1a 1h Research Articles

Synthesis and fluorescence property modulation of α-cyano-1,4-diphenylbutadiene derivatives containing triphenylamine structure

In this paper, a series of α-cyano-1,4-diphenylbutadiene derivatives containing triphenylamine structure were designed and synthesized. By changing the connection mode of the terminal diphenylamine, the angle between the donor and the acceptor was adjusted to further regulate the fluorescent wavelengths of 1a–1h from 456 nm to 621 nm in solution and 515 nm–614 nm in solid states.

Synthesis of novel benzimidazoles at room temperature, under solvent-free condition and their biological studies

An efficient and facile synthesis of substituted novel benzimidazoles (3a–3h) mediated by fruit juices viz. Cocos nucifera L. juice, Citrus limetta juice and Citrus sinensis L. juice, via condensation of substituted aldehydes (1a–1h) and o-phenylenediammine (2a) under solvent-free condition at room temperature is presented in this paper. The purity of compounds was confirmed by melting point and thin layer chromatography. All synthesized compounds (3a–3h) were fully characterized via NMR and FTIR spectral data and evaluated for in vitro herbicidal activity against Raphanus sativus L. (Radish) seeds. The compounds (3a–3h) were also evaluated for their antibacterial activity against Erwinia cartovora and Xanthomonas citri by inhibition zone method. Antifungal activity was also determined against Rhizoctonia solani and Colletotrichum gloeosporioides by poisoned food techniques method. From activity data, it was found that compounds 3d and 3e were most active against R. sativus L. (root) and R. sativus L. (shoot), respectively. Compound 3g has shown maximum inhibition zone i.e. 8.00 mm against E. cartovora at 2000 µg/mL concentration. Maximum X. citrii growth was inhibited by compounds 3a showing inhibition zone 5.20 mm at highest concentration. Compound 3f was found most active against R. solani and C. gloeosporioides fungus at 2000 µg/mL concentration. In comparison with the conventional methods, the present method complies with several key requirements of green chemistry principles such as the utilization of renewable feedstock, auxiliary aqueous conditions and reduces waste with the use of nature-derived catalyst. Therefore, the present method offers an attractive option because of its ecological safety, environmental acceptance, cost effective and easy workup process.

Design, synthesis and biological evaluation of 3-nitro-1,8-naphthalimides as potential antitumor agents

A series of 3-nitro-naphthalimides 1(1a–1h) were designed and synthesized as antitumor agents. MTT assay results showed that all these compounds exhibited obvious antiproliferative activity against SKOV3, HepG2, A549, T-24 and SMMC-7721 cancer cell lines, while compound 1a displayed the best antiproliferative activity against HepG2 and T-24 cell lines in comparison with mitonafide, with IC50 of 9.2 ± 1.8 and 4.133 ± 0.9 μM, respectively. In vivo antiproliferative activity assay results showed that compound 1a exhibited good antiproliferative activity in the HepG2 and T-24 models, compared with mitonafide. Action mechanism results showed that compound 1a could induced the damage of DNA and the inhibition topo I, accompanying by inducing the G2-stage arresting and the apoptosis of T-24 cancer cells through up-regulating expression levels of cyclin B1, cdc 2-pTy, Wee1, γH2AX, p21, Bax and cytochrome c and down-regulating expression of Bcl-2.

Synthesis and DNase I inhibitory properties of new benzocyclobutane-2,5-diones.

Aim: Eight new benzocyclobutane-2,5-diones (1a-1h) were synthesized, and their inhibitory properties against bovine pancreatic DNase I were examined in vitro. Methods & results: Compounds 1a-1h were synthesized using photocycloaddition of duroquinone with various phenyl-substituted ethylenes in the presence of 18W compact fluorescent lamp (visible light). Two compounds, 1,3,4,6-tetramethyl-7-phenylbicyclo[4.2.0]oct-3-ene-2,5-dione (1a) and 1,3,4,6-tetramethyl-7-p-tolylbicyclo[4.2.0]oct-3-ene-2,5-dione (1b) inhibited DNase I in a noncompetitive manner with IC50 values below 150 μM and showed to be more potent DNase I inhibitors than crystal violet, used as a positive control. In order to analyze potential binding sites for the studied compounds with DNase I, molecular docking study was performed. Conclusion: The studied benzocyclobutane-2,5-diones offer a good starting point for a design of new DNase I inhibitors.

