- Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists
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Relaxin family peptide receptors (RXFPs) are the potential therapeutic targets for neurological, cardiovascular, and metabolic indications. Among them, RXFP3 and RXFP4 (formerly known as GPR100 or GPCR142) are homologous class A G protein-coupled receptors with short N-terminal domain. Ligands of RXFP3 or RXFP4 are only limited to endogenous peptides and their analogues, and no natural product or synthetic agonists have been reported to date except for a scaffold of indole-containing derivatives as dual agonists of RXFP3 and RXFP4. In this study, a new scaffold of tricyclic derivatives represented by compound 7a was disclosed as a selective RXFP4 agonist after a high-throughput screening campaign against a diverse library of 52,000 synthetic and natural compounds. Two rounds of structural modification around this scaffold were performed focusing on three parts: 2-chlorophenyl group, 4-hydroxylphenyl group and its skeleton including cyclohexane-1,3-dione and 1,2,4-triazole group. Compound 14b with a new skeleton of 7,9-dihydro-4H-thiopyrano[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-8(5H)-one was thus obtained. The enantiomers of 7a and 14b were also resolved with their 9-(S)-conformer favoring RXFP4 agonism. Compared with 7a, compound 9-(S)-14b exhibited 2.3-fold higher efficacy and better selectivity for RXFP4 (selective ratio of RXFP4 vs. RXFP3 for 9-(S)-14b and 7a were 26.9 and 13.9, respectively).
- Lin, Lin,Lin, Guangyao,Zhou, Qingtong,Bathgate, Ross A.D.,Gong, Grace Qun,Yang, Dehua,Liu, Qing,Wang, Ming-Wei
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supporting information
(2021/03/16)
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- Design, Synthesis, and Study of the Insecticidal Activity of Novel Steroidal 1,3,4-Oxadiazoles
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A series of novel steroidal derivatives with a substituted 1,3,4-oxadiazole structure was designed and synthesized, and the target compounds were evaluated for their insecticidal activity against five aphid species. Most of the tested compounds exhibited potent insecticidal activity against Eriosoma lanigerum (Hausmann), Myzus persicae, and Aphis citricola. Compounds 20g and 24g displayed the highest activity against E. lanigerum, showing LC50 values of 27.6 and 30.4 μg/mL, respectively. Ultrastructural changes in the midgut cells of E. lanigerum were detected by transmission electron microscopy, indicating that these steroidal oxazole derivatives might exert their insecticidal activity by destroying the mitochondria and nuclear membranes in insect midgut cells. Furthermore, a field trial showed that compound 20g exhibited effects similar to those of the positive controls chlorpyrifos and thiamethoxam against E. lanigerum, reaching a control rate of 89.5% at a dose of 200 μg/mL after 21 days. We also investigated the hydrolysis and metabolism of the target compounds in E. lanigerum by assaying the activities of three insecticide-detoxifying enzymes. Compound 20g at 50 μg/mL exhibited inhibitory action on carboxylesterase similar to the known inhibitor triphenyl phosphate. The above results demonstrate the potential of these steroidal oxazole derivatives to be developed as novel pesticides.
- Bai, Hangyu,Jiang, Weiqi,Li, Qi,Li, Tian,Ma, Shichuang,Shi, Baojun,Wu, Wenjun
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p. 11572 - 11581
(2021/10/12)
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- Development of Novel (+)-Nootkatone Thioethers Containing 1,3,4-Oxadiazole/Thiadiazole Moieties as Insecticide Candidates against Three Species of Insect Pests
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To improve the insecticidal activity of (+)-nootkatone, a series of 42 (+)-nootkatone thioethers containing 1,3,4-oxadiazole/thiadiazole moieties were prepared to evaluate their insecticidal activities against Mythimna separata Walker, Myzus persicae Sulzer, and Plutella xylostella Linnaeus. Insecticidal evaluation revealed that most of the title derivatives exhibited more potent insecticidal activities than the precursor (+)-nootkatone after the introduction of 1,3,4-oxadiazole/thiadiazole on (+)-nootkatone. Among all of the (+)-nootkatone derivatives, compound 8c (1 mg/mL) exhibited the best growth inhibitory (GI) activity against M. separata with a final corrected mortality rate (CMR) of 71.4%, which was 1.54- and 1.43-fold that of (+)-nootkatone and toosendanin, respectively; 8c also displayed the most potent aphicidal activity against M. persicae with an LD50 value of 0.030 μg/larvae, which was closer to that of the commercial insecticidal etoxazole (0.026 μg/larvae); and 8s showed the best larvicidal activity against P. xylostella with an LC50 value of 0.27 mg/mL, which was 3.37-fold that of toosendanin and slightly higher than that of etoxazole (0.28 mg/mL). Furthermore, the control efficacy of 8s against P. xylostella in the pot experiments under greenhouse conditions was better than that of etoxazole. Structure-activity relationships (SARs) revealed that in most cases, the introduction of 1,3,4-oxadiazole/thiadiazole containing halophenyl groups at the C-13 position of (+)-nootkatone could obtain more active derivatives against M. separata, M. persicae, and P. xylostella than those containing other groups. In addition, toxicity assays indicated that these (+)-nootkatone derivatives had good selectivity to insects over nontarget organisms (normal mammalian NRK-52E cells and C. idella and N. denticulata fries) with relatively low toxicity. Therefore, the above results indicate that these (+)-nootkatone derivatives could be further explored as new lead compounds for the development of potential eco-friendly pesticides.
- Cheng, Wanqing,Fan, Jiangping,Guo, Yong,Han, Meiyue,Ma, Nannan,Yan, Xiaoting,Yang, Ruige
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p. 15544 - 15553
(2022/01/03)
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- Synthesis and biological evaluation of honokiol derivatives bearing 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3h)-ones as potential viral entry inhibitors against sars-cov-2
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The 2019 coronavirus disease (COVID-19) caused by SARS-CoV-2 virus infection has posed a serious danger to global health and the economy. However, SARS-CoV-2 medications that are specific and effective are still being developed. Honokiol is a bioactive component from Magnoliae officinalis Cortex with damp-drying effect. To develop new potent antiviral molecules, a series of novel honokiol analogues were synthesized by introducing various 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3H)-ones to its molecule. In a SARS-CoV-2 pseudovirus model, all honokiol derivatives were examined for their antiviral entry activities. As a result, 6a and 6p demonstrated antiviral entry effect with IC50 values of 29.23 and 9.82 μM, respectively. However, the parental honokiol had a very weak antiviral activity with an IC50 value more than 50 μM. A biolayer interfero-metry (BLI) binding assay and molecular docking study revealed that 6p binds to human ACE2 protein with higher binding affinity and lower binding energy than the parental honokiol. A competitive ELISA assay confirmed the inhibitory effect of 6p on SARS-CoV-2 spike RBD’s binding with ACE2. Importantly, 6a and 6p (TC50 > 100 μM) also had higher biological safety for host cells than honokiol (TC50 of 48.23 μM). This research may contribute to the discovery of potential viral entrance inhibitors for the SARS-CoV-2 virus, although 6p’s antiviral efficacy needs to be validated on SARS-CoV-2 viral strains in a biosafety level 3 facility.
