution of the 2-thio-6-oxo-1,6-dihydropyrimidine moiety to the stabilization of the complex. Graphical abstract image
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Novel benzimidazol-2-ylidene carbene precursors and their silver(I) complexes: Potential antimicrobial agents ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Murat Kaloğlu, Nazan Kaloğlu, İlknur Özdemir, Selami Günal, İsmail Özdemir Novel benzimidazolium salts were synthesized as N-heterocyclic carbene (NHC) precursors, these NHC precursors were metallated with Ag2O in dichloromethane at room temperature to give novel silver(I)–NHC complexes. Structures of these benzimidazolium salts and silver(I)–NHC complexes were characterized on the basis of elemental analysis, 1H NMR, 13C NMR, IR and LC–MS spectroscopic techniques. A series of benzimidazolium salts and silver(I)–NHC complexes were tested against standard bacterial strains: Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and the fungal strains: Candida albicans and Candida tropicalis. The results showed that benzimidazolium salts inhibited the growth of all bacteria and fungi strains and all silver(I)–NHC complexes performed good activities against different microorganisms. Graphical abstract image
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Ionophoric polyphenols selectively bind Cu2+, display potent antioxidant and anti-amyloidogenic properties, and are non-toxic toward Tetrahymena thermophila ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Alberto Martínez, Ralph Alcendor, Tanzeen Rahman, Magdalena Podgorny, Ismaila Sanogo, Rebecca McCurdy Alzheimer’s disease (AD) is the most common form of dementia affecting more than 28million people in the world. Only symptomatic treatments are currently available. Anticipated tri-fold increase of AD incidence in the next 50years has established the need to explore new possible treatments. Accumulation of extracellular amyloid-β (Aβ) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. The active role of some metal ions, especially Cu2+, in promoting both Aβ aggregation and reactive oxygen species formation has rendered ionophoric drugs as a promising treatment strategy. In this work, a series of 5 disease-modifying and multi-target ionophoric polyphenols (1–5), inspired on the structure of natural resveratrol, have been synthesized and characterized. All compounds bind Cu2+ selectively over other biologically relevant metal ions. They form 2:1 (compound/Cu2+) complexes with association constants log K a 12–14 depending on the molecular design. Our results indicate that compounds 1–5 possess excellent antioxidant properties: they inhibit the Cu2+-catalyzed reactive oxygen species production between 47% and 100%, and they scavenge DPPH (1,1-diphenyl-2-picryl-hydrazyl) and AAPH (2,2′-azobis(2-amindino-propane)dihydrochloride) free radicals in general better than clioquinol, resveratrol and ascorbic acid. In addition, compounds 1–5 interact with Aβ peptides and inhibit both the Cu2+-catalyzed aggregation and the self-assembly of Aβ(1–40) up to a ∼92% extent. Interestingly, 1–5 are also able to disaggregate up to ∼91% of pre-formed Aβ(1–40) aggregates. Furthermore, cytotoxic studies show remarkably low toxicity of 1–5 toward Tetrahymena thermophila with LD50 values higher than 150μM, comparable to non-toxic natural resveratrol. Graphical abstract image
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Development of CNS multi-receptor ligands: Modification of known D2 pharmacophores ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Jagan R. Etukala, Xue Y. Zhu, Suresh V.K. Eyunni, Edem K. Onyameh, Edward Ofori, Barbara A. Bricker, Hye J. Kang, Xi-Ping Huang, Bryan L. Roth, Seth Y. Ablordeppey Several known D2 pharmacophores have been explored as templates for identifying ligands with multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant receptors in the treatment of neuropsychiatric diseases. This approach has resulted in the identification of ligands that target multiple CNS receptors while avoiding others associated with deleterious effects. In particular, compounds 11, 15 and 22 may have potential for further development as antipsychotic agents as they favorably interact with the clinically relevant receptors including D2R, 5-HT1AR, and 5-HT7R. We have also identified the pair of compounds 11 and 10 as high affinity D2R ligands with and without SERT binding affinities, respectively. These differential binding profiles endow the pair with the potential for evaluating SERT contributions to antipsychotic drug activity in animal behavioral models. In addition, compound 11 has no significant affinity for 5-HT2CR and binds only moderately to the H1R, suggesting it may not induce weight gain or sedation when used clinically. Taken together, compound 11 displays an interesting pharmacological profile that necessitates the evaluation of its functional and in vivo effects in animal models which are currently ongoing. Graphical abstract image