Hydrazinolysis of aryl cinnamates and related esters: the α-effect arises from stabilization of five-membered cyclic transition state

A kinetic study is reported for nucleophilic substitution reactions of Y-substituted-phenyl cinnamates (1a–1h) with a series of primary amines including hydrazine in H2O containing 20 mol % DMSO at 25.0 °C. The Brønsted-type plot for the reaction of 2,4-dinitrophenyl cinnamate (1a) is linear with βnuc = 0.57 except hydrazine, which exhibits positive deviation from the linear correlation (i.e., the α-effect). The Brønsted-type plots for the reactions of 1a–1h with hydrazine and glycylglycine (glygly) are also linear with βlg = –0.71 and –0.87, respectively, when 1a is excluded from the linear correlation. Thus, the reactions have been concluded to proceed through a concerted mechanism on the basis of the linear Brønsted-type plots and magnitudes of the βnuc and βlg values. The α-effect shown by hydrazine is dependent on electronic nature of the substituent Y in the leaving group, e.g., it increases as the substituent Y becomes a weaker electron-withdrawing group (or as basicity of the leaving aryloxide increases), indicating that the α-effect is not due to destabilization of the ground state but mainly due to stabilization of the transition state. A five-membered cyclic TS structure, which could increase nucleofugality of the leaving aryloxide through H-bonding interaction, has been proposed to account for the leaving-group dependent α-effect found in this study. The theories suggested previously to rationalize the α-effect found for the related systems are also discussed.

Association of single nucleotide polymorphisms in CACNA 1A/CACNA 1C/CACNA 1H calcium channel genes with diabetic peripheral neuropathy in Chinese population.

The present study was conducted to explore the correlations between single nucleotide polymorphisms (SNPs) in the calcium channel CACNA 1A, CACNA 1C, and CACNA 1H genes and diabetic peripheral neuropathy (DPN) amongst the Chinese population. In total, 281 patients diagnosed with type 2 diabetes participated in the present study. These patients were divided into the case group, which was subdivided into the DPN (143 cases) and the non-DPN groups (138 cases). Subsequently, 180 healthy individuals that had undergone routine health examinations were also recruited and assigned to the control group. PCR-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotype and allele frequencies of CACNA 1A, CACNA 1C, and CACNA 1H genes; logistic regression analysis to investigate the association of gene polymorphisms with DNP. Gene–gene interactions were then detected by generalized multifactor dimensionality reduction (GMDR). The results revealed that CACNA 1A rs2248069 and rsl6030, CACNA 1C rs216008 and rs2239050, and CACNA 1H rs3794619, and rs7191246 SNPs were all associated with DPN, while rs2248069, rsl6030, rs2239050, and rs7191246 polymorphisms were attributed to the susceptibility to DPN. It was also observed that the optimal models were three-, four- and five-dimensional models with a prediction accuracy of 61.05% and the greatest consistency of cross-validation was 10/10. In summary, these findings demonstrated that the SNPs in the CACNA 1A, CACNA 1C, and CACNA 1H genes were involved in the pathophysiology of DPN. In addition, polymorphisms in the CACNA 1A, CACNA 1C, and CACNA 1H genes and their interactions also had effects on DPN.

Medium effect (water versus MeCN) on reactivity and reaction pathways for the SNAr reaction of 1-aryloxy-2,4-dinitrobenzenes with cyclic secondary amines

A kinetic study on SNAr reactions of 1-aryloxy-2,4-dinitrobenzenes (1a–1h) with a series of cyclic secondary amines in 80 mol% water – 20 mol% DMSO at 25.0 ± 0.1 °C is reported. The plots of kobsd versus amine concentration curve upward except for the reactions of substrates possessing a strong electron-withdrawing group in the leaving aryloxide with strongly basic piperidine. The curved plots indicate that the reactions proceed through both uncatalytic and catalytic routes. Linear Brønsted-type plots have been obtained for the uncatalyzed and catalyzed reactions of 1-(4-nitrophenoxy)-2,4-dinitrobenzene (1a) with βnuc = 0.84 and 0.78, respectively. The Yukawa–Tsuno plot for the uncatalyzed reactions of 1a–1h with piperidine results in an excellent linear correlation with ρ = 1.66 and r = 0.31. In contrast, rate constants for catalyzed reactions are independent of the electronic nature of the substituent in the leaving group. The current SNAr reactions have been proposed to proceed via a zwitterionic intermediate (MC±) that partitions to products through uncatalytic and catalytic routes. The catalyzed reaction from MC± has been concluded to proceed through a concerted mechanism with a six-membered cyclic transition state (TScycl) rather than via a stepwise pathway with a discrete anionic intermediate (MC−), the traditionally accepted mechanism. Medium effects on the reactivity and reaction mechanism are discussed. Particularly, hydrogen bonding of the amines to water precludes formation of kinetically significant dimers found in some aprotic solvents; no explicit role for water in the catalytic transition state is required or proposed. The specific stabilization of the leaving aryloxides substituted with strong electron-withdrawing groups accounts for the lack of the catalytic pathway in these systems (1a–1c) with piperidine nucleophile.