- Bai, Li-Ping,Guo, Yong,Jiang, Zhi-Hong,Liu, Jia-Zheng,Meng, Jie-Ru,Xu, Ting,Zheng, Zhi-Yuan
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- Iron-catalyzed oxidative amidation of acylhydrazines with amines
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A new approach for amide bond formation via a mild and efficient Iron-catalyzed cross-coupling reaction of acylhydrazines and amines using TBHP as oxidant is described. This protocol is compatible with a wide range of amines and acylhydrazines. In addition, the synthetic application of the reaction is presented.
- Wang, Yi-Jie,Zhang, Guo-Yu,Shoberu, Adedamola,Zou, Jian-Ping
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supporting information
(2021/08/18)
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- Antibacterial and Antiviral Activities of 1,3,4-Oxadiazole Thioether 4H-Chromen-4-one Derivatives
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Various 1,3,4-oxadiazole thioether 4H-chromen-4-one derivatives were conceived. The title compounds demonstrated striking inhibitory effects againstXac,Psa, andXoo. EC50data exhibited that A8 (19.7 μg/mL) had better antibacterial activity againstXoothan myricetin, BT, and TC. Simultaneously, the mechanism of action of A8 had been verified by SEM. The results of anti-tobacco mosaic virus indicated that A9 had the bestin vivoantiviral effect compared with ningnanmycin. From the data of MST, it could be seen that A9 (0.003 ± 0.001 μmol/L) exhibited a strong binding capacity, which was far superior to ningnanmycin (2.726 ± 1.301 μmol/L). This study shows that the 1,3,4-oxadiazole thioether 4H-chromen-4-one derivatives may become agricultural drugs with great potential.
- Cao, Xiao,Liu, Fang,Liu, Liwei,Liu, Tingting,Peng, Feng,Wang, Qifan,Xie, Chengwei,Xue, Wei,Yang, Jinsong
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p. 11085 - 11094
(2021/10/01)
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- Development of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction
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Defective in cullin neddylation 1(DCN1) is a co-E3 ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC50 value of 0.95 μM for DCN1-UBC12 interaction) was discovered. Further structure-based optimization leads to the development of SK-464 (IC50 value of 26 nM). We found that SK-464 not only directly bound to DCN1 in vitro, but also engaged cellular DCN1, suppressed the neddylation of cullin3, and hindered the migration and invasion of two DCN1-overexpressed squamous carcinoma cell lines (KYSE70 and H2170). These findings indicate that SK-464 may be a novel lead compound targeting DCN1-UBC12 interaction.
- Zhou, Wenjuan,Xu, Chenhao,Dong, Guanjun,Qiao, Hui,Yang, Jing,Liu, Hongmin,Ding, Lina,Sun, Kai,Zhao, Wen
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- Design, synthesis, and biological evaluation of phenyloxadiazole derivatives as potential antifungal agents against phytopathogenic fungi
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Abstract: A novel series of picarbutrazox-inspired oxadiazole hybrids was synthesized and the derivatives’ biological activity against phytopathogenic fungi was investigated. The molecules were designed by retaining the active fragment of tetrazolyl phenyloxime ether of lead compound picarbutrazox, while introducing the potentially active oxadiazole-derived fragment. Bioassay results revealed that some of the title compounds showed potent in vivo antifungal activities to control cucumber downy mildew. Therefore, this novel oxadiazole phenyloxadiazole derivative can be used as a potential antifungal agent to control cucumber downy mildew and other phytopathogenic fungi for crop protection. Graphic abstract: [Figure not available: see fulltext.].
- Li, Yitao,Yao, Wenqiang,Lin, Jian,Gao, Guoliang,Huang, Chang,Wu, Yang
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p. 121 - 135
(2021/01/05)
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- Synthesis, fungicidal activity, and 3D-QSAR of tetrazole derivatives containing phenyloxadiazole moieties
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In an effort to discover new agents with good fungicidal activities against CDM (cucumber downy mildew), a series of tetrazole derivatives containing phenyloxadiazole moieties were designed and synthesized. The EC50 values for fungicidal activities against CDM were determined. Bioassay results indicated that most synthesized compounds exhibited potential in vivo fungicidal activity against CDM. A CoMFA (comparative molecular field analysis) model based on the bioactivity was developed to identify some primary structural quality for the efficiency. The values of q2 and r2 for the established model were 0.791 and 0.982 respectively, which reliability and predict abilities were verified. Three analogues (q3, q4, q5) were designed and synthesized based on the model. All these compounds exhibited significant fungicidal activity on CDM with the EC50 of 1.43, 1.52, 1.77 mg·L?1. This work could provide a useful instruction for the further structure optimization.
- Li, Yi-Tao,Yao, Wen-Qiang,Zhou, Si,Xu, Jun-Xing,Lu, Hui,Lin, Jian,Hu, Xiao-Yun,Zhang, Shao-Kai
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supporting information
(2021/01/11)
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- Oxazole ring-containing honokiol thioether derivative and preparation method and application thereof
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The invention discloses an oxazole ring-containing honokiol thioether derivative, a preparation method thereof and application of the oxazole ring-containing honokiol thioether derivative as an alpha-glucosidase inhibitor, the chemical structure of the oxazole ring-containing honokiol thioether derivative is shown as a general formula (I), and R is selected from non-substituted or substituted phenyl. Compared with the prior art, the invention provides the novel honokiol thioether derivative containing the oxazole ring, and the honokiol thioether derivative containing the oxazole ring has good inhibitory activity on alpha-glucosidase, provides more possibilities for treating diabetes, and is expected to be used for preparing novel candidate drug molecules for treating diabetes. In addition, the preparation process is simple, the cost is low, and the yield is high.
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Paragraph 0042; 0045-0046
(2021/08/11)
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- Preclinical evaluation of 1,2,4-triazole-based compounds targeting voltage-gated sodium channels (VGSCs) as promising anticonvulsant drug candidates
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Epilepsy is a chronic neurological disorder affecting nearly 65–70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs (AEDs), still about 30–40% of patients cannot achieve a satisfactory seizure control. In our current research, we aimed at using the combined results of radioligand binding experiments, PAMPA-BBB assay and animal experimentations in order to design a group of compounds that exhibit broad spectrum of anticonvulsant activity. The synthesized 4-alkyl-5-substituted-1,2,4-triazole-3-thione derivatives were primarily screened in the maximal electroshock-induced seizure (MES) test in mice. Next, the most promising compounds (17, 22) were investigated in 6 Hz (32 mA) psychomotor seizure model. Protective effect of compound 22 was almost similar to that of levetiracetam. Moreover, these compounds did not induce genotoxic and hemolytic changes in human cells as well as they were characterized by low cellular toxicity. Taking into account the structural requirements for good anticonvulsant activity of 4-alkyl-5-aryl-1,2,4-triazole-3-thiones, it is visible that small electron-withdrawing substituents attached to phenyl ring have beneficial effects both on affinity towards VGSCs and protective activity in the animal models of epilepsy.
