Bioorganic & Medicinal Chemistry

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Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20
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Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20
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Synthesis and antiviral activity of maleopimaric and quinopimaric acids’ derivatives ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Elena V. Tretyakova, Irina E. Smirnova, Elena V. Salimova, Victor N. Odinokov A series of maleopimaric and quinopimaric acids’ derivatives modified in the E-ring, at the carbonyl- and carboxyl-groups were synthesized and evaluated for their activity in vitro against respiratory viruses (influenza; rhinovirus; adenovirus; and SARS), papilloma virus, and hepatitis B and C viruses. The antiviral screening of levopimaric acid diene adducts derivatives was carried out with minimal effect on SARS and influenza type B viruses. Excellent antiviral activity of the ozonolysis product of maleopimaric acid and dihydroquinopimaric methyl-(2-methoxycarbonyl)ethylene amide was found toward papilloma virus (HPV-11 strain) with the selectivity index of SI 30 and 20, respectively. Methyl (2-methoxycarbonyl)ethylene-, 1β-hydroxy-5′-kaprolaktamo- and 4β-hydroxy-4α,14α-epoxy-13(15)-ene-dihydroquinopimaric acid derivatives have also shown activity against replication of HCV nucleic acid and low toxicity. Graphical abstract image
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Discovery and SAR study of 2-(1-propylpiperidin-4-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) for the treatment of cancer ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Qihua Zhu, Xueyan Wang, Yan Hu, Xiaorong He, Guoqing Gong, Yungen Xu A series of imidazo[4,5-c]pyridine-7-carboxamide derivatives as poly(ADP-ribose) polymerase (PARP) inhibitors have been developed. All target compounds were evaluated for their PARP-1 inhibitory activity and some were further assessed for cellular potency. These efforts led to identification of a novel PARP-1 inhibitor 2-(1-propylpiperidin-4-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide 11a (XZ-120312). 11a displayed strong inhibition against the PARP-1 enzyme with an IC50 of 8.6±0.6nM and excellent potentiation of temozolomide cytotoxicity in cancer cell lines SW-620, MDA-MB-468 and A549 by 4.0, 3.0 and 7.7 times, respectively. Graphical abstract image
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Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anticancer activity as inhibitors of c-Met kinase ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Hebat-Allah S. Abbas, Aisha R. Al-Marhabi, Sally I. Eissa, Yousry A. Ammar In an effort to develop potent anti-cancer agents, we have synthesized some substituted quinoxaline derivatives. Reaction of 6-bromo-3-methylquinoxalin-2(1H)-one 1 with aromatic aldehydes furnished the styryl derivatives 2a–e. Alkylation of 1 with ethyl chloroacetate produced the N-alkyl derivatives 3. Hydrazinolysis of the ester derivative 3 with hydrazine hydrate afforded the hydrazide derivative 4. In addition, chlorination of 1 with phosphorus oxychloride afforded the 2-chloro derivative 5 which was used as a key intermediate for the synthesis of substituted quinoxaline derivatives 6–8, N-pyrazole derivative 9, tetrazolo[1,5-a]quinoxaline derivative 10 and Schiff base derivatives 13, 15 via reaction with several nucleophiles reagents. Docking methodologies were used to predict their binding conformation to explain the differences of their tested biological activities. All the tested compounds were screened in vitro for their cytotoxic effect on three tumor cell lines. Some new quinoxaline derivatives were studied as inhibitors of c-Met kinase, a receptor associated with high tumor grade and poor prognosis in a number of human cancers. Compounds 2e, 4, 7a, 12a, 12b and 13 showed the highest binding affinity with CDOCKER energy score, while showed the lowest IC50 values against three types of cancer cell lines. It is worth to mention that, compounds 2e, 7a, 12b and 13 showed comparable inhibition activity to the reference drug, while compounds 4 and 12a showed a more potent inhibition activity than Doxorubicin. Graphical abstract image
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Synthesis of novel acridine bis-sulfonamides with effective inhibitory activity against the carbonic anhydrase isoforms I, II, IX and XII ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): İbrahim Esirden, Ramazan Ulus, Burak Aday, Muhammet Tanç, Claudiu T. Supuran, Muharrem Kaya By using a multi component reaction system (MCR), nitro acridine sulfonamides were obtained from cyclic-1,3-diketones, 4-aminobenzene sulfonamide and aromatic aldehydes. Some novel acridine bis-sulfonamides 6a–l were then synthesized by the reaction between sulfonyl chlorides and the novel amino-acridine sulfonamides 5a and 5b, obtained by reduction of nitro-acridine sulfonamide derivatives 4a and 4b. The newly synthesized compounds were investigated as inhibitors of 4 human carbonic anhydrase isoforms (hCA, EC 4.2.1.1). Several of the compounds showed low micromolar inhibition against the medically relevant isoforms hCA I, II, IX, and XII. Graphical abstract image
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Mucin–drugs interaction: The case of theophylline, prednisolone and cephalexin ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Carlotta Pontremoli, Nadia Barbero, Guido Viscardi, Sonja Visentin The binding of mucin with three commercially available drugs (theophylline, cephalexin and prednisolone) belonging to different pharmaceutical classes was investigated. The studied drugs are normally used to treat the symptomatology of cystic fibrosis. The interaction between drugs and mucin has been investigated using fluorescence and UV–Vis absorption spectroscopy; quenching mechanism, binding constants, binding sites, thermodynamic parameters and binding distance of the interaction were obtained. Graphical abstract image
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A novel family of diarylpyrimidines (DAPYs) featuring a diatomic linker: Design, synthesis and anti-HIV activities ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Shuang-Xi Gu, Heng Qiao, Yuan-Yuan Zhu, Qi-Chao Shu, Hui Liu, Xiu-Lian Ju, Erik De Clercq, Jan Balzarini, Christophe Pannecouque To improve the conformational flexibility and positional adaptability of the traditional diarylpyrimidines (DAPYs), a family of diarylpyrimidines featuring a C–N diatomic linker between the left wing benzene ring and the central pyrimidine was firstly designed, synthesized, and evaluated for in vitro anti-HIV activity. Most of target molecules showed excellent activities against wild-type (WT) HIV-1. Among them the most potent two compounds 12h and 12r displayed extremely potent WT HIV-1 inhibitory activities with an EC50 of 2.6nM and 3.0nM, respectively, while their selective index (CC50/EC50) values were both over 1000. Another compound 12b (EC50 14.9nM) was also noteworthy due to its high SI of 18,614. Moreover, all of compounds were evaluated for their WT HIV-1 reverse transcriptase activities, which shown that the newly synthesized CH 2 NH-DAPYs bind to HIV-1 RT and belong to the genuine NNRTIs. However, the synthesized compounds lack the activities against HIV-1 double mutant (RES056) and HIV-2 (ROD). Thus it is an upcoming objective to improve the activities against HIV-1 double mutants. Graphical abstract image