Synthesis and biological evaluation of novel tricyclic oxazine and oxazepine fused quinazolines. Part 2: Gefitinib analogs

Two series of novel tricyclic oxazine and oxazepine fused quinazolines have been designed and synthesized. The in vitro antitumor effect of the title compounds was screened on N87, A431, H1975, BT474 and Calu-3 cell lines. Compared to gefitinib and erlotinib, compounds 1a–1h were found to demonstrate more potent antitumor activities. Several derivatives could counteract EGF-induced phosphorylation of EGFR in cells, and their potency was comparable to the reference compounds. Compounds 1a–1f, 1h were chosen for further evaluation of EGFR and HER2 in vitro kinase inhibitory activity. Compounds 1c–1f, 1h effectively inhibited the in vitro kinase activity of EGFR and HER2 with similar efficacy as gefitinib and erlotinib.

Reactivity of 1,2,3-triazoles towards sulfonyl chlorides. A novel approach to 1- and 2-sulfonyl-4-azolyl-1,2,3-triazoles

The reactions of N-unsubstituted triazoles with sulfonyl chlorides afforded mixtures of regioisomeric 1- and 2-sulfonyl-1,2,3-triazoles. In some cases, pure regioisomers were obtained by crystallization of mixtures of isomers. 1,2,3-Triazoles bearing thiadiazole, isoxazole and benzene rings react with mesyl chloride and tosyl chloride to form mainly 1-substituted 1,2,3-triazoles. Conversely, reactions of triazoles 1a,b and oxadiazolyl triazole 1h with more bulky 1-(2,4-dimethylphenyl)sulfonyl chloride affords mainly 2-substitued products. Oxadiazole 1b furnishes an equal mixture of the regioisomeric products 3 and 4 as a result of the reaction with mesyl and tosyl chlorides. Higher temperatures increase the ratio of isomers in favor of the 2-substituted triazole. The ratio of isomers depends on both the nature of the azolyl ring and on the size of the substituent in the sulfonyl chloride. Based on the results of experimental and theoretical data, 1-substituted and 2-substituted 1,2,3-triazoles can be considered as the kinetic and thermodynamic products.

Correlations among experimental and theoretical NMR data to determine the absolute stereochemistry of darcyribeirine, a pentacyclic indole alkaloid isolated from Rauvolfia grandiflora

Darcyribeirine (1) is a pentacyclic indole alkaloid isolated from Rauvolfia grandiflora. Stereochemistry of 1 was previously proposed based on 1D (coupling constant data) and 2D (NOESY correlations) NMR techniques, having been established a configuration 3R, 15S, and 20R (isomer 1a). Stereoisomers of 1 (i.e., 1a–1h) can be grouped into four sets of enantiomers. Carbon chemical shifts and hydrogen coupling constants were calculated using BLYP/6-31G* theory level for the eight isomers of 1. Calculated NMR data of 1a–1h were correlated with the corresponding experimental data of 1. The best correlations between theoretical and experimental carbon chemical shift data were obtained for the set of enantiomers 1e/1f to structures in the gaseous phase and considering solvent effects (using PCM and explicit models). Similar results were obtained when the same procedure was performed to correlations between theoretical and experimental coupling constant data. Finally, optical rotation calculations indicate 1e as its absolute stereochemistry. Orbital population analysis indicates that the hydrogen bonding between N–H of 1e and DMSO is due to contributions of its frontier unoccupied molecular orbitals, mainly LUMO+1, LUMO+2, and LUMO+3.

Synthesis and anticancer activity evaluation of some acridine derivatives

9-Amino acridine derivatives (1a–1h) on condensation with 9, 10-dihydroanthracene-9, 10-α, β-succinic anhydride (2) at room temperature gave condensation products (3a–3h). Microwave-assisted condensation of 9-amino acridine derivatives (1a–1d) with phthalic anhydride, cis 1,2,3,6-tetrahydrophthalimide, and 2,5-pyrroledione gave corresponding condensation products 4a–4d, 5a–5d & 6a–6d, respectively, in good yields. All these compounds were screened for in vitro anticancer activity against five human cancer cell lines i.e., breast (T47D), lung (NCl H-522), colon (HCT-15), ovary (PA-1), and liver (Hep G2). Compounds 3a (breast T47D), 3 g (lung NCl H-522), 4a (liver Hep G2), and 6b (colon HCT-15) exhibited IC50 values 5.4, 4.2, 4.5, and 2.4 µM, respectively, and hence possess good anticancer activity.