- Kaproń, Barbara,?uszczki, Jarogniew J.,Siwek, Agata,Karcz, Tadeusz,Nowak, Gabriel,Zagaja, Miros?aw,Andres-Mach, Marta,Stasi?owicz, Anna,Cielecka-Piontek, Judyta,Kocki, Janusz,Plech, Tomasz
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- Discovery of [1,2,4]triazole derivatives as new metallo-β-lactamase inhibitors
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The emergence and spread of metallo-β-lactamase (MBL)-mediated resistance to β-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse β-lactam resistance has not been established yet. We here report a series of [1,2,4]triazole derivatives and analogs, which displayed inhibition to the clinically relevant subclass B1 (Verona integron-encoded MBL-2) VIM-2. 3-(4-Bromophenyl)-6,7-dihydro-5H-[1,2,4]triazolo [3,4-b][1,3]thiazine (5l) manifested the most potent inhibition with an IC50 (half-maximal inhibitory concentration) value of 38.36 μM. Investigations of 5l against other B1 MBLs and the serine β-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that 5l bound to the VIM-2 active site via the triazole involving zinc coordination and made hydrophobic interactions with the residues Phe61 and Tyr67 on the flexible L1 loop. This work provided new triazole-based MBL inhibitors and may aid efforts to develop new types of inhibitors combating MBL-mediated resistance.
- Yuan, Chen,Yan, Jie,Song, Chen,Yang, Fan,Li, Chao,Wang, Cheng,Su, Huiling,Chen, Wei,Wang, Lijiao,Wang, Zhouyu,Qian, Shan,Yang, Lingling
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- Synthesis, biological evaluation of benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety as potential anti-oxidant and anti-inflammatory agents
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Twenty benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety were synthesized and evaluated for their anti-oxidant and anti-inflammatory activities. Among these compounds, 8h and 8l were appeared to have high radical scavenging efficacies as 0.05 ± 0.02 and 0.07 ± 0.03 mmol/L of IC50 values in ABTS+[rad] bioassay, respectively. In anti-inflammatory tests, compound 8h displayed good activity with 57.35% inhibition after intraperitoneal administration, which was more potent than the reference drug (indomethacin). Molecular modeling studies were performed to investigate the binding mode of the representative compound 8h into COX-2 enzyme. In vitro enzyme study implied that compound 8h exerted its anti-inflammatory activity through COX-2 inhibition.
- Bai, Xue-Qian,Cui, Ming-Yue,Li, Chun-Shi,Liang, Cheng-Wu,Song, Ze-Wen,Wang, Hui-Yan,Zhang, Tian-Yi,Zheng, Xian-Jing
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- Design and synthesis of new norfloxacin-1,3,4-oxadiazole hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)
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Toward the search of new antibacterial agents to control methicillin-resistant Staphylococcus aureus (MRSA), a class of new norfloxacin-1,3,4-oxadiazole hybrids were designed and synthesized. Antibacterial activities against drug-sensitive bacteria S. aureus and clinical drug resistant isolates of MRSA were evaluated. Compound 5k exhibited excellent antibacterial activities against S. aureus (MIC: 2 μg/mL) and MRSA1–3 (MIC: 0.25–1 μg/mL). The time-kill kinetics demonstrated that compound 5k had an advantage over commonly used antibiotics vancomycin in killing S. aureus and MRSA. Moreover, compound 5k could inhibit the bacteria and destroy their membranes in a short time, and showed very low cytotoxicity to NRK-52E cells. Some interesting structure-activity relationships (SARs) were also discussed. These results indicated that these norfloxacin-1,3,4-oxadiazole hybrids could be further developed into new antibacterial agents against MRSA.
- Guo, Yong,Xu, Ting,Bao, Chongnan,Liu, Zhiyan,Fan, Jiangping,Yang, Ruige,Qin, Shangshang
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- Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR-2 inhibitors
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Novel series of benzoxazoles 4a-f-16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT-116, and MCF-7 cells. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5e was found to be the most potent against HepG2, HCT-116, and MCF-7 with IC50 = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 μM, respectively. Compounds 5c, 5f, 6b, 5d, and 6c showed the highest anticancer activities against HepG2 cells with IC50 of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 μM, respectively; HCT-116 cells with IC50 of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 μM, respectively; and MCF-7 cells with IC50 of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 μM, respectively, compared with sorafenib as a reference drug with IC50 of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 μM, respectively. The most active compounds 5c-f and 6b,c were further evaluated for their vascular endothelial growth factor receptor-2 (VEGFR-2) inhibition. Compounds 5e and 5c potently inhibited VEGFR-2 at lower IC50 values of 0.07 ± 0.01 and 0.08 ± 0.01 μM, respectively, compared with sorafenib (IC50 = 0.1 ± 0.02 μM). Compound 5f potently inhibited VEGFR-2 at low IC50 value (0.10 ± 0.02 μM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR-2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.
- El-Helby, Abdel-Ghany A.,Sakr, Helmy,Eissa, Ibrahim H.,Abulkhair, Hamada,Al-Karmalawy, Ahmed A.,El-Adl, Khaled
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- Development of novel liver?X?receptor modulators based on a 1,2,4-triazole scaffold
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Liver X Receptor (LXR) agonists have been reported as a potential treatment for atherosclerosis, Alzheimer's disease and hepatitis C virus (HCV) infection. We have designed and synthesized a series of potent compounds based on a 1,2,4-triazole scaffold as novel LXR modulators. In cell-based cotransfection assays these compounds generally functioned as LXR agonists and we observed compounds with selectivity towards LXRα (7-fold) and LXRβ (7-fold) in terms of potency. Assessment of the effects of selected compounds on LXR target gene expression in HepG2 cells revealed that compounds 6a-b and 8a-b behaved as inverse agonists on FASN expression even though they were agonists in the LXRα and LXRβ cotransfection assays. Interestingly, these compounds had no effect on the expression of SREBP-1c confirming a unique LXR modulator pharmacology. Molecular docking studies and evaluation of ADME properties in-silico show that active compounds possess favorable binding modes and ADME profiles. Thus, these compounds may be useful for in vivo characterization of LXR modulators with unique profiles and determination of their potential clinical utility.