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Synthesis and investigation of novel benzimidazole derivatives as antifungal agents ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Nishad Thamban Chandrika, Sanjib K. Shrestha, Huy X. Ngo, Sylvie Garneau-Tsodikova The rise and emergence of resistance to antifungal drugs by diverse pathogenic fungal strains have resulted in an increase in demand for new antifungal agents. Various heterocyclic scaffolds with different mechanisms of action against fungi have been investigated in the past. Herein, we report the synthesis and antifungal activities of 18 alkylated mono-, bis-, and trisbenzimidazole derivatives, their toxicities against mammalian cells, as well as their ability to induce reactive oxygen species (ROS) in yeast cells. Many of our bisbenzimidazole compounds exhibited moderate to excellent antifungal activities against all tested fungal strains, with MIC values ranging from 15.6 to 0.975μg/mL. The fungal activity profiles of our bisbenzimidazoles were found to be dependent on alkyl chain length. Our most potent compounds were found to display equal or superior antifungal activity when compared to the currently used agents amphotericin B, fluconazole, itraconazole, posaconazole, and voriconazole against many of the strains tested. Graphical abstract image
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Synthesis and Th1-immunostimulatory activity of α-galactosylceramide analogues bearing a halogen-containing or selenium-containing acyl chain ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Md. Imran Hossain, Shinya Hanashima, Takuto Nomura, Sébastien Lethu, Hiroshi Tsuchikawa, Michio Murata, Hiroki Kusaka, Shunsuke Kita, Katsumi Maenaka A novel series of CD1d ligand α-galactosylceramides (α-GalCers) were synthesized by incorporation of the heavy atoms Br and Se in the acyl chain backbone of α-galactosyl-N-cerotoylphytosphingosine. The synthetic analogues are potent CD1d ligands and stimulate mouse invariant natural killer T (iNKT) cells to selectively enhance Th1 cytokine production. These synthetic analogues would be efficient X-ray crystallographic probes to disclose precise atomic positions of alkyl carbons and lipid–protein interactions in KRN7000/CD1d complexes. Graphical abstract image
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Synthesis and biological evaluation of novel N-arylidenequinoline-3-carbohydrazides as potent β-glucuronidase inhibitors ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Muhammad Taha, Sadia Sultan, Herizal Ali Nuzar, Fazal Rahim, Syahrul Imran, Nor Hadiani Ismail, Humera Naz, Hayat Ullah Thirty N-arylidenequinoline-3-carbohydrazides (1–30) have been synthesized and evaluated against β-glucuronidase inhibitory potential. Twenty four analogs showed outstanding β-glucuronidase activity having IC50 values ranging between 2.11±0.05 and 46.14±0.95 than standard d-saccharic acid 1,4 lactone (IC50 =48.4±1.25μM). Six analogs showed good β-glucuronidase activity having IC50 values ranging between 49.38±0.90 and 80.10±1.80. Structure activity relationship and the interaction of the active compounds and enzyme active site with the help of docking studies were established. Our study identifies novel series of potent β-glucuronidase inhibitors for further investigation. Graphical abstract image