Kinetic study on SNAr reaction of 1-(y-substituted-phenoxy)-2,4-dinitrobenzenes with cyclic secondary amines in acetonitrile: evidence for cyclic transition-state structure.

A kinetic study is reported for SNAr reactions of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes (1a-1h) with amines in MeCN. The plots of pseudo-first-order rate constant versus amine concentration curve upward, indicating that the reactions are catalyzed by a second amine molecule. The Brønsted-type plots for the reaction of 1-(4-nitrophenyl)-2,4-dinitrobenzene (1a) with secondary amines are linear with βnuc = 1.10 and 0.85 for the uncatalyzed and catalyzed reactions, respectively, while the Yukawa-Tsuno plots for the reactions of 1a-1h with piperidine result in excellent linear correlations with ρY = 1.85 and r = 0.27 for the uncatalyzed reaction and ρY = 0.73 and r = 0.23 for the catalyzed reaction. The catalytic effect decreases with increasing amine basicity or electron-withdrawing ability of the substituent Y in the leaving group. Activation parameters calculated from the rate constants measured at five different temperatures for the catalyzed reaction of 1a with piperidine are ΔH(‡) = 0.38 kcal/mol and ΔS(‡) = -55.4 cal/(mol K). The catalyzed reaction from a Meisenheimer complex (MC(±)) is proposed to proceed through a concerted mechanism with a cyclic transition-state rather than via a stepwise pathway with an anionic intermediate, MC(-). Deuterium kinetic isotope effects provide further insight into the nature of the concerted transition state.

Synthesis and biological evaluation of novel tricyclic oxazine and oxazepine fused quinazolines. Part 1: Erlotinib analogs

Two series of novel tricyclic oxazine and oxazepine fused quinazolines have been designed and synthesized. The in vitro antitumor effect of the title compounds was screened on N87, A431, H1975, BT474 and Calu-3 cell lines. Compared to erlotinib and gefitinib, compounds 1a–1h were found to demonstrate more potent antitumor activities. Several derivatives could counteract EGF-induced phosphorylation of EGFR in cells, and their potency was comparable to the reference compounds. Compounds 1a–1h were chosen for further evaluation of EGFR and HER2 in vitro kinase inhibitory activity. Compounds 1b–1f, 1h effectively inhibited the in vitro kinase activity of EGFR and HER2 with similar efficacy as erlotinib and gefitinib.

Photoinduced regioselective arylation of N-vinyllactams and methylthiazoles by tetrachlorophthalimides

Abstract Photoinduced reactions of 4,5,6,7-tetrahalophthalimides (1a–1h) with selected N-vinyllactams (N-vinylpyrrolidinone, N-vinylcaprolactam) and methylthiazoles respectively lead to dehydrohalogenative coupling reactions between the phthalimide and these heterocycles. These mild and metal-free coupling reactions result in regioselective and stereoselective arylation of the heterocycles by the phthalimide, with the Z-isomer as the main products. Reaction mechanism for the photo-reactions is discussed

Knowledge-based hydrogen bond prediction and the synthesis of salts and cocrystals of the anti-malarial drug pyrimethamine with various drug and GRAS molecules

We have previously reported on hydrogen bond propensity calculations for the potential formation of adducts between pyrimethamine and dicarboxylic acids. Here we extend the range of potential synthon interactions using a variety of potential coformers. Specifically calculations were performed to predict the possibility of the formation of molecular adducts, 1a–1h, between the anti-malarial drug pyrimethamine (1) and (a) carbamazepine, (b) theophylline, (c) aspirin, (d) α-ketoglutaric acid, (e) saccharin, (f) p-coumaric acid, (g) succinimide and (h) L-isoleucine. The bonds of highest propensity were predicted between 1 and coformers (b–h), indicating a high probability of formation of adducts between 1 and b–h. In contrast the bonds of highest propensity were between reactants and the solvent for the adduct 1a, indicating either a high probability of the reactants crystallizing as solvates or incorporation of solvent into the adduct lattice. Experimental results agreed with the propensity calculations with the formation of a solvated cocrystal (1a·CH3OH). The successful application of hydrogen bond propensity calculations to the prediction of likely outcomes of these cocrystallization reactions suggests that this may be a useful tool in designing more targeted screening experiments.