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Identification and in silico prediction of metabolites of the model compound, tebufenozide by human CYP3A4 and CYP2C19 ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Naoki Shirotani, Moe Togawa, Shinichi Ikushiro, Toshiyuki Sakaki, Toshiyuki Harada, Hisashi Miyagawa, Masayoshi Matsui, Hirohisa Nagahori, Kazuki Mikata, Kazuhiko Nishioka, Nobuhiro Hirai, Miki Akamatsu The metabolites of tebufenozide, a model compound, formed by the yeast-expressed human CYP3A4 and CYP2C19 were identified to clarify the substrate recognition mechanism of the human cytochrome P450 (CYP) isozymes. We then determined whether tebufenozide metabolites may be predicted in silico. Hydrogen abstraction energies were calculated with the density functional theory method B3LYP/6-31G∗. A docking simulation was performed using FRED software. Several alkyl sites of tebufenozide were hydroxylated by CYP3A4 whereas only one site was modified by CYP2C19. The accessibility of each site of tebufenozide to the reaction center of CYP enzymes and the susceptibility of each hydrogen atom for metabolism by CYP enzymes were evaluated by a docking simulation and hydrogen abstraction energy estimation, respectively. Graphical abstract image
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Adenosine analogs as inhibitors of tyrosyl-tRNA synthetase: Design, synthesis and antibacterial evaluation ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Wei Wei, Wei-Kang Shi, Peng-Fei Wang, Xiao-Tong Zeng, Pan Li, Ji-Rong Zhang, Qian Li, Zhi-Ping Tang, Jia Peng, Lang-Zhou Wu, Mei-Qun Xie, Chan Liu, Xian-Hui Li, Ying-Chun Wang, Zhu-Ping Xiao, Hai-Liang Zhu Herein we describe the synthesis and evaluation of a series of adenosine analogs for in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Out of these compounds, compound c6 has much stronger antibacterial potency against Pseudomonas aeruginosa than ciprofloxacin, and was determined to target tyrosyl-tRNA synthetase with IC50 of 0.8±0.07μM. Structure–activity relationship analysis suggested that introduction of a fluorine atom at the 3′-position of benzene ring of the phenylacetyl moiety significantly increased affinities to the enzyme. In comparison with isopropylidene analogs, 2′,3′-deprotected compounds displayed higher inhibitory activity. Molecular dockings provided an explanation for observations in biological assays. Graphical abstract image
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Synthesis of methyl (132R/S)-alkyl-pyropheophorbide a and a non-epimerized chlorophyll a mimic ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Shin Ogasawara, Hitoshi Tamiaki The (132 R/S)-methoxycarbonyl group of methyl pheophorbides a/a′ (chlorophyll a/a′ derivatives) was converted to methyl, ethyl, propyl, and isopropyl groups through the C132-alkylation under basic conditions followed by pyrolysis in 2,4,6-collidine with lithium iodide. All the resulting products, methyl 132-alkyl-pyropheophorbides a, predominantly gave the (132 R)-stereoisomers with about one tenth of the (132 S)-epimers. Their stereochemistry was determined by 1D/2D NMR and their optical properties were characterized by visible absorption and circular dichroism spectroscopy. Methyl (132 R)-propyl-pyropheophorbide a was converted to (132 R)-propyl-pyrochlorophyll a by ester exchanging and magnesium chelating reactions. The synthetic chlorophyll a analogue showed non-epimerization at the 132-position in pyridine-d 5 at 40°C, while naturally occurring chlorophyll a was easily epimerized under the same conditions to give its epimeric mixture. Graphical abstract image
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Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Bharani Thangavelu, Pravin Bhansali, Ronald E. Viola Aspartate-β-semialdehyde dehydrogenase (ASADH) lies at the first branch point in the aspartate metabolic pathway which leads to the biosynthesis of several essential amino acids and some important metabolites. This pathway is crucial for many metabolic processes in plants and microbes like bacteria and fungi, but is absent in mammals. Therefore, the key microbial enzymes involved in this pathway are attractive potential targets for development of new antibiotics with novel modes of action. The ASADH enzyme family shares the same substrate binding and active site catalytic groups; however, the enzymes from representative bacterial and fungal species show different inhibition patterns when previously screened against low molecular weight inhibitors identified from fragment library screening. In the present study several approaches, including fragment based drug discovery (FBDD), inhibitor docking, kinetic, and structure–activity relationship (SAR) studies have been used to guide ASADH inhibitor development. Elaboration of a core structure identified by FBDD has led to the synthesis of low micromolar inhibitors of the target enzyme, with high selectivity introduced between the Gram-negative and Gram-positive orthologs of ASADH. This new set of structures open a novel direction for the development of inhibitors against this validated drug-target enzyme. Graphical abstract image
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Synthesis of chiral ND-322, ND-364 and ND-364 derivatives as selective inhibitors of human gelatinase ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Yugang Yan, Xueying Chen, Xinying Yang, Jian Zhang, Wenfang Xu, Yingjie Zhang Compounds 10 (ND-322) and 15 (ND-364) are potent selective inhibitors for gelatinases, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). However, both of them are racemates. Herein we report facile synthesis of optically active (R)- and (S)-enantiomers of compounds 10 and 15. And the sulfonyl of 15 was transformed to sulfinyl to obtain four epimeric mixtures. All synthesized thiirane-based compounds were evaluated in MMP2 and MMP9 inhibitory assays. Our results indicated that the configuration of thiirane moiety had little effects on gelatinase inhibition, but the substitution of sulfinyl for sulfonyl was detrimental to gelatinase inhibition. Besides, all target compounds exhibited no inhibition against other two Zn2+ dependant metalloproteases, aminopeptidase N (APN) and histone deacetylases (HDACs), which confirmed the unique Zn2+ chelation mechanism of thiirane moiety against gelatinases. Graphical abstract image
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1,3,7-Triethyl-substituted xanthines—possess nanomolar affinity for the adenosine A1 receptor ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Mietha M. Van der Walt, Gisella Terre’Blanche Adenosine A1 receptors are attracting great interest as drug targets for their role in cognitive deficits. Antagonism of the adenosine A1 receptor may offer therapeutic benefits in complex neurological diseases, such as Alzheimer’s and Parkinson’s disease. The aim of this study was to discover potential selective adenosine A1 receptor antagonists. Several analogs of 8-(3-phenylpropyl)xanthines (3), 8-(2-phenylethyl)xanthines (4) and 8-(phenoxymethyl)xanthines (5) were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that the 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d), among each series, displayed the highest affinity for the adenosine A1 receptor with K i values in the nanomolar range. This ethyl-substitution pattern was previously unknown to enhance adenosine A1 receptor binding affinity. The 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d) behaved as adenosine A1 receptor antagonists in GTP shift assays performed with either rat cortical or whole brain membranes expressing adenosine A1 receptors. Further, in vivo evaluation of 3d showed reversal of adenosine A1 receptor agonist-induced hypolocomotion. In conclusion, the most potent evaluated compound, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (3d), showed both in vitro and in vivo activity, and therefore represent a novel adenosine A1 receptor antagonist that may have potential as a drug candidate for dementia disorders. Graphical abstract image