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Hydrophobic substituents increase the potency of salacinol, a potent α-glucosidase inhibitor from Ayurvedic traditional medicine ‘Salacia’ ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Genzoh Tanabe, Weijia Xie, Gorre Balakishan, Mumen F.A. Amer, Nozomi Tsutsui, Haruka Takemura, Shinya Nakamura, Junji Akaki, Kiyofumi Ninomiya, Toshio Morikawa, Isao Nakanishi, Osamu Muraoka Using an in silico method, seven analogs bearing hydrophobic substituents (8a: Me, 8b: Et, 8c: n-Pent, 8d: n-Hept, 8e: n-Tridec, 8f: isoBu and 8g: neoPent) at the 3′-O-position in salacinol (1), a highly potent natural α-glucosidase inhibitor from Ayurvedic traditional medicine ‘Salacia’, were designed and synthesized. In order to verify the computational SAR assessments, their α-glucosidase inhibitory activities were evaluated in vitro. All analogs (8a–8g) exhibited an equal or considerably higher level of inhibitory activity against rat small intestinal α-glucosidases compared with the original sulfonate (1), and were as potent as or higher in potency than the clinically used anti-diabetics, voglibose, acarbose or miglitol. Their activities against human maltase exhibited good relationships to the results obtained with enzymes of rat origin. Among the designed compounds, the one with a 3′-O-neopentyl moiety (8g) was most potent, with an approximately ten fold increase in activity against human maltase compared to 1. Graphical abstract image
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Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors – Part 3 ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Tomoya Yukawa, Yoshihisa Nakada, Nobuki Sakauchi, Taku Kamei, Masami Yamada, Yusuke Ohba, Ikuo Fujimori, Hiroyuki Ueno, Maiko Takiguchi, Masako Kuno, Izumi Kamo, Hideyuki Nakagawa, Yasushi Fujioka, Tomoko Igari, Yuji Ishichi, Tetsuya Tsukamoto Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the pK a value of the acidic moiety. The resulting compound 9 exhibited favorable PK profiles, probably because of the effect of intramolecular hydrogen bond, which was supported by a its single-crystal structure. The compound 9, 1-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, which exhibited peripheral NET-selective inhibition at tested doses in rats by oral administration, increased urethral resistance in a dose-dependent manner. Graphical abstract image
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Isomeric iodinated analogs of nimesulide: Synthesis, physicochemical characterization, cyclooxygenase-2 inhibitory activity, and transport across Caco-2 cells ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Yumi Yamamoto, Jun Arai, Takuya Hisa, Yohei Saito, Takahiro Mukai, Takashi Ohshima, Minoru Maeda, Fumihiko Yamamoto Isomeric iodinated derivatives of nimesulide, with an iodine substituent on the phenoxy ring, were prepared with the aim of identifying potential candidate compounds for the development of imaging agents targeting cyclooxygenase-2 (COX-2) in the brain. Both the experimental log P 7.4 and pK a values for these iodinated analogs were in the acceptable range for passive brain penetration. The para-iodo-substituted analog was a more potent and selective COX-2 inhibitor than nimesulide, with a potency that was comparable to the reference drug, celecoxib. Iodination at the ortho- or meta-position of the phenoxy ring was associated with a substantial loss of COX-2 inhibitory activity. Transport studies across Caco-2 cell monolayers in the presence and absence of a P-glycoprotein (P-gp) inhibitor, verapamil, indicated that the para-iodo-substituted analog was not a P-gp transport substrate; this feature is a prerequisite for potential in vivo brain imaging compounds. The para-iodo-substituted analog of nimesulide appears to be an attractive candidate for the development of radioiodine-labeled tracers for in vivo brain imaging of COX-2 levels. Graphical abstract image
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A new motif for inhibitors of geranylgeranyl diphosphate synthase ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Benjamin J. Foust, Cheryl Allen, Sarah A. Holstein, David F. Wiemer The enzyme geranylgeranyl diphosphate synthase (GGDPS) is believed to receive the substrate farnesyl diphosphate through one lipophilic channel and release the product geranylgeranyl diphosphate through another. Bisphosphonates with two isoprenoid chains positioned on the α-carbon have proven to be effective inhibitors of this enzyme. Now a new motif has been prepared with one isoprenoid chain on the α-carbon, a second included as a phosphonate ester, and the potential for a third at the α-carbon. The pivaloyloxymethyl prodrugs of several compounds based on this motif have been prepared and the resulting compounds have been tested for their ability to disrupt protein geranylgeranylation and induce cytotoxicity in myeloma cells. The initial biological studies reveal activity consistent with GGDPS inhibition, and demonstrate a structure–function relationship which is dependent on the nature of the alkyl group at the α-carbon. Graphical abstract image