New bispyrazoline derivatives built around aliphatic chains: Synthesis, characterization and antimicrobial studies

The bispyrazolines 3a–3h built around the alkyl chains of varying lengths have been synthesized from the cyclization reactions of bischalcones with phenyl hydrazine. The bischalcones 2a–2h were obtained from the Claisen–Schmidt reactions of acetophenone with various bisaldehydes 1a–1h. The intermediate bischalcones and final bisheterocyclic compounds have been characterized by means of IR, 1H-NMR, 13C-NMR, Mass (ESI) and elemental analysis. The antibacterial and antifungal activities of the synthesized compounds were also evaluated against the Klubsellia pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Bacillius subtilis and Aspergillius janus, Aspergillus niger and Pencillium glabrum, respectively. The antimicrobial behaviour of the bispyrazolines 3a–3h is found to be dependent on the length of internal spacer unit.

Synthesis, crystal structures, and photophysical properties of a series of novel tetrahydrobenzodiacridines

Several novel 6,7,14,15-tetrahydro-benzo[1,2-c:4,5-c′]diacridine derivatives (1a–1h) were synthesized in this study. Compounds 1a–1h were thermally robust with high decomposition temperatures (≥359.5°C) and high melting points (223.7°C–452.2°C). On the other hand, compound 1b was crystallized in a triclinic system, containing space groups P-1. Compounds 1a–1h showed UV–vis absorption (λmaxAbs) in the range of 372nm–377nm in chloroform solutions and 381nm–389nm in solid states. They also showed fluorescence (λmaxEm) in the range of 374nm–389nm in chloroform solutions and 421nm–457nm in solid states. Moreover, these compounds exhibited good fluorescence quantum yields ranging from 43.5% to 96.1%. Compounds 1a–1h showed a formal reduction potential in the range of −1.95V to −2.13V (vs. SCE), and their LUMO and HOMO levels were 2.27eV–2.45eV and 4.92eV–6.31eV, respectively. These results demonstrate that novel 6,7,14,15-tetrahydro-benzo[1,2-c:4,5-c′]diacridine derivatives (1a-1h) are promising thermally stable blue light-emitting materials with good electron transport and good hole-blocking properties for organic light-emitting diodes.

Hydrotalcite: recyclable, novel heterogeneous catalyst for facile, environmentally benign and high yielding multi-component synthesis and mechanistic study under solvent free conditions

The synthesis of the 4H-pyrimido[2,1-b][1,3]benzothiazole (1a–1h), 1,2,4-triazoloquinazolines (2a,2b), octahydroquinazolinones (3a,3b) and fused thiazolo[2,3-b]quinazolinone (4a,4b) by multicomponent reactions using aldehydes, dicarbonyl and 2-amino benzothiazole/3-amino-1,2,4-triazole/urea/thiorea has been carried out in the presence of Mg–Al–CO3 and Ca–Al–CO3 hydrotalcite as a heterogeneous catalyst. Hydrotalcites need short reaction times, are non-toxic, easy to work up and reusable under solvent free conditions, hence making this process environment friendly. A detailed mechanistic study shows that the reaction using urea proceeds through imine intermediate 6. In addition, we have isolated and characterized the key intermediate of the reaction by using hydrotalcite.

Microwave-assisted synthesis of 3′-indolyl substituted 4H-chromenes catalyzed by DMAP and their antimicrobial activity

A new series of indole-based chromene derivatives 4a–4p has been synthesized by one pot cyclocondensation reaction of 2-phenyl-1H-indole-3-carbaldehyde 1a–1h; malononitrile 2; and 1,3-cyclohexanedione/dimedone 3a/b under microwave irradiation catalyzed by an organocatalyst 4-(N,N-dimethylamino) pyridine. Easy experimental procedure, high yield, selectivity, and shorter reaction time are the imperative features of this method. All the compounds were screened against a representative panel of bacteria and fungi. Some of the compounds are found to be equipotent or more potent than that of standard drugs as evident from SAR study.

Synthesis and calming activity of 2-amino-4-(4-β-d-allopyranoside-phenyl)-6-3(4)-substituted phenylpyrimidines

Using helicid as starting material, E-4-β-D-allopyranoside-cinnamic-4-substituted phenylketones (1a–1h) containing the structure of chalcones were synthesized; then these chalcones were reacted with guanidine hydrochloride through a 1,4-Michael reaction, giving 2-amino-4-(4-β-D-allopyranoside-phenyl)-6-3(4)substituted phenylpyrimidines (2a–2h), which were characterized by IR, 1 H NMR, and HR-MS. The target compounds were evaluated by the spontaneous locomotor activity test, showing that all of them had good calming activity; compound 2f was found to have the greatest.