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1.
Shi-Yong Fan Zhi-Bing Zheng Chun-Lai Mi Xin-Bo Zhou Hui Yan Ze-Hui Gong Song Li 《Bioorganic & medicinal chemistry》2009,17(2):621-624
Human rhinovirus (HRV) is the most important etiologic agent causing common colds. No effective anti-HRV agents are currently available. In this paper we describe the synthesis and the evaluation of novel chloropyridazine derivatives (compounds 5a–g) as potent human rhinovirus (HRV) capsid-binding inhibitors. Results showed that compound 5e and 5f exhibited effective anti-HRV activity against HRV-2 and HRV-14. In addition, compound 5e and 5f showed lower cytotoxicity than Pirodavir. 相似文献
2.
《Bioscience, biotechnology, and biochemistry》2013,77(3):450-454
Productivity and some properties of anti-Human Rotavirus (HRV) hen egg yolk antibody (IgY) were compared with those of anti-HRV rabbit serum antibody (IgG). The hens immunized with HRV (Wa strain, serotype 1 and Mo strain, serotype 3) were found to continuously to lay eggs without any change in the egg laying rate and the yolk of the eggs laid over a year showed a high level of neutralization titer against HRV. The production of anti-HRV IgY by a hen (one year) was at least 15 times (anti-Wa) and 120 times (anti-Mo) more effective than those by an immunized rabbit in the neutralization titer of the antibodies.The stability of anti-HRV IgY at temperature above 70°C and low pH 2–3 was less than that of anti-HRV rabbit IgG. The temperature corresponding to the maximum of denaturation endotherm (Tmax) of IgY was 73.9°C while that of rabbit IgG was 77.0°C in the analysis by differential scanning calorimetry. This discrepancy in heat and acidic pH stability found between the two antibodies as discussed with regard to their protein structures. 相似文献
3.
Bishyajit Kumar Biswas Yashwardhan R. Malpani Neul Ha Do-Hyun Kwon Jin Soo Shin Hae-Soo Kim Chonsaeng Kim Soo Bong Han Chong-Kyo Lee Young-Sik Jung 《Bioorganic & medicinal chemistry letters》2017,27(15):3582-3585
Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6–8.85 μM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8–2.6 μM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively. 相似文献
4.
2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder 总被引:5,自引:0,他引:5
Brown RN Cameron R Chalmers DK Hamilton S Luttick A Krippner GY McConnell DB Nearn R Stanislawski PC Tucker SP Watson KG 《Bioorganic & medicinal chemistry letters》2005,15(8):2051-2055
A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality. 相似文献
5.
Xiaofang Chen Xinxin Hu Yanbin Wu Yonghua Liu Cong Bian Tongying Nie Xuefu You Laixing Hu 《Bioorganic & medicinal chemistry letters》2017,27(4):841-844
A series of 4,4′-bis-[2-(6-N-substituted-amidino)indolyl] diphenyl ether have been synthesized and tested for their in vitro antibacterial activity including a range of Gram-positive and Gram-negative pathogens and cytotoxicity. Most of these compounds have mainly shown anti-Gram positive bacteria activities especially against drug resistant bacterial strains MRSA, MRSE and VRE. The anti-MRSA and anti-MRSE activities of compound 7a and 7j were more potent than that of the lead compound 2, levofloxacin and vancomycin. Interestingly, 7j had greatly improved anti negative bacterial activity, especially for the producing NDM-1 Klebsiella pneumonia strain and less toxic than that of the lead compound 2. 相似文献
6.
A series of 3-benzyl chromenes and chromans were synthesized and tested in vitro against human rhinovirus (HRV) 1B and 14, two representative serotypes for rhinovirus group B and A, respectively. All the new compounds, with the exception of 3-benzyl-2H-chromene (3a), showed a potent activity against HRV serotype 1B within micro or submicromolar range (IC50s from 0.11 to 6.62 μM). The low cytotoxicity of all the derivatives resulted in compounds with high therapeutic index (TI). On the contrary, HRV 14 infection was only weakly inhibited by the majority of these compounds. The 3-benzylidenechromans 2b and 2c showed the highest anti-HRV 1B activity (IC50 0.12 and 0.11 μM, respectively) coupled with remarkable TI (625.00 and 340.91, respectively). Mechanism of action studies on (Z)-3-(4-chlorobenzylidene)chroman (2b) suggest that the new compounds behave as capsid binders and interfere with very early stages of HRV 1B replication, similarly to related flavanoids. 相似文献
7.