- Goher, Shaimaa S.,Griffett, Kristine,Hegazy, Lamees,Elagawany, Mohamed,Arief, Mohamed M.H.,Avdagic, Amer,Banerjee, Subhashis,Burris, Thomas P.,Elgendy, Bahaa
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p. 449 - 453
(2019/01/04)
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- Design, synthesis, insecticidal activity and 3D-QSR study for novel trifluoromethyl pyridine derivatives containing an 1,3,4-oxadiazole moiety
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A series of trifluoromethyl pyridine derivatives containing 1,3,4-oxadiazole moiety was designed, synthesized and bio-assayed for their insecticidal activity. The result of bio-assays indicated the synthesized compounds exhibited good insecticidal activity against Mythimna separata and Plutella xylostella, most of the title compounds show 100% insecticidal activity at 500 mg L-1 and >80% activity at 250 mg L-1 against the two pests. Compounds E18 and E27 showed LC50 values of 38.5 and 30.8 mg L-1 against Mythimna separata, respectively, which were close to that of avermectin (29.6 mg L-1); compounds E5, E6, E9, E10, E15, E25, E26, and E27 showed 100% activity at 250 mg L-1, which were better than chlorpyrifos (87%). CoMFA and CoMSIA models with good predictability were proposed, which revealed the electron-withdrawing groups with an appropriate bulk at 2- and 4-positions of benzene ring could enhance insecticidal activity.
- Xu,Wang,Luo,Yu,Guo,Fu,Zhao,Wu
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p. 6306 - 6314
(2018/02/19)
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- Design, synthesis, evaluation, and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents
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Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100 mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC50 >100 μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.
- Wei, Zhi-Yu,Chi, Ke-Qiang,Wang, Ke-Si,Wu, Jie,Liu, Li-Ping,Piao, Hu-Ri
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p. 1797 - 1803
(2018/04/23)
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- Copper-Catalyzed Cascade Synthesis of [1,2,4]-Triazoloquinazolinones
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An efficient and practical method for the synthesis of 1,2,4-triazolo[5,1- b ]quinazolin-9(3 H)-ones has been developed via the copper-catalyzed domino reactions of readily available substituted N ′-acetyl-2-bromobenzohydrazides with cyanamide. The protocol uses inexpensive CuI as the catalyst, and no other ligand or additive was required. The target products were prepared in good to excellent yields with tolerance of various functional groups.
- Lou, Zhenbang,Man, Ningning,Yang, Haijun,Zhu, Changjin,Fu, Hua
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supporting information
p. 1395 - 1399
(2018/05/03)
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- Facile synthesis, biological evaluation and molecular docking studies of novel substituted azole derivatives
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In this study, we synthesized the series of novel azole derivatives and evaluated for enzyme inhibition assays, corresponding kinetic analysis and molecular modeling. Among the investigated bioassays, the oxadiazole derivatives 4a-k were found potent α-glucosidase inhibitors while the Schiff base derivatives 7a-k exhibited considerable potential toward urease inhibition. The inhibition kinetics for the most active compounds were analyzed by the Lineweaver–Burk plots to investigate the possible binding modes of the synthesized compounds toward the tested proteins. Moreover, the detailed docking studies were performed on the synthesized library of 4a-k and 7a-k to study the molecular interaction and binding mode in the active site of the modeled yeast α-glucosidase and Jack Bean Urease, respectively. It could be inferred from docking results that theoretical studies are in close agreement to that of the experimental results. The structure of one of the compound 7k was characterized by the single crystal X-ray diffraction analysis in order to find out the predominant conformation of the molecules.
- Rafiq, Muhammad,Saleem, Muhammad,Jabeen, Farukh,Hanif, Muhammad,Seo, Sung-Yum,Kang, Sung Kwon,Lee, Ki Hwan
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p. 177 - 191
(2017/03/15)
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- 1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases
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Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole–thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.
- Sevaille, Laurent,Gavara, Laurent,Bebrone, Carine,De Luca, Filomena,Nauton, Lionel,Achard, Maud,Mercuri, Paola,Tanfoni, Silvia,Borgianni, Luisa,Guyon, Carole,Lonjon, Pauline,Turan-Zitouni, Gülhan,Dzieciolowski, Julia,Becker, Katja,Bénard, Lionel,Condon, Ciaran,Maillard, Ludovic,Martinez, Jean,Frère, Jean-Marie,Dideberg, Otto,Galleni, Moreno,Docquier, Jean-Denis,Hernandez, Jean-Fran?ois
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p. 972 - 985
(2017/06/27)
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- Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin–dioxazole combination as tubulin targeting anticancer agents
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The advancement of cancer-fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin-derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC50?=?2.54?±?0.82?μm against MCF-7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF-7 in a way depending on the dosage. The time- and dose-dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D-QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics.
- Wang, Zi-Zhen,Sun, Wen-Xue,Wang, Xue,Zhang, Ya-Han,Qiu, Han-Yue,Qi, Jin-Liang,Pang, Yan-Jun,Lu, Gui-Hua,Wang, Xiao-Ming,Yu, Fu-Gen,Yang, Yong-Hua
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p. 236 - 243
(2017/07/13)
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- Design and optimization of N-acylhydrazone pyrimidine derivatives as E. coli PDHc E1 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study
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By targeting the thiamin diphosphate (ThDP) binding site of Escherichia coli (E. coli) pyruvate dehydrogenase multienzyme complex E1 (PDHc E1), a series of novel ‘open-chain’ classes of ThDP analogs A, B, and C with N-acylhydrazone moieties was designed and synthesized to explore their activities against E. coli PHDc E1 in vitro and their inhibitory activity against microbial diseases were further evaluated in vivo. As a result, A1–23 exhibited moderate to potent inhibitory activities against E. coli PDHc E1 (IC50 = 0.15–23.55 μM). The potent inhibitors A13, A14, A15, C2, had strong inhibitory activities with IC50 values of 0.60, 0.15, 0.39 and 0.34 μM against E. coli PDHc E1 and with good enzyme-selective inhibition between microorganisms and mammals. Especially, the most powerful inhibitor A14 could 99.37% control Xanthimonas oryzae pv. Oryzae. Furthermore, the binding features of compound A14 within E. coli PDHc E1 were investigated to provide useful insights for the further construction of new inhibitor by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that A14 had most powerful inhibition against E. coli PDHc E1 due to the establishment of stronger interaction with Glu571, Met194, Glu522, Leu264 and Phe602 at active site of E.coli PDHc E1. It could be used as a lead compound for further optimization, and may have potential as a new microbicide.
- He, Haifeng,Xia, Hongying,Xia, Qin,Ren, Yanliang,He, Hongwu
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p. 5652 - 5661
(2017/10/09)
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- New Biguanides as Anti-Diabetic Agents, Part II: Synthesis and Anti-Diabetic Properties Evaluation of 1-Arylamidebiguanide Derivatives as Agents of Insulin Resistant Type II Diabetes
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New 1-arylamidebiguanide hydrochloride salts were synthesized via reaction of hydrazide derivatives with dicyandiamide in acidic medium. The structure of the obtained derivatives was characterized by spectroscopic and elemental analysis tools. The anti-diabetic properties of the synthesized compounds were determined. Oral treatment of hyperglycemic rats with the synthesized biguanide derivatives showed a significant decrease of the elevated glucose in comparison with the anti-diabetic standard drug, metformin. The effects of the synthesized biguanide derivatives on the diabetic properties regarding liver function enzyme activities (AST, ALT, and ALP), lipid profiles (TC, TG, and TL), lipid peroxide, and nitrous oxide as well as histopathological characteristics were investigated and discussed.