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2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Sze Wei Leong, Faridah Abas, Kok Wai Lam, Khozirah Shaari, Nordin H. Lajis In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6μM and 0.6μM, respectively. Further structure–activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes’ inhibition. The Lineweaver–Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer. Graphical abstract image
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Cyclopamine bioactivity by extraction method from Veratrum californicum ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Matthew W. Turner, Roberto Cruz, Jared Mattos, Nic Baughman, Jordan Elwell, Jenny Fothergill, Anna Nielsen, Jessica Brookhouse, Ashton Bartlett, Petr Malek, Xinzhu Pu, Matthew D. King, Owen M. McDougal Veratrum californicum, commonly referred to as corn lily or Californian false hellebore, grows in high mountain meadows and produces the steroidal alkaloid cyclopamine, a potent inhibitor of the Hedgehog (Hh) signaling pathway. The Hh pathway is a crucial regulator of many fundamental processes during vertebrate embryonic development. However, constitutive activation of the Hh pathway contributes to the progression of various cancers. In the present study, a direct correlation was made between the extraction efficiency for cyclopamine from root and rhizome by eight methods, and the associated biological activity in Shh-Light II cells using the Dual-Glo® Luciferase Assay System. Alkaloid recovery ranged from 0.39 to 8.03mg/g, with ethanol soak being determined to be the superior method for obtaining biologically active cyclopamine. Acidic ethanol and supercritical extractions yielded degraded or contaminated cyclopamine with lower antagonistic activity towards Hh signaling. Graphical abstract image
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Discovery of a novel small molecule agonist scaffold for the APJ receptor ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Sanju Narayanan, Rangan Maitra, Jeffery R. Deschamps, Katherine Bortoff, James B. Thomas, Yanyan Zhang, Keith Warner, Vineetha Vasukuttan, Ann Decker, Scott P. Runyon The apelinergic system includes a series of endogenous peptides apelin, ELABELA/TODDLER and their 7-transmembrane G-protein coupled apelin receptor (APJ, AGTRL-1, APLNR). The APJ receptor is an attractive therapeutic target because of its involvement in cardiovascular diseases and potentially other disorders including liver fibrosis, obesity, diabetes, and neuroprotection. To date, pharmacological characterization of the APJ receptor has been limited due to the lack of small molecule functional agonists or antagonists. Through focused screening we identified a drug-like small molecule agonist hit 1 with a functional EC50 value of 21.5±5μM and binding affinity (K i) of 5.2±0.5μM. Initial structure–activity studies afforded compound 22 having a 27-fold enhancement in potency and the first sub-micromolar full agonist with an EC50 value of 800±0.1nM and K i of 1.3±0.3μM. Preliminary SAR, synthetic methodology, and in vitro pharmacological characterization indicate this scaffold will serve as a favorable starting point for further refinement of APJ potency and selectivity. Graphical abstract image
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Synthesis and evaluation of antitubercular activity of fluorinated 5-aryl-4-(hetero)aryl substituted pyrimidines ()
Publication date: 15 August 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 16 Author(s): Egor V. Verbitskiy, Svetlana A. Baskakova, Marionella A. Kravchenko, Sergey N. Skornyakov, Gennady L. Rusinov, Oleg N. Chupakhin, Valery N. Charushin Various 5-(fluoroaryl)-4-(hetero)aryl substituted pyrimidines have been synthesized based on the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SN H) reactions starting from commercially available 5-bromopyrimidine and their antitubercular activity against Mycobacterium tuberculosis H37Rv has been explored. The outcome of the study disclose that, some of the compounds have showed promising activity in micromolar concentration against Mycobacterium tuberculosis H37Rv, Mycobacterium avium, Mycobacterium terrae, and multidrug-resistant strains isolated from tuberculosis patients in Ural region (Russia). The data concerning the ‘structure–activity’ relationship for fluorinated compounds have been discussed. Graphical abstract image
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