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Rhododendrol glycosides as stereospecific tyrosinase inhibitors ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Takehiro Iwadate, Ken-ichi Nihei Rhododendrol derivatives 3–12 have been synthesized in six steps, including aldol condensation and/or trichloroacetimidate glycosylation as the key reactions. Each derivative showed effective inhibition of tyrosinase-catalyzed oxidation processes. In particular, a series of synthetic derivatives having an R-stereogenic center at C-2 proved to be more potent than their respective epimers. In addition, the glycosylation on the phenylbutanoid scaffold increased the difference in activity between the isomers. This suggests that the sugar moiety plays an important role in eliciting their potent inhibitory activity. Graphical abstract image
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Soluble epoxide hydrolase inhibitory activity of anthraquinone components from Aloe ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Ya Nan Sun, Jang Hoon Kim, Wei Li, A. Reum Jo, Xi Tao Yan, Seo Young Yang, Young Ho Kim Aloe is a short-stemmed succulent herb widely used in traditional medicine to treat various diseases and as raw material in cosmetics and heath foods. In this study, we isolated and identified two new anthraquinone derivatives, aloinoside C (6) and aloinoside D (7), together with six known compounds from an aqueous dissolved Aloe exudate. Their structures were identified by spectroscopic analysis. The inhibitory effects of the isolated compounds on soluble epoxide hydrolase (sEH) were evaluated. Compounds 1–8 inhibited sEH activity potently, with IC50 values ranging from 4.1±0.6 to 41.1±4.2μM. A kinetic analysis of compounds 1–8 revealed that the inhibitory actions of compounds 1, 6 and 8 were non-competitive, whereas those of compounds 2–5 and 7 were the mixed-type. Molecular docking increases our understanding of receptor–ligand binding of all compounds. These results demonstrate that compounds 1–8 from Aloe are potential sEH inhibitors. Graphical abstract image
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Design, synthesis and structure–activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Zheng Li, Xuekun Wang, Xue Xu, Jianyong Yang, Qianqian Qiu, Hao Qiang, Wenlong Huang, Hai Qian The free fatty acid receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure–activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice. Graphical abstract image
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Synthesis of alkylsulfonyl and substituted benzenesulfonyl curcumin mimics as dual antagonist of L-type Ca2+ channel and endothelin A/B2 receptor ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Chong-Bin Park, Chan Mug Ahn, Sangtae Oh, Daeho Kwon, Won-Chul Cho, Woon-Seob Shin, Yuan Cui, Ye Sol Um, Byong-Gon Park, Seokjoon Lee We synthesized a library of curcumin mimics with diverse alkylsulfonyl and substituted benzenesulfonyl modifications through a simple addition reaction of important intermediate, 1-(3-Amino-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-propenone (10), with various sulfonyl chloride reactants and then tested their vasodilatation effect on depolarization (50mM K+)- and endothelin-1 (ET-1)-induced basilar artery contraction. Generally, curcumin mimics with aromatic sulfonyl groups showed stronger vasodilation effect than alkyl sulfonylated curcumin mimics. Among the tested compounds, six curcumin mimics (11g, 11h, 11i, 11j, 11l, and 11s) in a depolarization-induced vasoconstriction and seven compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s) in an ET-1-induced vasoconstriction showed strong vasodilation effect. Based on their biological properties, synthetic curcumin mimics can act as dual antagonist scaffold of L-type Ca2+ channel and endothelin A/B2 receptor in vascular smooth muscle cells. In particular, compounds 11g and 11s are promising novel drug candidates to treat hypertension related to the overexpression of L-type Ca2+ channels and ET peptides/receptors-mediated cardiovascular diseases. Graphical abstract image
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Enzymatic synthesis and RNA interference of nucleosides incorporating stable isotopes into a base moiety ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Akihiko Hatano, Mitsuya Shiraishi, Nanae Terado, Atsuhiro Tanabe, Kenji Fukuda Thymidine phosphorylase was used to catalyze the conversion of thymidine (or methyluridine) and uracil incorporating stable isotopes to deoxyuridine (or uridine) with the uracil base incorporating the stable isotope. These base-exchange reactions proceeded with high conversion rates (75–96%), and the isolated yields were also good (64–87%). The masses of all synthetic compounds incorporating stable isotopes were identical to the theoretical molecular weights via EIMS. 13C NMR spectra showed spin–spin coupling between 13C and 15N in the synthetic compounds, and the signals were split, further proving incorporation of the isotopes into the compounds. The RNA interference effects of this siRNA with uridine incorporating stable isotopes were also investigated. A 25mer siRNA had a strong knockdown effect on the MARCKS protein. The insertion position and number of uridine moieties incorporating stable isotopes introduced into the siRNA had no influence on the silencing of the target protein. This incorporation of stable isotopes into RNA and DNA has the potential to function as a chemically benign tracer in cells. Graphical abstract image
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Design, synthesis and pharmacological evaluation of pyrimidobenzothiazole-3-carboxylate derivatives as selective L-type calcium channel blockers ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Rupesh Chikhale, Sonali Thorat, Amit Pant, Ankush Jadhav, Krishna Chary Thatipamula, Ratnadeep Bansode, G. Bhargavi, Nazira Karodia, M.V. Rajasekharan, Anant Paradkar, Pramod Khedekar L-type voltage gated calcium channels play essential role in contraction of various skeletal and vascular smooth muscles, thereby plays important role in regulating blood pressure. Dihydropyridine receptors have been targeted for development of newer antihypertensive agents, one of the structurally analogs nucleus dihydropyrimidines have been reported earlier by us as a potential agent toward development of calcium channel modulator. A pre-synthetic QSAR was run and on the basis of structure activity relationship a series of twenty three molecules was synthesized and studied by myosin light chain kinase assay (MLCK), Angiotensin Converting Enzyme (ACE) colorimetric assay, non-invasive blood pressure (NIBP) and invasive blood pressure (IBP) methods. Molecules with significant efficacy were studied for their single crystal X-ray diffraction, molecular docking, molecular dynamics and post-synthetic QSAR. The NIBP and IBP methods screened molecules with better percentage inhibition versus time compared to standard drug Nifedipine. The lead compound ethyl 2-methyl-4-(3-nitrophenyl)-4H-pyrimido [2,1-b] [1,3] benzothiazole-3-carboxylate (26) presented a triclinic structure with polymeric chain packing in lattice. 26 exhibited IC50on MLCK assay of 2.1±1.7μM with selectivity of L-type calcium channels and comparative to Nifedipine. It offered satisfactory physicochemical properties with partition coefficient of (C log P) 4.64. Its pharmacokinetic profile is also good with C max at 0.40μg/ml by oral route with T max reaching in 0.5h which means in 30min. 26 also exhibits superior t 1/2 of 5.4h and oral bioavailability of (F) 56.75% with an AUC0–∞ of 0.84μgh/ml. Molecular docking studies indicates toward the interaction of lead compound via hydrogen bonds with Lys144, Glu181 and Asp183, it forms the Van der Walls interactions with Ser18, Asp20, Asn187, Pro185, Glu180, Glu181 and Arg10 with Glide score and Glide energy to be −3.602 and −47.098, respectively. Post-synthetic QSAR of newly synthesized molecules indicates toward improvement with respect to steric descriptor which contributed negatively in former series. Graphical abstract image