- Basyouni, Wahid M.,Abbas, Samir Y.,El Shehry, Mohamed F.,El-Bayouki, Khairy A.M.,Aly, Hanan F.,Arafa, Azza,Soliman, Mahmoud S.
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- Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors
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A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58–84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions.. In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of ?64.92,-203.25 and ?140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values ?170.91, ?256.84 and ?235.97 kcal/mol, respectively.
- Nisa, Mehr-un,Munawar, Munawar A.,Iqbal, Amber,Ahmed, Asrar,Ashraf, Muhammad,Gardener, Qurra-tul-Ann A.,Khan, Misbahul A.
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supporting information
p. 396 - 406
(2017/07/10)
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- Design, synthesis, and negative inotropic evaluation of 4-phenyl-1H-1,2,4-triazol-5(4H)-one derivatives containing triazole or piperazine moieties
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In this study, four novel series of 4-phenyl-1H-1,2,4-triazol-5(4H)-one derivatives containing triazole or piperazine moieties were designed, synthesized, and evaluated for negative inotropic activity by measuring the left atrium stroke volume in isolated rabbit heart preparations. Almost all of the compounds showed an ability to moderate the cardiac workload by decreasing the heart rate and contractility. Among them, 7h was found to be the most potent with a change in stroke volume of ?48.22?±?0.36% at a concentration of 3?×?10?5?mol/L (metoprolol: ?9.74?±?0.14%). The cytotoxicity of these compounds was evaluated using the human cervical cancer cell line HeLa, the liver cancer cell line Hep3B, and the human normal hepatic cell line LO2. A preliminary study of the mechanism of action for the compound 7h on the regulation of atrial dynamics with ATP-sensitive K+ channel and L-type Ca2+ channel blockers glibenclamide and nifedipine was performed in the isolated perfused beating rabbit atria.
- Wei, Zhi-Yu,Cui, Bai-Ri,Cui, Xun,Wu, Yan-Ling,Fu, Yang,Liu, Li-Ping,Piao, Hu-Ri
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- Design, synthesis and antibacterial activity of isatin derivatives as FtsZ inhibitors
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Seven isatin derivatives have been designed, and their chemical structures were characterized by single crystal X-ray diffraction studies, 1H NMR, MS, and elemental analysis. Structural stabilization followed by intramolecular as well as intermolecular H-bonds makes these molecules as perfect examples in molecular recognition with self-complementary donor and acceptor units within a single molecule. These compounds were evaluated for antimicrobial activities. Docking simulations have been performed to position compounds into the FtsZ active site to determine their probable binding models. All of the compounds exhibited better antibacterial activities. Interestingly, compound 5c and 5d exhibited better antibacterial activities with IC50 values of 0.03 and 0.05 μmol/mL against Staphylococcus aureus, respectively. Compound 5g displays antibacterial activity with IC50 values of 0.672 and 0.830 μmol/mL against Escherichia coli and Pseudomonas aeruginosa, respectively.
- Lian, Zhi-Min,Sun, Juan,Zhu, Hai-Liang
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- Acylhydrazone derivative used for treating heart failure
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The invention belongs to the technical field of medicines, and relates to design and preparation method for acylhydrazone derivatives shown as a general formula I, and the acylhydrazone derivatives can be used for treating systolic heart failure comprising congestive heart failure.
- -
-
Paragraph 0084; 0085; 0086
(2016/10/08)
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- Synthesis and antibacterial activity of some new quinaxaline-benzohydrazides
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Quinoxalines have been found to exhibit various biological activities such as antibacterial, antifungal, anti-tubercular, anxiolytic, anticancer, antioxidant, anti-inflammatory, anti-HIV, antihelmintic and anticonvulsant. The present study aims towards synthesis, characterization and determination of antimicrobial susceptibility testing of various novel quinoxaline derivatives. The quinoxaline-benzohydrazides 6a-m have been obtained by the condensation of quinoxaline-2-carboxaldehyde 4 with various benzohydrazides 5a-m in ethanol at reflux temperature. All the newly synthesized quinoxaline-benzohydrazide derivatives have been characterized by 1H NMR, IR and mass spectroscopic analysis. The synthesized quinoxaline-benzohydrazides 6a-m have been screened for antibacterial activity. Most of the compounds show significant antibacterial activity.
- Haripriya,Laxminarayana,Thirumala Chary
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p. 207 - 212
(2017/01/18)
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- Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors
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A novel serie of escitalopram triazoles (60-88) and a tetrazole (89) have been synthesized and subjected to a study to establish the inhibitory potential of these compounds toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Some selectivity in inhibition has been observed. The 4-chlorophenyl- (75, IC50, 6.71 ± 0.25 μM) and 2-methylphenyl- (70, IC50, 9.52 ± 0.23 μM) escitalopram triazole derivatives depicted high AChE inhibition, while 2-fluorophenyl- (76, IC50 = 4.52 ± 0.17 μM) and 4-fluorophenyl- (78, IC50 = 5.31 ± 0.43 μM) have found to be excellent BChE inhibitors. It has also been observed that ortho, meta and para substituted electron donating groups increase the inhibition, while electron withdrawing groups reduce the inhibition. Docking analyses of inhibitors with AChE have depicted the binding energies for 70 and 75 as ΔGbind -6.42 and -6.93 kcal/mol, respectively, while ligands 76 and 78 have shown the binding affinity ΔGbind -9.04 and -8.51 kcal/mol, respectively, for BChE.
- Mehr-Un-Nisa,Munawar, Munawar A.,Chattha, Fauzia A.,Kousar, Samina,Munir, Jawaria,Ismail, Tayaba,Ashraf, Muhammad,Khan, Misbahul A.
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supporting information
p. 6014 - 6024
(2015/11/11)
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- Novel hybrid-pyrrole derivatives: Their synthesis, antitubercular evaluation and docking studies
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Using novel hybrid molecules for the treatment of tuberculosis is one of the latest approaches. Keeping this concept in mind, thirty two hybrid compounds were synthesized, with pyrrole as one of the moieties, clubbed to coumarin, ibuprofen and isoniazid. The compounds were evaluated against Mycobacterium tuberculosis H37Rv strain. Compounds 7e and 8e exhibited MIC of 3.7 and 5.10 μg mL-1 and growth inhibition of 95% and 92%, respectively. These compounds were also active against single drug resistant bacterial strains. The compounds were devoid of cytotoxicity when tested against Vero African green monkey kidney cell line. Docking study was carried out on enoyl acyl carrier protein enzyme to provide some understanding into the mechanism of action of these compounds.
