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1.
The heats of formation (HOFs), thermal stability, and detonation properties for a series of nitrogen-bridged 1,2,4,5-tetrazine-, furazan-, and 1H-tetrazole-based polyheterocyclic compounds (3,6-bis(1H-1,2,3,4-tetrazole-5-ylamino)-1,2,4,5- tetrazine (TST), 3,6-bis(furazan-5-ylamino)-1,2,4,5-tetrazine (FSF), 3,4-bis(1,2,4,5- tetrazine-3-ylamino)-furazan (SFS), 3,4-bis(1H-1,2,3,4-tetrazole-5-ylamino)-furazan (TFT), 1,5-bis(1,2,4,5-tetrazine-3-ylamino)-1H-1,2,3,4-tetrazole (STS), and 1,5-bis(furazan-3-ylamino)-1H-1,2,3,4-tetrazole (FTF) derivatives) were systematically studied by using density functional theory. The results show that the -N(3) or -NHNH(2) group plays a very important role in increasing the HOF values of the derivatives. Among these series, the SFS derivatives have lower energy gaps, while the TFT derivatives have higher ones. Incorporation of the -NH(2) group into the FSF, SFS, STS, or FTF ring is favorable for enhancing its thermal stability, whereas the substitution of the -NHNH(2) group could increase the thermal stability of the TST, SFS, STS, or FTF ring. The calculated detonation properties indicate that the -NO(2) or -NF(2) is very helpful for enhancing the detonation performance for these derivatives. Considering the detonation performance and thermal stability, six derivatives may be regarded as promising candidates of high-energy density materials (HEDMs). These results provide basic information for the molecular design of novel HEDMs.  相似文献   

2.
In order to discover lead compounds with novel action mechanism, a series of tetrazolinone derivatives bearing structurally diverse substituents, 1-aryl-4-substituted-1,4-di-hydro-5H-tetrazol-5-ones 2, 1-((5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)-4-(substituted)- phenyl-1H-tetrazol-5(4H)-ones 5, and 1-((5-(alkylthio)-1,3,4-thiadiazol-2-yl)methyl)-4- (substituted)phenyl-1H-tetrazol-5(4H)-ones 7, were designed and synthesized in good yields by a multiple-step synthetic procedure. The results of greenhouse in vivo test indicated that all the target compounds did not displayed herbicidal activity, however, some of them exhibited excellent in vivo insecticidal activity against Tetranychus cinnabarinus at the concentration of 250 mg L-1. To our knowledge, this is the first report about the insecticidal activity of tetrazolinone derivatives, which indicated that the tetrazolinone scaffold could be identified as a novel insecticidal lead structure. The present work demonstrated that optimizing a target-diverse scaffold is an effective way to discover new lead compounds with new action mechanism or biological activity.  相似文献   

3.
The heats of formation (HOFs), electronic structures, energetic properties, and thermal stabilities of a series of energetic bridged di-1,3,5-triazine derivatives with different substituents and linkages were studied using density functional theory. It was found that the groups -N(3) and -N=N- are effective structural units for improving the HOF values of the di-1,3,5-triazine derivatives. The effects of the substituents on the HOMO-LUMO gap combine with those of the bridge groups. The calculated detonation velocities and detonation pressures indicate that substituting the -ONO(2), -NF(2), or -N=N- group is very useful for enhancing the detonation performance of these derivatives. Analysis of the bond dissociation energies for several relatively weak bonds suggests that most of the derivatives have good thermal stability. On the whole, the -NH(2), -N(3), -NH-, and -CH=CH- groups are effective structural units for increasing the thermal stabilities of the derivatives. Based on detonation performance and thermal stability, nine of the compounds can be considered potential candidates for high energy density materials with reduced sensitivity.  相似文献   

4.
We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (Ki <1 nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.  相似文献   

