共查询到20条相似文献,搜索用时 20 毫秒
1.
Makonen Belema Van N. Nguyen Denis R. St. Laurent Omar D. Lopez Yuping Qiu Andrew C. Good Peter T. Nower Lourdes Valera Donald R. O’Boyle Jin-Hua Sun Mengping Liu Robert A. Fridell Julie A. Lemm Min Gao Jay O. Knipe Nicholas A. Meanwell Lawrence B. Snyder 《Bioorganic & medicinal chemistry letters》2013,23(15):4428-4435
The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the initial program lead, stilbene 2a. Structure–activity relationship (SAR) studies that uncovered an alternate phenylglycine-based cap series that exhibit further improvements in virology profile, along with some insights into the pharmacophoric elements associated with the GT-1a potency, are described. 相似文献
2.
Minoru Tanaka Xin Li Hidemasa Hikawa Takafumi Suzuki Katsuhiko Tsutsumi Masashi Sato Osamu Takikawa Hideharu Suzuki Yuusaku Yokoyama 《Bioorganic & medicinal chemistry》2013,21(5):1159-1165
Indoleamine 2,3-dioxygenase (IDO) plays a significant role in several disorders such as Alzheimer’s disease, age-related cataracts and tumors. A series of novel tryptoline derivatives were synthesized and evaluated for their inhibitory activity against IDO. Substituted tryptoline derivatives (11a, 11c, 11e, 12b and 12c) were demonstrated to be more potent than known inhibitor MTH-Trp. Suzuki–Miyaura cross-coupling reaction of 11a–d with phenylboronic acid proceeded in high yields. In most cases, C5 and C6 substitutions on the corresponding indole ring were well tolerated. The tryptoline derivative 11c is a promising chemical lead for the discovery of novel IDO inhibitors. 相似文献
3.
Preeti M. Chaudhary Sayalee R. Chavan Fazal Shirazi Meenakshi Razdan Prachi Nimkar Shailaja P. Maybhate Anjali P. Likhite Rajesh Gonnade Braja G. Hazara Mukund V. Deshpande Sunita R. Deshpande 《Bioorganic & medicinal chemistry》2009,17(6):2433-2440
Click reaction approach toward the synthesis of two sets of novel 1,2,3-triazolyl linked uridine derivatives 19a–19g and 21a–21g was achieved by Cu(I)-catalyzed 1,3-dipolar cycloaddition of 5′-azido-5′-deoxy-2′,3′-O-(1-methylethylidene)uridine (17) with propargylated ether of phenols 18a–18g and propargylated esters 20a–20g. Structure of one of the representative compound 19d was unambiguously confirmed by X-ray crystallography. Chitin synthase inhibition study of all these compounds 19a–19g and 21a–21g was carried out to develop antifungal strategy. Compounds 19d, 19e, 19f, and 21f were identified as potent chitin synthase inhibitors by comparing with nikkomycin. Compounds 19a, 19b, 19c, 19d, 21a, and 21b showed good antifungal activity against human and plant pathogens. Compounds 19a, 19b, 19f, 21c, 21f, and 21g were identified as lead chitin synthase inhibitors for further modifications by comparing results of inhibition of growth, % germ tube formation and chitin synthase activity. 相似文献
4.
《Bioorganic & medicinal chemistry letters》2014,24(14):3064-3068
Three tertiary benzenesulfonamide inhibitors 4a–c were radiolabeled with 18F and evaluated for imaging carbonic anhydrase IX (CA IX) expression with positron emission tomography. All three inhibitors exhibit <10 nM affinity for CA IX with no measurable affinity for CA II. Despite good affinity/selectivity to CA IX and excellent stability in plasma, uptake of [18F]4a–c in CA IX-expressing HT-29 tumours was low without significant contrast. [18F]4a,b were excreted rapidly, while [18F]4c exhibited significant in vivo defluorination leading to high bone uptake. Due to minimal uptake in HT-29 tumours compared to normal organs/tissues, 18F-labeled benzenesulfonamides [18F]4a–c are not suitable as CA IX imaging agents. 相似文献
5.