- Saha, Rikta,Alam, Md. Mumtaz,Akhter, Mymoona
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p. 12807 - 12820
(2015/02/19)
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- Synthesis and antimicrobial evaluation of 5-aryl-1,2,4-triazole-3-thione derivatives containing a rhodanine moiety
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Three series of 5-aryl-1,2,4-triazole-3-thione derivatives containing a rhodanine moiety (5a-k, 6a-i, and 7a-i) have been synthesized, characterized and evaluated for their antibacterial activity. Some of these displayed potent antibacterial activity against several Gram-positive and Gram-negative bacterial strains (including multidrug-resistant clinical isolates) with minimum inhibitory concentration (MIC) values in the range of 4-64 μg/mL and minimum bactericidal concentration (MBC) values in the range of 8-256 μg/mL. Compared with previously reported rhodanine derivatives, these compounds exhibited a broad spectrum of antibacterial activity by means of introducing 4-amino-5-aryl-1,2,4-triazole-3-thione moiety. Notably, compound 5f exhibited good antibacterial activity against Staphylococcus aureus RN 4220, S. aureus 209, S. aureus 503, Gram-negative bacteria (Escherichia coli 1924), and Candida albicans 7535 with MBC values of 8 or 16 μg/ml. All of the compounds synthesized in the current Letter were characterized by 1H NMR, 13C NMR, infrared and mass spectroscopy.
- Li, Chao,Liu, Jia-Chun,Li, Ya-Ru,Gou, Cheng,Zhang, Mei-Ling,Liu, Hong-Yan,Li, Xiao-Zhen,Zheng, Chang-Ji,Piao, Hu-Ri
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supporting information
p. 3052 - 3056
(2015/06/22)
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- Synthesis and antimicrobial activity of new imidazole-hydrazone derivatives
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Hydrazones demonstrated significant antimicrobial activity, antitubercular activity and antitumoral activity in medicinal areas. The imidazole nucleus is well known to play an important role in living organisms since it is incorporated into the histidine molecule and many other important biological, pharmacological and therapeutic activities. Condensation of 4-phenyl-1H-imidazole-2-carbaldehyde (3) with various selected benzohydrazides (4a-m) resulted in imidazole-hydrazone derivatives (5a-m). They were evaluated for antibacterial and antifungal activity against A. Niger, C. albicans (fungal strains), E. coli and P. aeruginosa (Gram-negative bacteria), S. aureus and S. pyogenes (Gram-positive bacteria) using griseofluvin (for fungi) and ciprofloxacin (for bacteria) as the standard drugs. In general, it is observed that most of the compounds were found to be potent against both the bacterial and fungal strains.
- Prasanna, V. Laxmi,Narender
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p. 3605 - 3608
(2015/12/24)
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- Synthesis, anti-HIV activity and Molecular modeling study of 3-aryl-6-adamantylmethyl-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazole derivatives
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A series of novel 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 6a-l were synthesized by a simple method with the aim of developing novel HIV non-nucleoside reverse transcriptase inhibitors. All the synthesized compounds were structurally confirmed by spectral analyses. The structure of 6a was unambiguously verified by X-ray structure determination. The synthesized compounds were evaluated for their anti-HIV activity and four analogs displayed moderate inhibitory activity with EC50 values ranging from 10.10 to 12.40 μg mL-1. Molecular docking of 6g with HIV-1 reverse transcriptase was studied to rationalize some structureactivity relationships (SARs).
- Khan, Mahmood-Ul-Hassan,Hameed, Shahid,Farman, Muhammad,Al-Masoudia, Najim A.,Stoeckli-Evans, Helen
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p. 609 - 616
(2016/02/18)
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- Synthesis and evaluation of novel azoles as potent antifungal agents
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Using a rational approach to the design of antifungal agents, a series of azole agents with 1,3,4-oxadiazole side chains were designed and synthesized. The results of preliminary in vitro antifungal tests with eight human pathogenic compounds showed that all of the title compounds exhibited excellent activities against all of the tested fungi except Aspergillus fumigatus. Compounds 11e and 11f were found to be the most effective, with a minimum inhibitory concentration of 0.0039 μg/mL, followed by voriconazole, which has a MIC of 0.0625 μg/mL. The 1,3,4-oxadiazole side chain is not the major contributor but plays a role in eliciting the observed antifungal activity.
- Li, Liangjing,Ding, Hao,Wang, Baogang,Yu, Shichong,Zou, Yan,Chai, Xiaoyun,Wu, Qiuye
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p. 192 - 194
(2014/01/17)
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- Synthesis, biologicalevaluation, and molecular modeling of (E)-2-aryl-5-styryl-1,3,4-oxadiazolederivatives as acetylcholine esterase inhibitors
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A library of 2,5-disubstituted 1,3,4-oxadiazole derivatives of (E)-2-aryl-5-(3,4,5-trimethoxystyryl)-1,3,4-oxadiazoles 4(a-o) and (E)-2-aryl-5-(2-benzo[d][1,3]dioxol-5-yl)vinyl)-1,3,4-oxadiazoles 5(a-q) were synthesized and evaluated for their in vitro acetylcholinesterase (AChE) inhibitory activity. All the synthesized compounds exhibited moderate to good inhibitory activity toward the AChE enzyme. Among the oxadiazole derivatives examined, compounds 4a, 4g, 5c, and 5m (IC50 values of 24.89, 13.72, 37.65, and 19.63 μM, respectively) were found to be promising inhibitors of AChE. Molecular protein-ligand docking studies were examined for these compounds using GOLD docking software and their binding conformations were determined and the simultaneous interactions mode was also established for the potent derivatives. Springer Science+Business Media 2013.
- Kamal, Ahmed,Shaik, Anver Basha,Reddy, G. Narender,Kumar, C. Ganesh,Joseph, Joveeta,Kumar, G. Bharath,Purushotham, Uppula,Sastry, G. Narahari
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p. 2080 - 2092
(2014/05/06)
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- Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety
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A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC50 value of 2.84 μM. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells, with IC50 values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8n exhibited significant antiproliferative activity against A549 cells, with IC50 values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines.
- Zhang, Kai,Wang, Peng,Xuan, Li-Na,Fu, Xiao-Yun,Jing, Fen,Li, Sha,Liu, Yu-Ming,Chen, Bao-Quan
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p. 5154 - 5156
(2014/12/11)
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- Synthesis, characterization and antimicrobial activities of mercaptoxadiazoles, mercaptotriazoles and their derivatives
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Five member heterocycles are famous for their universal activities. Starting with suitably substituted hydrazides 1,3,4-oxadiazole-2-thiones (1-5) and 1,2,4-triazolethionamines (6-11) were synthesized which were later on converted into Mannich products (13-22) and traizolothiadiazines (23-28) respectively. Structures were established by FTIR, hydrogen, carbon NMR, and mass spectrometric analysis. Compounds were evaluated for their antimicrobial studies. Compounds 13, 19 and 23 showed maximum inhibitions in opposition to the bacterial strains while compounds 7, 11, 13 and 27 showed utmost percentage inhibition aligned with the yeast cells.