5.
The influence of (1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazole derivatives: 4-amino-3-(5-methyl-4-ethoxycarbonyl-(1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazole (TF4CH3) and 4,4′-bis(5-methyl-4-ethoxycarbo-nyl-1H-1,2,3-triazol-1-yl)-3,3′-azo-1,2,5-oxadiazole (2TF4CH3) on stimulation of human platelet soluble guanylate cyclase by YC-1, NO donors (sodium nitroprusside, SNP, and spermine NONO) and on a synergistic increase of NO-dependent activation of the enzyme in the presence of YC-1 has been investigated. Both compounds increased guanylate cyclase activation by YC-1, potentiated guanylate cyclase stimulation by NO donors and increased the synergistic effect of YC-1 on the NO-dependent activation of soluble guanylate cyclase. The similarity in the properties of the examined 1,2,3-triazol-1-yl-1,2,5-oxadiazole derivatives with that of YC-1 and a possible mechanism underlying the recognized properties of compounds used are discussed.  相似文献   

6.
Structure-activity relationship studies on 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery of 2-(2-[3-(pyridin-3-yloxy)phenyl]-2H-tetrazol-5-yl)pyridine (10)-a highly potent and selective mGlu5 receptor antagonist with good brain penetration and in vivo receptor occupancy in rat and cross-species oral bioavailability.  相似文献   

7.
A series of new chromone analogues bearing heterocyclic thioether moiety and aurone analogues bearing cyclic tertiary amine moiety were designed and synthesized under microwave irradiation. The synthetic protocol was found to present many advantages, such as higher yields, shorter reaction time (10-20 min), mild condition, and readily isolation of the products. The synthesized compounds were assayed for their antitumor activity against four kinds of human solid tumor cell lines including HCCLM-7, Hep-2, MDA-MB-435S, and SW-480. Two compounds, (Z)-2-((4-benzyl-piperazin-1-yl)methylene)benzofuran-3(2H)-one 5e and (Z)-2-((4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)methylene)benzofuran-3(2H)-one 5f, were identified as the most promising candidates with the IC(50) values in the range of 4.1-13.1 microM. Further cell cycle studies revealed that compounds 5e and 5f arrest the cell cycle in G(0)/G(1) phase and displayed apoptosis-inducing effect on Hep-2 cells.  相似文献   

8.
In search for a new antibacterial agent with improved antimicrobial spectrum and potency, we designed and synthesized a series of novel 3-((Z)-2-(4-nitrophenyl)-2-(1H-tetrazol-5-yl) vinyl)-4H-chromen-4-ones 7a-h by convergent synthesis approach. All the synthesized compounds were assayed for their in-vitro antibacterial activities against gram-negative and gram-positive bacteria. The preliminary structure-activity relationship, to elucidate the essential structure requirements for the antimicrobial activity that results into anti-MRSA (methicillin-resistant S. aureus) potential, has been described. Amongst the synthesized compounds 7d, 7e, 7f and 7h were found to possess activity against methicillin-resistant S. aureus in addition to the activity against other bacterial strains such as E. faecalis, S. pneumoniae, and E. coli.  相似文献   

9.
Structure-activity relationship studies performed around 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile for the purpose of developing novel mGlu5 receptor antagonists are described. Synthesis of a series of four-ring tetrazoles led to the discovery of 3-[3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine, a highly potent, brain penetrant, azole-based mGlu5 receptor antagonist.  相似文献   

10.
Multi-tetrazole derivatives with conjugated structures were designed and investigated in this study. Using quantum chemistry methods, the crystal structures, electrostatic potentials (ESPs), multicenter bond orders, HOMO–LUMO energy gaps, and detonation properties of the derivatives were calculated. As expected, these molecules with conjugated structures showed low energies of their crystal structures, molecular layering in their crystals, high average ESPs, high multicenter bond order values, and enhanced detonation properties. The derivative 1,2-di(1H-tetrazol-5-yl)diazene (N2) was predicted to have the best density (1.87 g/cm3), detonation velocity (9006 m/s), and detonation pressure (36.8 GPa) of the designed molecules, while its total crystal energy was low, suggesting that it is relatively stable. Its sensitivity was also low, as the molecular stacking that occurs in its crystal allows external forces to be dissipated into movements of crystal layers. Finally, its multicenter bond order was high, indicating a highly conjugated structure.  相似文献   