《Bioorganic & medicinal chemistry》2020,28(19):115679
The therapy of chronic hepatitis C virus infections has significantly improved with the development of direct-acting antivirals (DAAs), which contain NS3/4A protease, NS5A, and NS5B polymerase inhibitors. However, mutations in specific residues in these viral target genes are associated with resistance to the DAAs. Especially inhibitors of NS3/4A protease and NS5A, such as grazoprevir and velpatasvir, have a low barrier to resistant mutations. As a result, the mutations influence the virological outcomes after DAA treatment. CypA inhibitors, as host-targeted agents, act on host factors to inhibit HCV replication, exhibiting a high resistance barrier and pan-genotype activities against HCV. Therefore, they can be developed into alternative, more effective anti-HCV agents. However, CypA inhibitors are natural products and analogs. Based on previous studies, bisamide derivatives were designed and synthesized to develop a novel class of CypA inhibitors. Bisamide derivative 7c is a promising compound with potent anti-HCV activity at subtoxic concentrations. Surface plasmon resonance experiments revealed that 7c directly binds to CypA. All these studies indicated that the derivative 7c is a potent CypA inhibitor, which can be used as a host-targeted agent in combination with other antiviral agents for anti-HCV treatment. 相似文献
6.
Florence Popowycz Cédric Schneider Salvatore DeBonis Dimitrios A. Skoufias Frank Kozielski Carlos M. Galmarini Benoît Joseph 《Bioorganic & medicinal chemistry》2009,17(9):3471-3478
Pyrazolo[1,5-a]-1,3,5-triazine myoseverin derivatives 1a–c were prepared from 4-(N-methyl-N-phenylamino)-2-methylsulfanylpyrazolo[1,5-a]-1,3,5-triazine 2. Their cytotoxic activity, inhibition of tubulin polymerization, and cell cycle effects were evaluated. Compounds 1a and 1c are potent tubulin inhibitors and displayed specific antiproliferative activity in colorectal cancer cell lines at micromolar concentrations. 相似文献
7.
Paul V. Fish Mark D. Andrews M. Jonathan Fray Alan Stobie Florian Wakenhut Gavin A. Whitlock 《Bioorganic & medicinal chemistry letters》2009,19(10):2829-2834
Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5–9 are inhibitors of monoamine reuptake. Structure–activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l–a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series. 相似文献
8.
《Bioorganic & medicinal chemistry》2016,24(13):2882-2886
Four novel scaffolds consisting of total 24 compounds (1a–1o, 2a–2c, 3a–3c and 4a–4c) bearing aromatic sulfonamide and coumarin moieties connected through various linkers were synthesized in order to synergize the inhibition potential of both the moieties against four selected human carbonic anhydrase isoforms (hCA I, II, IX & XII). All compounds were found to be potent inhibitors of tumor associated hCA IX & XII while at the same time required large amounts to inhibit off-targeted housekeeping hCA I & II. Selectivity was more pronounced against hCA II over I, and hCA XII over IX. Results were compared with antitumor drug acetazolamide. One derivative 2b of series 2 was found to be a better selective inhibitor of hCA IX and XII. 相似文献
9.
Sheng-Jiao Yan Han Zheng Chao Huang Yu-Yun Yan Jun Lin 《Bioorganic & medicinal chemistry letters》2010,20(15):4432-4435
Novel polyhalo 2,4-diaminoquinazolines 3a–3d were prepared by reacting polyhaloisophthalonitriles with guanidine carbonate under solvent-free conditions and in the absence of a catalyst with good yields (74–95%). A series of highly functionalized 2,4-diaminoquinazolines 4–5 were then synthesized based on 3a–3c. The anticancer activities of compounds 3–5 were evaluated in vitro against human cell lines such as Skov-3, HL-60, A431, A549, and HepG-2. Some of the compounds showed excellent cytotoxic activity and 5a was found to be the most potent derivative, with an IC50 value lower than 2.5 μg/mL against the five tumor cell lines, making it more active than cisplatin. Representative compounds were also preliminarily evaluated as HIV-1 inhibitors in vitro, and 3c showed the most potent anti-HIV-1 activity with EC50 values of 0.6 and 1.6 μg/mL, and TI values of >59.6 and 66.6, respectively. 相似文献
10.
Y. Liu C. Esteva-Font C. Yao P.W. Phuan A.S. Verkman M.O. Anderson 《Bioorganic & medicinal chemistry letters》2013,23(11):3338-3341
The kidney urea transport protein UT-B is an attractive target for the development of small-molecule inhibitors with a novel diuretic (‘urearetic’) action. Previously, two compounds in the triazolothienopyrimidine scaffold (1a and 1c) were reported as UT-B inhibitors. Compound 1c incorporates a 1,1-difluoroethyl group, which affords improved microsomal stability when compared to the corresponding ethyl-substituted compound 1a. Here, a small focused library (4a–4f) was developed around lead inhibitor 1c to investigate the requirement of an amidine-linked thiophene in the inhibitor scaffold. Two compounds (4a and 4b) with nanomolar inhibitory potency (IC50 ≈ 40 nM) were synthesized. Computational docking of lead structure 1c and 4a–4f into a homology model of the UT-B cytoplasmic surface suggested binding with the core heterocycle buried deep into the hydrophobic pore region of the protein. 相似文献
11.