《Animal : an international journal of animal bioscience》2020,14(2):379-387
Heart rate variability (HRV) is a proxy measure of autonomic function and can be used as an indicator of swine stress. While traditional linear measures are used to distinguish between stressed and unstressed treatments, inclusion of nonlinear HRV measures that evaluate data structure and organization shows promise for improving HRV interpretation. The objective of this study was to evaluate the inclusion of nonlinear HRV measures in response to an acute heat episode. Twenty 12- to 14-week-old growing pigs were individually housed for 7 days and acclimated to thermoneutral conditions (20.35°C ± 0.01°C; 67.6% ± 0.2% RH) before undergoing one of the two treatments: (1) thermoneutral control (TN; n = 10 pigs) or (2) acute heat stress (HS; n = 10 pigs; 32.6°C ± 0.1°C; 26.2% ± 0.1% RH). In Phase 1 of the experimental procedure (P1; 60 min), pigs underwent a baseline HRV measurement period in thermoneutral conditions before treatment [Phase 2; P2; 60 min once gastrointestinal temperature (Tg) reached 40.6°C], where HS pigs were exposed to heated conditions and TN pigs remained in thermoneutral conditions. After P2, all pigs were moved back to thermoneutral conditions (Phase 3; P3; 60 min). During each phase, Tg data were collected every 5 min and behavioural data were collected to evaluate the amount of time each pig spent in an active posture. Additionally, linear (time and frequency domain) and nonlinear [sample entropy (SampEn), de-trended fluctuation analysis, percentage recurrence, percentage determinism (%DET), mean diagonal line length in a recurrence plot] HRV measures were quantified. Heat stressed pigs exhibited greater Tg (P = 0.002) and spent less time in an active posture compared to TN pigs during P2 (P = 0.0003). Additionally, low frequency to high frequency ratio was greater in HS pigs during P3 compared to TN pigs (P = 0.02). SampEn was reduced in HS pigs during P2 (P = 0.01) and P3 (P = 0.03) compared to TN pigs. Heat stressed pigs exhibited greater %DET during P3 (P = 0.03) and tended to have greater %DET (P = 0.09) during P2 than TN pigs. No differences between treatments were detected for the remaining HRV measures. In conclusion, linear HRV measures were largely unchanged during P2. However, changes to SampEn and %DET suggest increased heat stress as a result of the acute heat episode. Future work should continue to evaluate the benefits of including nonlinear HRV measures in HRV analysis of swine heat stress. 相似文献
8.
Saila Ismail Clare A. Stokes Elizabeth C. Prestwich Rebecca L. Roberts Jatinder K. Juss Ian Sabroe Lisa C. Parker 《PloS one》2014,9(12)
Human rhinoviruses (HRV) are a major cause of exacerbations of airways disease. Aspects of cell signalling responses to HRV infection remain unclear, particularly with regard to signalling via PI3K, and the PI3K-dependent pathway, autophagy. We investigated the roles of PI3K and autophagy in the responses of epithelial cells to major and minor group HRV infection. The PI3K inhibitor 3-MA, commonly used to inhibit autophagy, markedly reduced HRV-induced cytokine induction. Further investigation of potential targets of 3-MA and comparison of results using this inhibitor to a panel of general and class I-selective PI3K inhibitors showed that several PI3Ks cooperatively regulate responses to HRV. Targeting by siRNA of the autophagy proteins Beclin-1, Atg7, LC3, alone or in combination, or targeting of the autophagy-specific class III PI3K had at most only modest effects on HRV-induced cell signalling as judged by induction of proinflammatory cytokine production. Our data indicate that PI3K and mTOR are involved in induction of proinflammatory cytokines after HRV infection, and that autophagy has little role in the cytokine response to HRV or control of HRV replication. 相似文献
9.