- Mumtaz, Amara,Saeed, Aamer,Malik, Imran
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p. 852 - 857
(2015/01/30)
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- An integration of condensation/Ullmann-type coupling/bicyclization sequences: Copper-catalyzed three-component direct synthesis of [1,2,4]triazolo[1,5-b]isoquinolin-5(1H)-ones
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A highly efficient three-component domino protocol has been developed for the synthesis of [1,2,4]triazolo[1,5-b]isoquinolin-5(1H)-ones from simple and readily available o-halogenated benzohydrazides, aldehydes and nitriles. This domino process involves sequential selective condensation, copper-catalyzed intermolecular C-arylation and bicyclization. Notably, the use of ligands and anaerobic conditions can be avoided in this reaction.
- Jia, Feng-Cheng,Xu, Cheng,Cai, Qun,Wu, An-Xin
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supporting information
p. 9914 - 9916
(2014/08/18)
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- Synthesis and insecticidal activities of cis-configuration nitenpyram analogues with benzoyl hydrazines
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To research on the structure-activity relationships of our designed neonicotinoid compounds, a series of novel cis-configuration nitenpyram analogues with benzoyl hydrazines were designed and synthesized. The structures of all compounds were confirmed by IR, 1H NMR, MS, and elemental analysis. Preliminary bioassays indicated that all the analogues exhibited good insecticidal activities against Nilaparvata legen and Aphis medicagini at 500 mg L-1.
- Xu, Xiao,Sun, Chuan-Wen,Yang, Ding-Rong,Bu, Hong-Fei,Wang, Jing,Xu, Yong-Hua
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p. 945 - 948
(2013/08/23)
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- Synthesis, antibacterial activities, and 3d-qsar of sulfone derivatives containing 1, 3, 4-oxadiazole moiety
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A series of sulfone derivatives containing 1, 3, 4-oxadiazole moiety were prepared and evaluated for their antibacterial activities by the turbidimeter test. Most compounds inhibited growth of Ralstonia solanacearum (R. solanacearum) from tomato and tobacco bacterial wilt with high potency, among which compounds 5a and 5b exhibited the most potent inhibition against R. solanacearum from tomato and tobacco bacterial wilts with EC50 values of 19.77 and 8.29 μg/mL, respectively. Our results also demonstrated that 5a, 5b, and a number of other compounds were more potent than commercial bactericides Kocide 3000 and Thiodiazole Copper, which inhibited R. solanacearum from tomato bacterial wilt with EC50 values of 93.59 and 99.80 μg/mL and tobacco bacterial wilt with EC50 values of 45.91 and 216.70 μg/mL, respectively. The structure-activity relationship (SAR) of compounds was studied using three-dimensional quantitative structure-activity relationship (3D-QSAR) models created by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) based on compound bioactivities against tomato and tobacco bacterial wilts. The 3D-QSAR models effectively predicted the correlation between inhibitory activity and steric-electrostatic properties of compounds.
- Li, Pei,Yin, Juan,Xu, Weiming,Wu, Jian,He, Ming,Hu, Deyu,Yang, Song,Song, Baoan
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p. 546 - 556
(2013/11/06)
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- Acyl hydrazides: Potent antioxidants
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Twenty-eight acyl hydrazides (1-28) are subjected for nitric oxide scavenging activities and their structureactivity relationship (SAR) is established. Compounds 1-28 showed a varying degree of activity having IC 50 values in the range of 9.1 ± 6.5 - 231.1 μM. It was found that twenty-five (25) out of twenty-eight (28) compounds, showed an excellent nitric oxide scavenging activity. It was observed that the activity mainly depends on the substitution on acyl hyrazide moiety. 3-Propylpyrozole-5- carbohydrazide (27) was found to be the most active in the series with an IC50 value of 9.1 μM. Thus, compound 27 may serve as a lead compound for further development as potent antioxidant agent.
- Khan, Khalid Mohammed,Rani, Mubeen,Ambreen, Nida,Ejaz, Asma,Perveen, Shahnaz,Haider, Syed Moazzam,Choudhary, Mohammad Iqbal,Voelter, Wolfgang
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scheme or table
p. 135 - 139
(2012/07/28)
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- Synthesis, crystal structure and anti-HIV activity of 2-adamantyl/ adamantylmethyl-5-aryl-1,3,4-oxadiazoles
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Two series of 2-adamantyl/adamantylmethyl-5-aryl-1,3,4-oxadiazoles (4a-l and 5a-l) were synthesized by cyclodehydration of adamantan-1-carboxylic acid/adamantylacetic acid with various aryl hydrazides (3a-l) in the presence of POCl3. The synthesis was supported by spectroanalytical techniques and verified further by crystal structure determination of compounds 4e and 5k. The synthesized compounds were screened for their inhibitory activity against HIV-1 and HIV-2 in MT-4 cells. Compound 5b exhibited a moderate activity in vitro for the replication of both virus types, suggesting for further structural modification as a new lead in the development of an antiviral agent.
- Khan, Mahmood-Ul-Hassan,Hameed, Shahid,Akhtar, Tashfeen,Al-Masoudi, Najim A.,Stoeckli-Evans, Helen
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p. 1190 - 1197,8
(2012/12/12)
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- Synthesis, crystal structure and anti-HIV activity of 2-adamantyl/ adamantylmethyl-5-aryl-1,3,4-oxadiazoles
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Two series of 2-adamantyl/adamantylmethyl-5-aryl-1,3,4-oxadiazoles (4a-l and 5a-l) were synthesized by cyclodehydration of adamantan-1-carboxylic acid/adamantylacetic acid with various aryl hydrazides (3a-l) in the presence of POCl3. The synthesis was supported by spectroanalytical techniques and verified further by crystal structure determination of compounds 4e and 5k. The synthesized compounds were screened for their inhibitory activity against HIV-1 and HIV-2 in MT-4 cells. Compound 5b exhibited a moderate activity in vitro for the replication of both virus types, suggesting for further structural modification as a new lead in the development of an antiviral agent.