Xianfeng Li Yong-Kang Zhang Yang Liu Charles Z. Ding Yasheen Zhou Qun Li Jacob J. Plattner Stephen J. Baker Suoming Zhang Wieslaw M. Kazmierski Lois L. Wright Gary K. Smith Richard M. Grimes Renae M. Crosby Katrina L. Creech Luz H. Carballo Martin J. Slater Richard L. Jarvest Pia Thommes Julia A. Hubbard Jon Wright 《Bioorganic & medicinal chemistry letters》2010,20(19):5695-5700
A novel series of P2–P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action. 相似文献
12.
Mattia Mori Davide Deodato Mohan Kasula Davide M. Ferraris Adriana Sanna Alessandro De Logu Menico Rizzi Maurizio Botta 《Bioorganic & medicinal chemistry letters》2018,28(4):637-641
Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a–d, 5f–n, and 7a–b) exhibited Zmp1 inhibition with IC50 values in the range 1.3–43.9?µM, whereas only aminothiazoles 12b and 12d proved active with IC50 values of 41.3 and 35.7?µM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10?µg/ml. This work represents a step forward in targeting Zmp1 by small molecules. 相似文献
13.
Wenchao Qu Karl Ploessl Hong Truong Mei-Ping Kung Hank F. Kung 《Bioorganic & medicinal chemistry letters》2009,19(13):3382-3385
A facile synthesis of six 4-iodophenyl tagged sphingosine (SP) derivatives bearing alkyl chain lengths from 6 to 13 is described. The key steps for the assembly of these molecules, 5a–f, are Suzuki–Miyaura cross-coupling and cross-metathesis reactions. The feasibility of radiolabeling was demonstrated by synthesizing two 125I labeled compounds, [125I]5c and [125I]5e. In vitro enzyme assays indicated that the molecules, 5c–e, are potent inhibitors. Thus, they deserve further evaluation as potential radioactive probes for tumor imaging. 相似文献
14.
Yassir Younis Roger Hunter Clare I. Muhanji Ian Hale Rajinder Singh Christopher M. Bailey Todd J. Sullivan Karen S. Anderson 《Bioorganic & medicinal chemistry》2010,18(13):4661-4673
Four double-drug HIV NRTI/NNRTI inhibitors 15a–d of the type [d4U]-spacer-[HI-236] in which the spacer is varied as 1-butynyl (15a), propargyl-1-PEG (15b), propargyl-2-PEG (15c) and propargyl-4-PEG (15d) have been synthesized and biologically evaluated as RT inhibitors against HIV-1. The key step in their synthesis involved a Sonogashira coupling of 5-iodo d4U’s benzoate with an alkynylated tethered HI-236 precursor followed by introduction of the HI-236 thiourea functionality. Biological evaluation in both cell-culture (MT-2 cells) as well as using an in vitro RT assay revealed 15a–c to be all more active than d4T. However, overall the results indicate the derivatives are acting as chain-extended NNRTIs in which for 15b–d the nucleoside component is likely situated outside of the pocket but with no evidence for any synergistic double binding between the NRTI and NNRTI sites. This is attributed, in part, to the lack of phosphorylation of the nucleoside component of the double-drug as a result of kinase recognition failure, which is not improved upon with the phosphoramidate of 15d incorporating a 4-PEG spacer. 相似文献
15.
Masato Oikawa Minoru Ikoma Makoto Sasaki Martin B. Gill Geoffrey T. Swanson Keiko Shimamoto Ryuichi Sakai 《Bioorganic & medicinal chemistry》2010,18(11):3795-3804
Here, we report our second-generation synthesis of 12 artificial glutamate analogs, starting from heterotricycle intermediates 3a–3d, readily prepared in three steps including tandem Ugi/Diels-Alder reactions. The new synthesis employs imidate intermediates for the deoxygenation of pyrrolidones (10a–10d to 6a–6d), and each advanced intermediate 6a–6d was diversified into three glutamate analogs (1a–1d, 5a–5d, 7a–7d) in 1–2 steps.In vitro electrophysiological assays revealed that the new piperidine-type analog 7c alters neuronal function with lower potency than 1a. Conversely, intracranial injection of 7c into mice produced a greater degree of hypoactivity than 1a. Our recent investigation has revealed that this series of compounds antagonizes AMPA-type glutamate receptor-mediated currents in a subtype selective manner. The more efficient syntheses of this novel set of neuroactive molecules will facilitate their pharmacological characterization. 相似文献
16.
Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly synthesized Schiff’s bases 4–18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a–8a with inhibition constants (KI) in the range 93.5–428.1 nM (AAZ and SLC-0111: KI, 250.0 and 5080.0 nM, respectively). Compounds 4a–8a proved to be effective hCA II inhibitors, with KI ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: KI, 12.0 and 960.0 nM, respectively). Compounds 4a–8a effectively inhibited hCA IX, with KI in the range 8.5–24.9 nM; these values are superior or equivalent to that of AAZ and SLC-0111 (KI, 25.0 and 45.0 nM, respectively). Compounds 4a–8a displayed effective hCA XII inhibitory activity with KI values ranging from 8.6 to 43.2 nM (AAZ and SLC-0111: KI, 5.7 and 4.5 nM, respectively). However, compounds 9b–13b and 14c–18c were found to be micromolar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected. 相似文献
17.
Yongqiang Li Pengxiang Zhang Qiaoqiao Ma Haibin Song Yuxiu Liu Qingmin Wang 《Bioorganic & medicinal chemistry letters》2012,22(22):6858-6861
Two series of 2-phenylpyrroles: 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2-carboxamide (5a–5d) and 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2-carboxylate (6a–6c) were synthesized by a novel trifluoromethyl transformation. The result of insecticidal bioassays indicated that 6a–6c had moderate larvicidal activity against oriental armyworm and 6b also had good acaricidal activity, so 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2-carboxylate derivatives were expected to become lead compounds for new pesticides. 相似文献
18.
Sham M. Sondhi Reshma Rani Partha Roy S.K. Agrawal A.K. Saxena 《Bioorganic & medicinal chemistry letters》2009,19(5):1534-1538
A number of N-substituted cyclic imides 3a–e, 5a–e, 7a–d, and 9a–e have been synthesized in very high yields, by condensation of various diacids 2, 4, 6, and 8 with different amines under microwave irradiation. These compounds were screened for anticancer and anti-inflammatory activities, and compounds 3c, 3e, 5c, 9c, and 9d exhibited anticancer activity against colon (COLO 205) cancer better than 5-fluorouracil and mitomycin-C, and compound 9b exhibited anti-inflammatory activity better than standard drug phenyl butazone. 相似文献
19.
Sham M. Sondhi Reshma Rani Jaiveer Singh Partha Roy S.K. Agrawal A.K. Saxena 《Bioorganic & medicinal chemistry letters》2010,20(7):2306-2310
Heterocyclic benzimidazole derivatives 3a–h, 5a–c and 7a–d have been synthesized by condensation of succinic acid (1) homophthalic acid (4) and 2,3-pyrazinedicarboxlic acid (6) with various substituted diamines under microwave irradiation in good yields. Structures assigned to 3a–h, 5a–c and 7a–d are fully supported by spectral data. All these compounds were screened for anti-inflammatory and anticancer activities. At a dose of 50 mg/kg po compounds 3b (39.4%) and 3c (39.2%) exhibited anti-inflammatory activity, comparable to standard ibuprofen which showed 39% activity at 50 mg/kg po and compound 7c exhibit good anticancer activity against ovary (IGR-OV-1), breast (MCF-7) and CNS(SF-295) human cancer cell lines. 相似文献
20.
《Bioorganic & medicinal chemistry letters》2014,24(13):2845-2850
Four series of cassiarin A derivatives with alkanoyl (3a–3d), aroyl (4a–4d), hydroxy/amino-substituted ethylene glycol (5a–5c) and selenium-containing (6a) side chains were synthesized. Their antitumor activities were evaluated against BT474, CHAGO, HepG2, KATO-III, SW620 and CaSki cancer cell lines. Preliminary results demonstrated that 5b had moderate activities against HepG2 and KATO-III cell lines, while 5c showed moderate to high cytotoxicity against most tested cell lines. In addition, 6a exhibited moderate cytotoxicity against cervical cells, CaSki. DNA-binding and ethidium bromide displacement experiments suggested that 5c and 5b binds to DNA via an intercalative mode, whereas 6a did not. However, the selenium-containing cassiarin A derivative 6a inhibited topoisomerase II with more than 95% inhibition at the concentration of 50 μM. These cassiarin A derivatives showed lower toxicity to normal cells, WI-38 than amonafide therefore they are potential lead compounds to be further developed as new anticancer agents. 相似文献