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Cardiovascular activity of the chiral xanthone derivatives ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Natalia Szkaradek, Anna Rapacz, Karolina Pytka, Barbara Filipek, Dorota Żelaszczyk, Przemysław Szafrański, Karolina Słoczyńska, Henryk Marona A series of 6 derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure, the effect on blood pressor response and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Two compounds revealed nanomolar affinity for α1-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals’ models. They were enantiomers of previously described (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one hydrochloride and revealed similar antiarrhythmic potential in adrenaline induced model of arrhythmia in rats after intravenous injection (ED50 =0.53mg/kg and 0.81mg/kg, respectively). These values were lower than values obtained for reference drug urapidil. These compounds were more active in this experiment than urapidil (ED50 =1.26mg/kg). The compound 5 administered iv at doses of 0.62–2.5mg/kg at the peak of arrhythmia prevented and/or reduced the number of premature ventricular beats in a statistically significant manner. The ED50 value was 1.20mg/kg. The S-enantiomer (6) given at the same doses did not show therapeutic antiarrhythmic activity in this model. These compounds significantly decreased the systolic and diastolic blood pressure throughout the whole observation period in anesthetized, normotensive rats. The studied enantiomers showed higher toxicity than urapidil, but imperceptibly higher that another cardiovascular drugs, that is, carvedilol or propranolol. They were also evaluated for mutagenic potential in the Ames (Salmonella) test. It was found that at the concentrations tested the compounds were non mutagenic when compared to solvent control. Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found. Graphical abstract image
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From carbohydrates to drug-like fragments: Rational development of novel α-amylase inhibitors ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Jamil Al-Asri, Erika Fazekas, Gábor Lehoczki, Andrej Perdih, Cornelia Görick, Matthias F. Melzig, Gyöngyi Gyémánt, Gerhard Wolber, Jérémie Mortier Starch catabolism leading to high glucose level in blood is highly problematic in chronic metabolic diseases, such as type II diabetes and obesity. α-Amylase catalyzes the hydrolysis of starch, increasing blood sugar concentration. Its inhibition represents a promising therapeutic approach to control hyperglycaemia. However, only few drug-like molecule inhibitors without sugar moieties have been discovered so far, and little information on the enzymatic mechanism is available. This work aims at the discovery of novel small α-amylase binders using a systematic in silico methodology. 3D-pharmacophore-based high throughput virtual screening of small compounds libraries was performed to identify compounds with high α-amylase affinity. Twenty-seven compounds were selected and biologically tested, revealing IC50 values in the micromolar range and ligand efficiency higher than the one of the bound form of acarbose, which is used as a reference for α-amylase inhibition. Graphical abstract image
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Effect of alkyl group on transnitrosation of N-nitrosothiazolidine thiocarboxamides ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Keiko Inami, Yuta Ono, Sonoe Kondo, Ikuo Nakanishi, Kei Ohkubo, Shunichi Fukuzumi, Masataka Mochizuki S-Nitrosoglutathione (GSNO) relaxes vascular smooth muscles, prevents platelet aggregation, and acts as a potential in vivo nitric oxide donor. 3-Nitroso-1,3-thiazolidine-4-thiocarboxamide (1), a N-nitrosothio-proline analogue, exhibited a high GSNO formation activity. In this study, two compounds (2 and 3) based on compound 1 were newly synthesized by introducing either one or two methyl groups onto a nitrogen atom on the thioamide substituent in 1. The pseudo-first-order rate constants (k obs) for the GSNO formation for the reaction between the compound and glutathione followed the order 1 > 2 ≒ 3 . Thus, the introduction of a methyl group(s) onto the thioamide group led to a decrease in the transnitrosation activity. On the basis of density functional theoretical calculations, the transnitrosation for the N-nitrosothiazolidine thiocarboxamides was proposed to proceed via a bridged intermediate pathway. Specifically, the protonated compound 1 forms a bridged structure between the nitrogen atom in the nitroso group and two sulfur atoms—one in the ring and the other in the substituent. The bridged intermediate gives rise to a second intermediate in which the nitroso group is bonded to the sulfur atom in the thioamide group. Finally, the nitroso group is transferred to GSH to form GSNO. Graphical abstract image
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Synthesis, in vitro biological activities and in silico study of dihydropyrimidines derivatives ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Assem Barakat, Mohammad Shahidul Islam, Abdullah Mohammed Al-Majid, Hazem A. Ghabbour, Hoong-Kun Fun, Kulsoom Javed, Rehan Imad, Sammer Yousuf, M. Iqbal Choudhary, Abdul Wadood We describe here the synthesis of dihydropyrimidines derivatives 3a–p, and evaluation of their α-glucosidase enzyme inhibition activities. Compounds 3b (IC50 =62.4±1.5μM), 3c (IC50 =25.3±1.26μM), 3d (IC50 =12.4±0.15μM), 3e (IC50 =22.9±0.25μM), 3g (IC50 =23.8±0.17μM), 3h (IC50 =163.3±5.1μM), 3i (IC50 =30.6±0.6μM), 3m (IC50 =26.4±0.34μM), and 3o (IC50 =136.1±6.63μM) were found to be potent α-glucosidase inhibitors in comparison to the standard drug acarbose (IC50 =840±1.73μM). The compounds were also evaluated for their in vitro cytotoxic activity against PC-3, HeLa, and MCF-3 cancer cell lines, and 3T3 mouse fibroblast cell line. All compounds were found to be non cytotoxic, except compounds 3f and 3m (IC50 =17.79±0.66–20.44±0.30μM), which showed a weak cytotoxic activity against the HeLa, and 3T3 cell lines. In molecular docking simulation study, all the compounds were docked into the active site of the predicted homology model of α-glucosidase enzyme. From the docking result, it was observed that most of the synthesized compounds showed interaction through carbonyl oxygen atom and polar phenyl ring with active site residues of the enzyme. Graphical abstract image