The presence of toxic substances in the Great Lakes (GL) continues to be a significant concern. Eleven of the most persistent and ubiquitous substances were identified as “critical Great Lakes pollutants” by the International Joint Commission (IJC). In some areas of the GL these toxic substances bioaccumulate in sediment and organisms, biomagnify in food webs, and persist at high levels. The Agency for Toxic Substances and Disease Registry (ATSDR) Great Lakes Human Health Effects Research Program (GLHHERP) characterizes contaminant exposures via GL fish consumption and investigates the potential for short- and long-term adverse health effects. The program has identified a set of eight indicators to determine risk. The GLHHERP findings indicate: (1) vulnerable populations are still being exposed to persistent toxic substances (2) body burden levels are two to four times higher than in the general U.S. population, (3) women and minorities are less knowledgeable about fish advisories than other segments of the population, (4) the presence of neurodevelopmental deficits in newborns, and cognitive deficits in children and adults, and (5) disturbances in reproductive parameters have been demonstrated in adults. The public health implications of these findings and the need for intervention strategies are discussed. 相似文献
10.
Saulo L. Capim Gabriela M. Gonçalves Gabriela C.M. dos Santos Bruno G. Marinho Mário L.A.A. Vasconcellos 《Bioorganic & medicinal chemistry》2013,21(19):6003-6010
We present in this article syntheses of six new hybrids compounds (4–9) that were efficiently prepared in one or two steps (70–84.6%) from our previous prototype (±)-cis-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl)methanol (3) and the NSAIAs: acetyl salicylic acid, indomethacin, ibuprofen, ketoprofen, naproxen and diclofenac. The acetic acid-induced writhing method is able to determine that all investigated new hybrids showed stronger antinociceptive properties (2- to 10-fold less ED50 values) than their precursors. The highest antinociceptive effect was observed for compound 9 showing more than 10-fold less ED50 values than diclofenac and ninefold less ED50 value than compound 2. All compounds presented greater activity than the control group in the tail-flick test confirming the central antinociceptive effect. New hybrids did not alter the motor performance of mice by rota-rod performance and open-field tests. Investigated compounds 4–9 were not toxic after oral administration (LD50 >2000 mg/kg). 相似文献
11.
Anne Décor Chantal Grand-Maître Oliver Hucke Jeff O’Meara Cyrille Kuhn Léa Constantineau -Forget Christian Brochu Eric Malenfant Mégan Bertrand-Laperle Josée Bordeleau Elise Ghiro Marc Pesant Gulrez Fazal Vida Gorys Michael Little Colette Boucher Sylvain Bordeleau Pascal Turcotte Annick Gauthier 《Bioorganic & medicinal chemistry letters》2013,23(13):3841-3847
We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication. 相似文献
12.
Bennett L. Ibey Jody C. Ullery Olga N. Pakhomova Caleb C. Roth Iurii Semenov Hope T. Beier Melissa Tarango Shu Xiao Karl H. Schoenbach Andrei G. Pakhomov 《Biochemical and biophysical research communications》2014
Multiple studies have shown that bipolar (BP) electric pulses in the microsecond range are more effective at permeabilizing cells while maintaining similar cell survival rates as compared to monopolar (MP) pulse equivalents. In this paper, we investigated whether the same advantage existed for BP nanosecond-pulsed electric fields (nsPEF) as compared to MP nsPEF. To study permeabilization effectiveness, MP or BP pulses were delivered to single Chinese hamster ovary (CHO) cells and the response of three dyes, Calcium Green-1, propidium iodide (PI), and FM1-43, was measured by confocal microscopy. Results show that BP pulses were less effective at increasing intracellular calcium concentration or PI uptake and cause less membrane reorganization (FM1-43) than MP pulses. Twenty-four hour survival was measured in three cell lines (Jurkat, U937, CHO) and over ten times more BP pulses were required to induce death as compared to MP pulses of similar magnitude and duration. Flow cytometry analysis of CHO cells after exposure (at 15 min) revealed that to achieve positive FITC-Annexin V and PI expression, ten times more BP pulses were required than MP pulses. Overall, unlike longer pulse exposures, BP nsPEF exposures proved far less effective at both membrane permeabilization and cell killing than MP nsPEF. 相似文献
13.