11.
The heats of formation (HOFs), electronic structure, energetic properties, and thermal stabilities for a series of 1,4-bis(1-azo-2,4-dinitrobenzene)-iminotetrazole derivatives with different substituents and substitution positions and numbers of nitrogen atoms in the nitrobenzene rings were studied using the DFT-B3LYP method. All the substituted compounds have higher HOFs than their parent compounds. As the number of nitrogen atoms in the nitrobenzene ring increases, the HOFs of the derivatives with the same substituent rise gradually. Replacing carbon atoms in the nitrobenzene with nitrogen atoms to form N–N bonds is very helpful in improving their HOFs. Most of the substituted compounds have higher HOMO–LUMO gaps than the corresponding unsubstituted compounds. Substitution of the –NO2, –NF2, or –ONO2 group and an increase in the number of nitrogen atoms in the nitrobenzene rings are useful for enhancing their detonation performance. The substituents’ substitution is not favorable for improving thermal stability. Considering detonation performance and thermal stability, five compounds may be considered potential candidates for high energy density compounds (HEDCs).  相似文献   

12.
Structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy.  相似文献   

13.
Methods for the synthesis of each of the four stereoisomers of 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane ( 10, 11, 12 , and 13 ) and 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.1]heptane ( 18, 19, 20 , and 21 ), and the two stereoisomers of 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane ( 27 and 28 ) were developed. The relative configuration of the compounds was determined on the basis of previously described 1H NOE experiments, and the absolute configuration of 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octanes ( 10, 11, 12 , and 13 ) and 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane ( 27 and 28 ) was determined by single crystal X-ray crystallography. Optical purity was determined by capillary electrophoresis (CE) using chiral selectors as trimethyl-β-cyclodextrin and heparin dissolved in the running buffer. All the 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicycles had low nanomolar affinity for muscarinic receptors as determined by displacement of radiolabelled oxotremorine-M (3H-Oxo-M) and pirenzepine (3H-Pz) from cortical rat brain homogenates. The binding assay discriminated between diastereomers, but only a minor degree of enantioselectivity was observed in the binding assays. Chirality 9:739–749, 1997. © 1997 Wiley-Liss, Inc.  相似文献   

14.
The reference standards methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate (5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide (5c), and their corresponding desmethylated precursors 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoic acid (6a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-hydroxybenzamide (6b), were synthesized from 5-amino-2,2-difluoro-1,3-benzodioxole and 3-substituted benzoic acids in 5 and 6 steps with 33% and 11%, 30% and 7% overall chemical yield, respectively. Carbon-11-labeled casein kinase 1 (CK1) inhibitors, [11C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate ([11C]5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-[11C]methoxybenzamide ([11C]5c), were prepared from their O-desmethylated precursor 6a or 6b with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–45% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370–740?GBq/μmol with a total synthesis time of ~40-min from EOB.  相似文献   

15.
The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.  相似文献   

16.
The known complex trans-RuCl2(NBD)Py2 (1, NBD is norbornadiene, Py is pyridine) reacts with either (R)-BINAP ((R)-2, 2'-bis(diphenylphosphino)-1,1'-binaphthyl), (S;S)-Chiraphos ((2S;3S-(-)-2,3-bis(diphenylphosphino)butane), (S;S)-Skewphos ((2S;4S)-(-)-2,4-bis(diphenylphosphino)pentane), (R)-(S)-Josiphos ((R)-(-)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl-dicyclohexylpho sphine), (R;R)-Norphos ((2R;3R)-(-)-2, 3-bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene), or (R;R)-Me-DUPHOS ((-)-1,2-bis((2R;5R)-2, 5-dimethylphospholano)benzene) to generate in high yields the crystalline complexes trans-RuCl2(P-P*)Py2 (P-P* is the corresponding chiral bis(phosphine)). The complexes trans-RuCl2(P-P*)Py2 are active enantioselective hydrogenation catalysts for ketoesters and noncarboxylic olefins in the presence of small amounts of HBF4 (aq.). They are active for hydrogenation of carboxylic substrates in the presence of Et3N. Reaction of trans-RuCl2(P-P*)Py2 with (rac)-1,2-diphenylethylene-diamine (N-N*, either enantiomer) forms in good yields the corresponding compounds trans-RuCl2(P-P*)(N-N*). Representative hydrogenations with these catalysts are presented.  相似文献   