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Solid- and solution-phase synthesis and application of R6G dual-labeled oligonucleotide probes ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Aleksander Yu. Skoblov, Maxim V. Vichuzhanin, Valentina M. Farzan, Olga A. Veselova, Tatiana A. Konovalova, Alexander T. Podkolzin, German A. Shipulin, Timofei S. Zatsepin A novel N-TFA-protected carboxyrhodamine 6G (R6G) phosphoramidite was synthesized for use in an automated DNA synthesis to prepare 5′-labeled oligonucleotides. Deprotection and purification conditions were optimized for 5′-labeled and dual-labeled oligonucleotide probes. As an alternative we synthesized an azide derivative of R6G for CuAAC post-synthetic oligonucleotide labeling. Dual-labeled probes obtained by both methods showed the same efficacy in a quantitative PCR assay. R6G-labeled probes demonstrated superior properties in a qPCR assay in comparison with alternative HEX, JOE and SIMA dyes due to more efficient fluorescence quenching by BHQ-1. We successfully used R6G dual-labeled probes for rotavirus genotyping. Graphical abstract image
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Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Marketa Bernaskova, Angela Schoeffmann, Wolfgang Schuehly, Antje Hufner, Igor Baburin, Steffen Hering In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignan honokiol together with its isomer magnolol are the main constituents of Magnolia bark extracts. We have previously identified a nitrogen-containing honokiol derivative (3-acetylamino-4′-O-methylhonokiol, AMH) as a high efficient modulator of GABAA receptors. Here we further elucidate the structure-activity relation of a series of nitrogenated biphenyl-neolignan derivatives by analysing allosteric modulation and agonistic effects on α1β2γ2S GABAA receptors. The strongest I GABA enhancement was induced by compound 5 (3-acetamido-4′-ethoxy-3′,5-dipropylbiphenyl-2-ol, E max: 123.4±9.4% of I GABA-max) and 6 (5′-amino-2-ethoxy-3′,5-dipropylbiphenyl-4′-ol, E max: 117.7±13.5% of I GABA-max). Compound 5 displayed, however, a significantly higher potency (EC50 =1.8±1.1μM) than compound 6 (EC50 =20.4±4.3μM). Honokiol, AMH and four of the derivatives induced significant inward currents in the absence of GABA. Strong partial agonists were honokiol (inducing 78±6% of I GABA-max), AMH (63±6%), 5′-amino-2-O-methylhonokiol (1) (59±1%) and 2-methoxy-5′-nitro-3′,5-dipropylbiphenyl-4′-ol (3) (52±1%). 3-N-Acetylamino-4′-ethoxy-3′,5-dipropyl-biphenyl-4′-ol (5) and 3-amino-4′-ethoxy-3′,5-dipropyl-biphenyl-4′-ol (7) were less efficacious but even more potent (5: EC50 =6.9±1.0μM; 7: EC50 =33.2±5.1μM) than the full agonist GABA. Graphical abstract image
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Design, synthesis, and biological evaluation of amide imidazole derivatives as novel metabolic enzyme CYP26A1 inhibitors ()
Publication date: 15 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 20 Author(s): Bin Sun, Kai Liu, Jing Han, Li-yu Zhao, Xiao Su, Bin Lin, Dong-Mei Zhao, Mao-Sheng Cheng All-trans-retinoic acid (ATRA) as a physiological metabolite of vitamin A is widely applied in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. CYP26A1 enzyme, induced by ATRA in liver and target tissues, metabolizes ATRA into 4-hydroxyl-RA. Inhibition of CYP26A1 metabolic enzyme represents a promising strategy for discovery of new specific anticancer agents. Herein, we describe the design, synthesis and biological evaluation of a series of new amide imidazole derivatives as retinoic acid metabolism blocking agents (RAMBAs) toward CYP26A1 enzyme. First, based on the recent theoretical models (Sun et al., J. Mol. Graph. Model., 2015, 56, 10–19) a series of RAMBAs with novel scaffolds were designed using fragment-based drug discovery approach. Subsequently, the new RAMBAs were synthesized and evaluated for their biological activities. All the compounds demonstrated appropriate enzyme activities and cell activities. The promising inhibitors 20 and 23 with IC50 value of 0.22μM and 0.46μM toward CYP26A1, respectively, were further evaluated for CYP selectivity and the metabolic profile of ATRA. Both compounds 20 and 23 showed higher selectivity for CYP26A1 over other CYPs (CYP2D6, CYP3A4) when compared to liarozole. They also showed better inhibitory activities for the metabolism of ATRA when also compared to liarozole. These studies further validated the pharmacophore and structure–activity relationship models obtained about CYP26A1 inhibitors and highlighted the promising activities of the new series of CYP26A1 inhibitors designed from such models. They also paved the way for future development of those candidates as potential drugs. Graphical abstract image
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Structure Activity Relationships of Benzyl C-region Analogues of 2-(3-Fluoro-4-methylsulfonamidophenyl) propanamides as Potent TRPV1 Antagonists ()
Publication date: Available online 9 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Jihyae Ann, Aeran Jung, Mi-Yeon Kim, Hyuk-Min Kim, HyungChul Ryu, Sunjoo Kim, Dong Wook Kang, Sunhye Hong, Minghua Cui, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with Ki (CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region. Graphical abstract image
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Synthesis and evaluation of C-5 modified 2’-deoxyuridine monophosphates as inhibitors of M.tuberculosis thymidylate synthase ()
Publication date: Available online 9 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Liudmila A. Alexandrova, Vladimir O. Chekhov, Eduard R. Shmalenyuk, Sergey N. Kochetkov, Rania Abu El-Asrar, Piet Herdewijn A series of 5’-monophosphates of 5-substituted 2’-deoxyuridine analogues, which recently demonstrated in vitro substantial suppression of two strains of M. tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as potential inhibitors of M. tuberculosis thymidylate synthases: classical (ThyA) and flavin dependent thymidylate synthase (ThyX). A systematic SAR study and docking revealed 5-undecyloxymethyl-2’-deoxyuridine 5’-monophosphate 3b, displaying an IC50 value against ThyX of 8.32 μM. All derivatives lack activity against the ThyA. It can be assumed that the mechanism of action of 3b may be partially associated with the inhibition of the ThyX. Graphical abstract image
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New macrocyclic analogues of the natural histone deacetylase inhibitor FK228; Design, Synthesis and Preliminary biological evaluation ()
Publication date: Available online 9 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Minghong Ni, Emiliano Esposito, Victor Paul Raj, Laura Muzi, Franco Zunino, Valentina Zuco, Denis Cominetti, Sergio Penco, Alma Dal Pozzo Among the natural histone deacetylase inhibitors (HDACi), the bicyclic depsipeptide macrolactone FK228 stands out for its unique chemical structure and mechanism of action. In order to expand the chemical diversity, exploiting the FK228 peculiar structure, we have synthesized a collection of 24 simplified novel analogues. A first series consists of bicyclic macrolactones, where the carboxy terminus of the natural compound was substituted by peptidomimetic aminomethylphenylacetic acid derivatives. These analogues, 7a-i, showed submicromolar cytotoxic activity, even though very low inhibitory activity against HDAC enzymes, suggesting that most probably they behave with a mechanism different from the natural compound. One of the most active members in the group, 7g, was evaluated in vivo and exhibited significant antitumor activity. This evidence supports that the activity is unrelated to HDAC inhibition and these compounds represent a novel series of promising active agents. Another analogue series consists of monocyclic macrolactones, 9a-c and 10a-d which lack the disulfide bridge and bear the protected sulfur on the linear external chain; they showed similar cytotoxic activities compared to the natural compound, but proved to be very sensitive to the nature of the sulfur protection. In fact, when the sulfur was protected by an 1-octanoyl residue, like in 9b, the product displayed a one digit nanomolar activity. The results provide evidence that our approach may be followed to develop novel series of FK228 analogues. Graphical abstract image