In the present study, novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl) quinolines (4a-l) were recognized and evaluated as G-Protein Coupled Receptor (GPCR) ligands through molecular evaluations. Thrombin mediates adhesion of mast cell, a type of cell abundantly found in connective tissue and releasing histamine and other substances during inflammatory and allergic reactions, through phosphoinositol 3-kinase pathway. With this background, as preliminary, 4a-l are resolute to be potential leads, designated from their effective phosphoinositol 3-kinase (PI3-Kinase) inhibition potentials, best-docked scores, comparative ligand efficiency, and significant structural attributes evaluated by ab initio simulations. Since thrombin is one of the main reason for various cancer invasion in association with PI3Kinase, a thrombolytic potential of the compounds also analyzed. The experimental in vitro studies confirmed the significant enhancement as PI3Kinase inhibitors and appreciable enhancement in MTT assay of breast and skin cancer cell lines. Significantly, acetophenone substituent in the quinoline scaffold could be coherent to note the significant binding affinity to all the evaluated drug targets. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2014,24(13):2839-2844
A general method for the synthesis of substituted (1E,4E,6E)-1,7-diphenylhepta-1,4,6-trien-3-ones, based on the aldol condensations of substituted 4-phenylbut-3-en-2-ones and substituted 3-phenylacrylaldehydes, was achieved. The natural trienones 4 and 5 have been synthesized by this method, together with the trienone analogues 9–20. These analogues were evaluated for their cytotoxic activity against human oral cancer KB cell line. The structure–activity relationship study has indicated that the analogues with the 1,4,6-trien-3-one function are more potent than the curcuminoid-type function. Analogues with meta-oxygen function on the aromatic rings are more potent than those in the ortho- and para-positions. Free phenolic hydroxy group is more potent than the corresponding methyl ether analogues. Among the potent trienones, compounds 11, 18 and 20 were more active than the anticancer drug ellipticine. All compounds were also evaluated against the non-cancerous Vero cells and it was found that compounds 11, 12 and 17 were much less toxic than curcumin (1); they showed high selectivity indices of 35.46, 33.46 and 31.68, respectively. These analogues are regarded as the potent trienones for anti-oral cancer study. 相似文献
15.
《Bioorganic & medicinal chemistry》2019,27(11):2261-2267
A series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained sulfonamido were designed and synthesized, and their anticancer effects in vitro was evaluated to develop some new PI3Kα inhibitors. Most of desired compounds exhibited the better antiproliferative activities against four cancer cell lines than that of LY294002. Out of them, compound 4o displayed the potent antiproliferative activity and high selectivity against the PI3Kα protein and it can induce apoptosis of HCT116 in a dose-dependent manner. Western blot assay indicated that compound 4o obviously down-regulated expression of p-Akt (S473). Molecular docking was performed to clarify the possible binding mode between compound 4o and PI3Kα. All these results indicated that compound 4o could be a potential inhibitor of PI3Kα. 相似文献
16.
Yifan Feng Weiming Duan Shu Fan Hao Zhang San-Qi Zhang Minhang Xin 《Bioorganic & medicinal chemistry》2019,27(19):115035
PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC50 values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC50 = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kβ and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kβ. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC50 values of 0.16 and 0.12 μM. Western blot analysis indicated that A8 could attenuate the AKTS473 phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles. 相似文献
17.