17.
A new intercalating nucleic acid monomer X was obtained in high yield starting from alkylation of 4-iodophenol with (S)-(+)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol under Mitsunobu conditions followed by hydrolysis with 80% aqueous acetic acid to give a diol which was coupled under Sonogashira conditions with trimethylsilylacetylene (TMSA) to achieve the TMS protected (S)-4-(4-((trimethylsilyl)ethynyl)phenoxy)butane-1,2-diol. Tetrabutylammonium flouride was used to remove the silyl protecting group to obtain (S)-4-(4-ethynylphenoxy)butane-1,2-diol which was coupled under Sonogashira conditions with 2-(9-bromo-6H-indolo[2,3-b]quinoxalin-6-yl)-N,N-dimethylethanamine to achieve (S)-4-(4-((6-(2-(dimethylamino)ethyl)-6H-indolo[2,3-b]quinoxalin-9-yl)ethynyl)phenoxy)butane-1,2-diol. This compound was tritylated with 4,4′-dimethoxytrityl chloride followed by treatment with 2-cyanoethyltetraisopropylphosphordiamidite in the presence of N,N′-diisopropyl ammonium tetrazolide to afford the corresponding phosphoramidite. This phosphoramidite was used to insert the monomer X into an oligonucleotide which was used for thermal denaturation studies of a corresponding parallel triplex.  相似文献   

18.
为了寻找有生物活性的次生代谢产物,对从采集自中国南海的软海绵(Halichondria sp.)进行了化学成分研究,从中共分离得到了9个化合物,并对部分化合物进行了抗菌活性测试。根据现代波谱技术并结合文献数据,鉴定化合物的结构为:1,2,3,4-四氢-3-羧基-2-卡波林(1),色氨酸(2),环(异亮氨酸-脯氨酸)(3),开环(脯氨酸-缬氨酸)(4),环(丙氨酸-脯氨酸)(5),胆甾醇(6),二-(2-乙基己基)邻苯二甲酸酯(7),邻苯二甲酸正丁异丁酯(8)和邻苯二甲酸二异丁酯(9)。  相似文献   

19.
The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistant linezolid bacterial strains was higher than that of linezolid.  相似文献   

20.
The heats of formation (HOFs), energetic properties, and thermal stability of a series of 1,7-diamino-1,7-dinitrimino-2,4,6-trinitro-2,4,6-triazaheptane derivatives with different substituents, different numbers of substituents, and different original chains are found by using the DFT-B3LYP method. The results show that -NO2 or -NH2 is an effective substituent for increasing the gas-phase HOFs of the title compounds, especially -NO2 group. As the numbers of substitutents increase, their HOFs enhance obviously. Increasing the length of original chain is helpful for improving their HOFs. The substitution of -NO2 is useful for enhancing their detonation performances and the effects of the length of original chains on detonation properties are coupled with those of the substituents. An analysis of the BDE of the weakest bonds indicates that the substitution of the -NH2 groups and replacing the -NO2 groups of N-NO2 by the -NH2 groups are favorable for improving their thermal stability, while the substitution of -NO2 and increasing the length of original chain decrease their thermal stability. Considering the detonation performance and thermal stability, seven compounds may be considered as the potential candidates of high energy density compounds.  相似文献   

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