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Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor ()
Publication date: Available online 9 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Masato Yoshikawa, Haruhi Kamisaki, Jun Kunitomo, Hideyuki Oki, Hironori Kokubo, Akihiro Suzuki, Tomomi Ikemoto, Kosuke Nakashima, Naomi Kamiguchi, Akina Harada, Haruhide Kimura, Takahiko Taniguchi Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER) = 6.2) despite the potent PDE10A inhibitory activity (IC50 = 0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER = 1.4) and an excellent PDE10A inhibitory activity (IC50 = 0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3 mg/kg by oral administration in mice. Graphical abstract image
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Synthesis of fucosylated lacto-N-tetraose using whole-cell biotransformation ()
Publication date: Available online 9 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Florian Baumgärtner, Lukas Jurzitza, Jürgen Conrad, Uwe Beifuss, Georg A. Sprenger, Christoph Albermann Fucosylated oligosaccharides present a predominant group of free oligosaccharides found in human milk. Here, a microbial conversion of lactose, D-glucose and L-fucose to fucosylated lacto-N-tetraose by growing Escherichia coli cultures is presented. The recombinant expression of genes encoding for the β1,3-N-acetylglucosaminyltransferase (LgtA) and the β1,3-galactosyltransferase (WbgO) enables the whole-cell biotransformation of lactose to lacto-N-tetraose. By the additional expression of a recombinant GDP-L-fucose salvage pathway together with a bacterial fucosyltransferase, lacto-N-tetraose is further converted into the respective fucosylated compounds. The expression of a gene encoding the α1,2-fucosyltransferase (FutC) in the lacto-N-tetraose producing E. coli strain led to the formation of lacto-N-fucopentaose I, whereas the expression of a gene encoding the α1,4-fucosyltransferase (FucT14) mainly led to the conversion of lacto-N-tetraose to lacto-N-difucohexaose II. Graphical abstract image
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Synthesis of Stereochemically Diverse Cyclic Analogs of Tubulysins ()
Publication date: Available online 9 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Yunjeong Park, Song Yi Bae, Jung-Mi Hah, Sang Kook Lee, Jae-Sang Ryu The synthesis of tubulysin analogs containing stereochemically diverse cyclic Tuv moieties is described. A tetrahydropyranyl moiety was incorporated into the Tuv unit by enantioselective hetero Diels-Alder reactions of Danishefsky’s diene and thiazole aldehyde. Four different stereoisomers of cyclic Tuv units were used as surrogates for the Tuv moiety. The synthesized stereochemically diverse simplified cyclic analogs were evaluated for the inhibition of tubulin polymerization. Graphical abstract image
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1,2,3-TRIAZOLE-BASED ANALOGUE OF BENZNIDAZOLE DISPLAYS REMARKABLE ACTIVITY AGAINST TRYPANOSOMA CRUZI ()
Publication date: Available online 9 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Peterson de Andrade, Oswaldo A. Galo, Marcelo R. Carvalho, Carla D. Lopes, Zumira A. Carneiro, Renata Sesti-Costa, Eduardo Borges de Melo, João S. Silva, Ivone Carvalho The current treatment of Chagas disease is based on the use of two drugs, nifurtimox and benznidazole, which present limited efficacy in the chronic stage of the disease and toxic side effects. Although some progress has been made in the development of new drugs to treat this disease, the discovery of novel compounds is urgently required. In this work we report the synthesis and biological evaluation of 1,2,3-triazole-based analogues of benznidazole. A small series of 27 compounds was successfully synthesized via microwave-assisted copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) from N-benzyl-2-azidoacetamide (1) and a set of commercial terminal alkynes. Analogues 24 (IC50 40 μM) and 28 (IC50 50 μM) showed comparable activities against trypomastigote form to benznidazole (IC50 34 μM) and analogue 15 (IC50 7 μM) was found to be the most active. Regarding the cytotoxicity assessment of the series, most compounds were not cytotoxic. This work shows that the designed strategy is efficiently capable of generating novel benzindazole analogues and reveals one analogue is more active than benznidazole. Graphical abstract image
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Targeted Shiga toxin-Drug Conjugates Prepared via Cu-Free Click Chemistry ()
Publication date: Available online 8 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Vesela Kostova, Estelle Dransart, Michel Azoulay, Laura Brulle, Siau-Kun Bai, Jean-Claude Florent, Ludger Johannes, Frédéric Schmidt The main drawback of the anticancer chemotherapy consists in the lack of drug selectivity causing severe side effects. The targeted drug delivery appears to be a very promising strategy for controlling the biodistribution of the cytotoxic agent only on malignant tissues by linking it to tumor-targeting moiety. Here we exploit the natural characteristics of Shiga toxin B sub-unit (STxB) as targeting carrier on Gb3-positive cancer cells. Two cytotoxic conjugates STxB–doxorubicin (STxB-Doxo) and STxB-monomethyl auristatin F (STxB-MMAF) were synthesised using copper-free “click” chemistry. Both conjugates were obtained in very high yield and demonstrated strong tumor inhibition activity in a nanomolar range on Gb3-positive cells. Graphical abstract image
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Design, Synthesis and Biological Activity of Phenoxyacetic Acid Derivatives as Novel Free Fatty Acid Receptor 1 Agonists ()
Publication date: Available online 8 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Zheng Li, Xuekun Wang, Xue Xu, Jianyong Yang, Wenting Xia, Xianhao Zhou, Wenlong Huang, Hai Qian The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose-stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid derivatives. Herein, we describe the further chemical modification of this series directed by ligand efficiency and ligand lipophilicity efficiency. All of these efforts lead to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity (43.6 nM), desired LE and LLE values. Moreover, compound 16 revealed a great potential for improving the hyperglycemia levels in both normal and type 2 diabetic mice without the risk of hypoglycemia even at the high dose of 40 mg/kg. Graphical abstract image
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Isomeric methoxy analogs of nimesulide for development of brain cyclooxygense-2 (COX-2)-targeted imaging agents: Synthesis, in vitro COX-2-inhibitory potency, and cellular transport properties ()