Qiyan Zhang Ruiyuan Cao An Liu Shihai Lei Yuexiang Li Jingjing Yang Song Li Junhai Xiao 《Bioorganic & medicinal chemistry letters》2017,27(17):4061-4065
The human rhinovirus (HRV) is the most significant cause of the common cold all over the world. The maturation and replication of this virus entirely depend on the activity of a virus-encoded 3C protease. Due to the high conservation among different serotypes and the minimal homology existing between 3C protease and known mammalian enzymes, 3C protease has been regarded as an attractive target for the treatment of HRV infections. In this study, we identified a novel (4R,5R)-N4-(2-((3-methoxyphenyl)amino)ethyl)-2,2-dimethyl-N5-(naphthalen-2-yl)-1,3-dioxolane-4,5-dicarboxamide (7a) to be a HRV 3C protease inhibitor via virtual screening. Further research has been focused on the design, synthesis and in vitro biological evaluation of 7a derivatives. The studies revealed that compound 7d has an IC50 value of 2.50 ± 0.7 µM against HRV 3C protease, and it thus could serve as a promising compound for the development of novel anti-rhinoviral medicines. 相似文献
18.
Maria Joao Matos Dolores Viña Carmen Picciau Francisco Orallo Lourdes Santana Eugenio Uriarte 《Bioorganic & medicinal chemistry letters》2009,19(17):5053-5055
A series of 6-methyl-3-phenylcoumarins 3-6 were synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. A comparative study between the three possible mono methoxy 3-phenyl derivatives and the p-hydroxy analogue is reported. The synthesis of these new resveratrol-coumarin hybrids was carried out by a Perkin reaction between the 5-methylsalicylaldehyde and the corresponding phenylacetic acids. The p-methoxy substituted compound 3 was hydrolyzed to 6 by a traditional reaction with hydriodic acid. The prepared compounds show high selectivity to the MAO-B isoenzyme, some of them with IC50 values in the low nanomolar range. Compound 4, with the methoxy group in meta position, is the most active of this series, with an IC50 against MAO-B of 0.80 nM, and is several times more potent and MAO-B selective than the R-(?)-deprenyl (reference compound). 相似文献
19.
Marin A Moreira Lima L Solano B Vicente E Pérez Silanes S Maurel S Sauvain M Aldana I Monge A Deharo E 《Experimental parasitology》2008,118(1):25-31
Derivatives of 3-trifluoromethyl-2-arylcarbonylquinoxaline 1,4-di-N-oxide (4b-g, 5b-g, 6a-g) were synthesized and evaluated for their capacity to inhibit the growth of chloroquine-resistant Plasmodium falciparum FCB1 strain in culture. Compound 7-chloro-2-(2-furylcarbonyl)-3-trifluoromethyl-1,4-quinoxaline di-N-oxide (5g) was the most active being almost 5 times more active than chloroquine. It was also 50 times more active against P. falciparum than toxic toward MCF7 cells. Structural characteristics for a quinoxaline to be active were defined: bioisosteric modification of phenyl group by 2-thienyl or 2-furyl subunits, R2 position must be free or occupied by a methyl group and R1 position must be free or occupied by Cl, CH3, OCH3 or CF3. 相似文献
20.
Structure–activity relationships of heteroaromatic esters as human rhinovirus 3C protease inhibitors
Isak Im Eui Seung Lee Soo Jeong Choi Ju-Yeon Lee Yong-Chul Kim 《Bioorganic & medicinal chemistry letters》2009,19(13):3632-3636
Human rhinovirus 3C protease (HRV 3Cpro) is known to be a promising target for development of therapeutic agents against the common cold because of the importance of the protease in viral replication as well as its expression in a large number of serotypes. To explore non-peptidic inhibitors of HRV 3Cpro, a series of novel heteroaromatic esters was synthesized and evaluated for inhibitory activity against HRV 3Cpro, to determine the structure–activity relationships. The most potent inhibitor, 7, with a 5-bromopyridinyl group, had an IC50 value of 80 nM. In addition, the binding mode of a novel analog, 19, with the 4-hydroxyquinolinone moiety, was explored by molecular docking, suggesting a new interaction in the S1 pocket. 相似文献