- Khan, Mahmood-Ul-Hassan,Akhtar, Tashfeen,Al-Masoudi, Najim A.,Stoeckli-Evans, Helen,Hameed, Shahid
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p. 1190 - 1197
(2013/01/15)
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- Microwave assisted synthesis of biologically active 4-hydroxy-N′- (phenylcarbonyl)-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide derivatives
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Microwave assisted synthesis of a series of 4-hydroxy-N′- (phenylcarbonyl)-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides from sodium saccharin is reported. Sodium o-benzosulfimide was N-alkylated with ethyl chloroacetate followed by base catalyzed ring expansion to six membered 1,2-benzothiazine through Gabriel-Coleman type rearrangement yielding ethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide. It was later condensed with a series of benzohydrazides synthesized from various carboxylic acids to get the title compounds. All the synthesized compounds were subjected to preliminary evaluation for their biological activity against series of Gram positive, Gram negative bacteria and fungi. Some of the compounds showed marked activity against the selected microorganisms.
- Zaheer, Muhammad,Zia-Ur-Rehman, Muhammad,Rahman, Salma,Ahmed, Naveed,Chaudhary, Muhammad Nawaz
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p. 1492 - 1496
(2013/06/27)
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- Inhibition of tobacco bacterial wilt with sulfone derivatives containing an 1,3,4-oxadiazole moiety
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A series of new sulfone compounds containing the 1,3,4-oxadiazole moiety were designed and synthesized. Their structures were identified by 1H and 13C nuclear magnetic resonance and elemental analyses. Antibacterial bioassays indicated that most compounds exhibited promising in vitro antibacterial bioactivities against tobacco bacterial wilt at 200 μg/mL. The relationship between structure and antibacterial activity was also discussed. Among the title compounds, 5′c, 5′h, 5′i, and 5′j could inhibit mycelia growth of Ralstonia solanacearum in vitro by approximately 50% (EC50) at 39.8, 60.3, 47.9, and 32.1 μg/mL, respectively. Among them, compound 5′j was identified as the most promising candidate due to its stronger effect than that of Kocide 3000 [Cu(OH)2] within the same concentration range. Field trials demonstrated that the control effect of compound 5′j against tobacco bacterial wilt was better than that of the commercial bactericide Saisentong. For the first time, the present work demonstrated that sulfone derivatives containing 1,3,4-oxadiazole can be used to develop potential bactericides for plants.
- Xu, Wei-Ming,Han, Fei-Fei,He, Ming,Hu, De-Yu,He, Jiang,Yang, Song,Song, Bao-An
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scheme or table
p. 1036 - 1041
(2012/06/04)
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- Synthesis and antitubercular activities of substituted benzoic acid N′-(substituted benzylidene/furan-2-ylmethylene)-N-(pyridine-3-carbonyl)- hydrazides
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A series of benzoic acid hydrazones and its nicotinyl derivatives (1-10) were prepared and evaluated for their antitubercular activity towards a strain of Mycobacterium tuberculosis (MTB). The structures of newly synthesized compounds were confirmed by infrared (IR) and 1H-nuclear magnetic resonance (NMR) spectral data and elemental analysis. The in vitro antitubercular activity of synthesized compounds against MTB was carried out in Middlebrook 7H11agar medium supplemented with OADC by agar dilution method. The antitubercular activity results indicated that nicotinic acid N-(3,5-dinitro-benzoyl)-N′-(4-methoxy-benzylidene)-hydrazide (1) is the most potent among the synthesized compounds with MIC of 3.5 × 10 -3 μM.
- Kumar, Pradeep,Narasimhan, Balasubramanian,Yogeeswari, Perumal,Sriram, Dharmarajan
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experimental part
p. 6085 - 6089
(2011/01/12)
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- Anion binding of N-(o-Methoxybenzamido)thioureas: Contribution of the intramolecular hydrogen bond in the N-benzamide moiety
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N-(o-Methoxybenzamido)- thioureas (2X/2Y) are found to show an enhanced anion binding affinity with binding constants over 107 mol -1L orders of magnitude for AcO- and a redshifted absorption of the anion binding complexes in acetonitrile (MeCN) relative to those of N-benzamidothioureas (1) that bear no o- OMe in the N-benzamide moiety, despite the electron-donating character of o-OMe. Absorption of the anion-2X/ 2Y complex was shown to be of the same charge-transfer nature as that of the anion-1 complex, but its dependence on substituent X is interestingly influenced by the o-MeO···HNC=O six-membered-ring intramolecular hydrogen bond identified in 2X/2Y. Such an intramolecular hydrogen bond is suggested to be responsible for the enhanced anion binding affinity. In the presence of this intramolecular hydrogen bond, the anion binding constant of 2X was found to be independent of substituent X at the N-phenyl ring, as in the case of 1, whereas that of 2Y showed an amplified dependence on substituent Y at the N′-phenyl ring, but to a lower extent than that of 1. A similar ring intramolecular hydrogen bond was purported to exist in 2Za, 2Zd, and 2Ze, which bear NHMe, F, and Cl as the ortho substituent in the N-benzamide moiety. In terms of the current roles of thiourea in not only anion recognition and sensing but also organocatalysis and crystal engineering, the present finding would be of significance for a wider structural diversity of smart thiourea derivatives with predesigned functions.
- Jiang, Qian-Qian,Darhkijav, Burenkhangai,Liu, Hao,Wang, Fang,Li, Zhao,Jiang, Yun-Bao
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experimental part
p. 543 - 549
(2010/08/20)
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- Synthesis, crystal structure and antiproliferative activity of 6-adamantyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
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A series of 3,6-disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 5a - l bearing an adamantyl moiety were synthesized by condensation of 4-amino-5-aryl-2H-1,2,4-triazole-3(4H)-thiones 4a - l with adamantyl-1- carboxylic acid in the presence of POCl3. The structures of the newly synthesized compounds were established using spectroanalytical techniques and verified further by the crystal structure determination of compounds 5a and 5j. The compounds were screened for their antiproliferative activity against a large panel of human cell lines.
- Khan, Mahmood-Ul-Hassan,Akhtar, Tashfeen,Yasin, Khawaja A.,Al-Masoudi, Najim A.,Jones, Peter G.,Hameed, Shahid
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scheme or table
p. 178 - 184
(2010/08/22)
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- Design, synthesis, and urease inhibition studies of a series of 4-amino-5-aryl-3H-1,2,4-triazole-3-thiones
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A series of 4-amino-5-aryl-3H-1,2,4-triazole-3-thiones was synthesized by reaction of aryl hydrazides with CS2 and hydrazine hydrate. The synthesized compounds were characterized by spectroanalytical techniques, and their urease inhibition activity was evaluated using jack bean urease. All but one of the synthesized compounds were active, and two of them were found to be more potent than the standard, with 50% inhibition concentration (IC 50) values of 17.5 ± 0.52 and 4.3 ± 0.169 μM, respectively (standard IC 50 = 21.0 ± 0.11 μM). Tentative statements regarding the role of different functional groups in binding to the enzyme active site are also presented.
- Khan, Mahmood-Ul-Hassan,Hameed, Shahid,Yasin, Khawaja A.,Akhtar, Tashfeen,Khan, Khalid M.
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experimental part
p. 479 - 484
(2011/08/03)
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