Publication date: Available online 8 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Yumi Yamamoto, Takuya Hisa, Jun Arai, Yohei Saito, Fumihiko Yamamoto, Takahiro Mukai, Takashi Ohshima, Minoru Maeda, Yasuhito Ohkubo Nimesulide analogs bearing a methoxy substituent either at the ortho-, meta- or para-position on the phenyl ring, were designed, synthesized, and evaluated for potential as radioligands for brain cyclooxygenase-2 (COX-2) imaging. The synthesis of nimesulide and regioisomeric methoxy analogs was based on the copper-mediated arylation of phenolic derivatives for the construction of diaryl ethers. These isomeric methoxy analogs displayed lipophilicity similar to that of nimesulide itself, as evidenced by their HPLC log P 7.4 values. In vitro inhibition studies using a colorimetric COX (ovine) inhibitor-screening assay demonstrated that the para-methoxy substituted analog retains the inhibition ability and selectivity observed for parent nimesulide toward COX-2 enzyme, whereas the meta- and ortho-methoxy substituents detrimentally affected COX-2-inhibition activity, which was further supported by molecular docking studies. Bidirectional transport cellular studies using Caco-2 cell culture model in the presence of the P-glycoprotein (P-gp) inhibitor, verapamil, showed that P-gp did not have a significant effect on the efflux of the para-methoxy substituted analog. Further investigations using the radiolabeled form of the para-methoxy substituted analog is warranted for in vivo characterization. Graphical abstract image
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Poly(amidoamine) dendrimers show carbonic anhydrase inhibitory activity against α-, β-, γ- and η-class enzymes ()
Publication date: Available online 8 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Fabrizio Carta, Sameh M. Osman, Daniela Vullo, Zeid AlOthman, Sonia Del Prete, Clemente Capasso, Claudiu T. Supuran Four generations of poly(amidoamine) (PAMAM) dendrimers incorporating benzenesulfonamide moieties were investigated as inhibitors of carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the α-, β-, γ- and η-classes which are present in pathogenic bacteria, fungi or protozoa. The following bacterial, fungal and protozoan organisms were included in the study: Vibrio cholerae, Trypanosoma cruzi, Leishmania donovani chagasi, Porphyromonas gingivalis, Cryptococcus neoformans, Candida glabrata, and Plasmodium falciparum. The eight pathozymes present in these organisms were efficiently inhibited by the four generations PAMAM-sulfonamide dendrimers, but multivalency effects were highly variable among the different enzyme classes. The Vibrio enzyme VchCA was best inhibited by the G3 dendrimer incorporating 32 sulfamoyl moieties. The Trypanosoma enzyme TcCA on the other hand was best inhibited by the first generation dendrimer G0 (with 4 sulfamoyl groups), whereas for other enzymes the optimal inhibitory power was observed for the G1 or G2 dendrimers, with 8 and 16 sulfonamide functionalities. This study thus proves that the multivalency may be highly relevant for enzyme inhibition for some but not all CAs from pathogenic organisms. On the other hand, some dendrimers investigated here showed a better inhibitory power compared to acetazolamide for enzymes from widespread pathogens, such as the η-CA from Plasmodium falciparum. Overall, the main conclusion is that this class of molecules may lead to important developments in the field of anti-infective CA inhibitors. Graphical abstract image
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Antitumour Benzothiazoles. 32. DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery ()
Publication date: Available online 3 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Erica L. Stone, Francesca Citossi, Rajinder Singh, Balvinder Kaur, Margaret Gaskell, Peter B. Farmer, Anne Monks, Curtis Hose, Malcolm F.G. Stevens, Chee-Onn Leong, Michael Stocks, Barrie Kellam, Maria Marlow, Tracey D. Bradshaw Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts‘ generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles‘ activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R2> 0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs’ activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines. Graphical abstract image
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The isolation and synthesis of a novel benzofuran compound from Tephrosia purpurea, and the synthesis of several related derivatives, which suppress histamine H1 receptor gene expression ()
Publication date: Available online 2 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Manik Chandra Shill, Asish Kumar Das, Tomohiro Itou, Sanmoy Karmakar, Pulok K. Mukherjee, Hiroyuki Mizuguchi, Yoshiki Kashiwada, Hiroyuki Fukui, Hisao Nemoto A novel naturally occurring compound with a benzofuran skeleton was isolated from a plant, Tephrosia purpurea collected in Bangladesh. The chemical synthesis of this compound confirmed its structure, and preliminary biological results showed its suppressive activity towards histamine H1 gene expression. One isomer and four derivatives were also synthesized, and their suppression activity was investigated. Although only small quantities of this compound can be isolated from its natural source, a 10 g scale synthesis was demonstrated by the newly developed method. Graphical abstract image
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Cleavage of DNA containing 5-fluorocytosine or 5-fluorouracil by type II restriction endonucleases ()
Publication date: Available online 2 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Agata Olszewska, Jitka Dadová, Michaela Mačková, Michal Hocek A systematic study of the cleavage of DNA sequences containing 5-fluorocytosine or 5-fluorouracil by type II restriction endonucleases (REs) was performed and the results compared with the same sequences containing natural pyrimidine bases, uracil or 5-methylcytosine. The results show that some REs recognize fluorine as a hydrogen on cytosine and cleave the corresponding sequences where the presence of m5dC leads to blocking of the cleavage. However, on uracil, the same REs recognize the F as a methyl surrogate and cleave the sequences which are not cleaved if uracil is incorporated instead of thymine. These results are interesting for understanding the recognition of DNA sequences by REs and for manipulation of the specific DNA cutting. Graphical abstract image
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Ultrasmall Dual-Modality Silica Nanoparticle Drug Conjugates: Design, Synthesis, and Characterization ()
Publication date: Available online 2 October 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Barney Yoo, Kai Ma, Li Zhang, Andrew Burns, Sonia Sequeira, Ingo Mellinghoff, Cameron Brennan, Ulrich Wiesner, Michelle S. Bradbury The physicochemical design and synthesis of effective cancer-directed and particle-based nanotherapeutic imaging agents remains a challenging task. Of critical importance is the ability to demonstrate maximum delivery, retention, and treatment efficacy for platforms designed to deposit their cargo at sites of disease without attendant dose-limiting toxicity. In this work, we describe dual-modality nanoparticle drug conjugates (NDCs) which utilize protease sensitive linkers to attached drug compounds and imaging labels to a clinically translated class of ultrasmall silica nanoparticle (C’ dots). We describe the synthesis and characterization of these linker-drug constructs. Linkers incorporating dipeptide enzyme substrates are attached to analogs of a prototypical epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), through a cleavable amide bond or para-aminobenzyloxycarbonyl (PABC) group. These constructs are conjugated onto C’ dots leading to the desired NDCs. These NDCs exhibit fast and predictable release kinetics in the presence of model proteases, and are stable in various biological media. Finally, in vitro assays show NDCs to be highly active in reducing phosphorylated EGFR levels in H1650 cells, a human tumor-derived cell line. The data suggests that NDCs exhibit desirable properties that warrant further development towards oncological therapy. Graphical abstract image
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Editorial board ()
Publication date: 1 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 19
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Graphical contents list ()
Publication date: 1 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 19
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Synthesis of five and six-membered heterocycles bearing an arylpiperazinylalkyl side chain as orally active antinociceptive agents ()
Publication date: 1 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 19 Author(s): Claudia Vergelli, Giovanna Ciciani, Agostino Cilibrizzi, Letizia Crocetti, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Gabriella Guerrini, Antonella Iacovone, Maria Paola Giovannoni A number of heterocycles bearing an arylpiperazinylalkyl side chain and structurally related to the previously described lead ET1 (4-amino-6-methyl-2-[3-(4-p-tolylpiperazin-1-yl)propyl]-5-vinylpyridazin-3(2H)-one) was synthesized and tested for their antinociceptive activity in Writhing Test. Many compounds, tested at doses of 20–40mg/kg po were able to reduce the number of abdominal constrictions by more than 47% and, in same cases, the potency is comparable to lead ET1 as for 5e, 24a, 27b and 27c. The analgesia induced by the active compounds was completely prevented by pretreatment with α 2-antagonist yohimbine, confirming the involvement of the adrenergic system in the mechanism of action for these new compounds. Graphical abstract image
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Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation ()
Publication date: 1 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 19 Author(s): Sari Ogasawara, Yuhei Kiyota, Yoshiro Chuman, Ayano Kowata, Fumihiko Yoshimura, Keiji Tanino, Rui Kamada, Kazuyasu Sakaguchi Protein phosphatase magnesium-dependent 1δ (PPM1D, Wip1) is a p53 inducible serine/threonine phosphatase. PPM1D is a promising target protein in cancer therapy since overexpression, missense mutations, truncating mutations, and gene amplification of PPM1D are reported in many tumors, including breast cancer and neuroblastoma. Herein, we report that a specific inhibitor, SL-176 that can be readily synthesized in 10 steps, significantly inhibits proliferation of a breast cancer cell line overexpressing PPM1D and induces G2/M arrest and apoptosis. SL-176 decreases PPM1D enzyme activity potently and specifically in vitro. These results demonstrate that SL-176 could be a useful lead compound in the development of effective anti-cancer agents. Graphical abstract image
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Synthesis and biological evaluation of novel 7-substituted 3-(4-phenoxyphenyl)thieno[3,2-c]pyridin-4-amines as potent Bruton’s tyrosine kinase (BTK) inhibitors ()
Publication date: 1 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 19 Author(s): Minhang Xin, Xinge Zhao, Wei Huang, Qiu Jin, Gang Wu, Yazhou Wang, Feng Tang, Hua Xiang A series of novel 7-substituted 3-(4-phenoxyphenyl)thieno[3,2-c]pyridin-4-amines as potent BTK inhibitors were designed, synthesized and evaluated. These thieno[3,2-c]pyridin-4-amine derivatives displayed variant inhibitory activities against BTK in vitro. Among these, 7-pyrazol-4-yl substituted 3-(4-phenoxyphenyl)thieno[3,2-c]pyridin-4-amine subseries showed high BTK inhibition and several compounds displayed superior BTK inhibitory activity. Comprehensive SAR was disclosed and compound 13b showed excellent potency (IC50 =11.8nM), outstanding hydrophilicity (A log P =3.53), and relatively good kinase selectivity, being a promising lead for further evaluation. Graphical abstract image
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Development of N-hydroxybenzamide derivatives with indole-containing cap group as histone deacetylases inhibitors ()
Publication date: 1 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 19 Author(s): Xiaoyang Li, Jingde Wu, Xiaoguang Li, Weiwei Mu, Xueliang Liu, Yiming Jin, Wenfang Xu, Yingjie Zhang Histone deacetylases inhibitors (HDACIs) have captured more and more attention in many diseases therapies, of which cancer is the most intractable. A novel series of N-hydroxybenzamide derivatives containing indole cap group was designed and synthesized. Most compounds exhibited excellent HDACs inhibitory activity, especially 8q–8v with low nanomolar IC50 values (1.5–13.0nM), which were much more potent than the positive control SAHA. The most potent compound 8r showed slightly higher growth inhibitory activity than SAHA in multiple tumor cell lines, even though, antiproliferative activity of 8r seemed inferior to its HDAC inhibition activity. Poor transcellular permeability obtained from the result of HDAC class I cellular assay could explain the inferior antiproliferative activity. In addition, 8r displayed similar HDAC IIa cellular activity to class I, which indicated 8r might be a potent pan-HDAC inhibitor. Graphical abstract image
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Synthesis of new opioid derivatives with a propellane skeleton and their pharmacologies: Part 5, novel pentacyclic propellane derivatives with a 6-amide side chain ()
Publication date: 1 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 19 Author(s): Ryo Nakajima, Naoshi Yamamoto, Shigeto Hirayama, Takashi Iwai, Akiyoshi Saitoh, Yasuyuki Nagumo, Hideaki Fujii, Hiroshi Nagase We designed and synthesized pentacyclic propellane derivatives with a 6-amide side chain to afford compounds with higher MOR/KOR ratio and lower sedative effects than nalfurafine. The obtained etheno-bridged derivative with a β-amide side chain, YNT-854, showed a higher MOR/KOR ratio than nalfurafine. YNT-854 also exhibited a higher dose ratio between the sedative effect and the analgesic effect than observed with nalfurafine, which may guide the future design of useful analgesics with a weaker sedative effect than nalfurafine. Graphical abstract image
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Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9 ()
Publication date: 1 October 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 19 Author(s): Louisa J. Phillipson, David H. Segal, Tracy L. Nero, Michael W. Parker, Soo San Wan, Melanie de Silva, Mark A. Guthridge, Andrew H. Wei, Christopher J. Burns The serine–threonine kinase CDK9 is a target of emerging interest for the development of anti-cancer drugs. There are multiple lines of evidence linking CDK9 activity to cancer, including the essential role this kinase plays in transcriptional regulation through phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. Indeed, inhibition of CDK9 has been shown to result in a reduction of short-lived proteins such as the pro-survival protein Mcl-1 in malignant cells leading to the induction of apoptosis. In this work we report our initial studies towards the discovery of selective CDK9 inhibitors, starting from the known multi-kinase inhibitor PIK-75 which possesses potent CDK9 activity. Our series is based on a pyrazolo[1,5-a]pyrimidine nucleus and, importantly, the resultant lead compound 18b is devoid of the structural liabilities present in PIK-75 and possesses greater selectivity. Graphical abstract image
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