Structure‐Guided Design of Thiazolidine Derivatives as Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors

The pantothenate biosynthetic pathway is essential for the persistent growth and virulence of Mycobacterium tuberculosis (Mtb) and one of the enzymes in the pathway, pantothenate synthetase (PS, EC: 6.3.2.1), encoded by the panC gene, has become an appropriate target for new therapeutics to treat tuberculosis. Herein, we report nanomolar thiazolidine inhibitors of Mtb PS developed by a rational inhibitor design approach. The thiazolidine compounds were discovered by using energy‐based pharmacophore modelling and subsequent in vitro screening, which resulted in compounds with a half maximal inhibitory concentration (IC₅₀) value of (1.12±0.12) μM . These compounds were subsequently optimised by a combination of modelling and synthetic chemistry. Hit expansion of the lead by chemical synthesis led to an improved inhibitor with an IC₅₀ value of 350 nM and an Mtb minimum inhibitory concentration (MIC) of 1.55 μM . Some of these compounds also showed good activity against dormant Mtb cells.     

Biological Evaluation of Potent Triclosan‐Derived Inhibitors of the Enoyl–Acyl Carrier Protein Reductase InhA in Drug‐Sensitive and Drug‐Resistant Strains of Mycobacterium tuberculosis

New triclosan (TRC) analogues were evaluated for their activity against the enoyl–acyl carrier protein reductase InhA in Mycobacterium tuberculosis (Mtb). TRC is a well‐known inhibitor of InhA, and specific modifications to its positions 5 and 4′ afforded 27 derivatives; of these compounds, seven derivatives showed improved potency over that of TRC. These analogues were active against both drug‐susceptible and drug‐resistant Mtb strains. The most active compound in this series, 4‐(n‐butyl)‐1,2,3‐triazolyl TRC derivative 3 , had an MIC value of 0.6 μg mL^?1 (1.5 μM ) against wild‐type Mtb. At a concentration equal to its MIC, this compound inhibited purified InhA by 98 %, and showed an IC₅₀ value of 90 nM . Compound 3 and the 5‐methylisoxazole‐modified TRC 14 were able to inhibit the biosynthesis of mycolic acids. Furthermore, mc²4914, an Mtb strain overexpressing inhA, was found to be less susceptible to compounds 3 and 14 , supporting the notion that InhA is the likely molecular target of the TRC derivatives presented herein.     

Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death

In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2–HDAC binding agents. Compound 3 [(E)‐N‐hydroxy‐5‐(3‐(4‐(3‐oxo‐3‐(pyridin‐3‐yl)prop‐1‐en‐1‐yl)phenyl)thioureido)pentanamide] emerged as the most interesting of the series, being able to inhibit TG2 and HDACs both in vitro (TG2 IC₅₀=13.3±1.5 μm , HDAC1 IC₅₀=3.38±0.14 μm , HDAC6 IC₅₀=4.10±0.13 μm ) and in cell‐based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μm and protects neurons against toxic insults induced by glutamate (5 mm ) with an EC₅₀ value of 3.7±0.5 μm .     

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin–cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC₅₀) against Pf drug‐sensitive NF54, and drug‐resistant K1 and W2 strains ranged from 0.03–2.6, 0.03–1.9, and 0.02–1.7 μm . Although the compounds are less active than the precursor artemisinin derivatives, the cholesterol moiety renders the compounds relatively insoluble in the culture medium, and variation in solubilities among the different compounds may reflect in the range of efficacies observed. Activities against Mtb H37Rv were assessed using a standardized colony‐forming unit (CFU) assay after 24 h pretreatment of cultures with each of the compounds. Percentage inhibition ranged from 3–38 % and 18–52 % at 10 and 80 μm , respectively. Thus, in contrast to the comparator drug artemether, the conjugates display enhanced activities. The immediate aims include the preparation of conjugates with enhanced aqueous solubilities, assays against malaria and TB in vivo, and for TB, assays using an infected macrophage model and assessment of granuloma influx.     

Structure‐Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain

In this study we explored the pharmaceutically underexploited ATPase domain of DNA gyrase (GyrB) as a potential platform for developing novel agents that target Mycobacterium tuberculosis. In this effort a combination of ligand‐ and structure‐based pharmacophore modeling was used to identify structurally diverse small‐molecule inhibitors of the mycobacterial GyrB domain based on the crystal structure of the enzyme with a pyrrolamide inhibitor (PDB ID: 4BAE ). Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound 5 [(E)‐5‐(5‐(2‐(1H‐benzo[d]imidazol‐2‐yl)‐2‐cyanovinyl)furan‐2‐yl)isophthalic acid; IC₅₀=4.6±0.1 μm ], which was subsequently tailored through a combination of molecular modeling and synthetic chemistry to yield the optimized lead compound 24 [(E)‐3‐(5‐(2‐cyano‐2‐(5‐methyl‐1H‐benzo[d]imidazol‐2‐yl)vinyl)thiophen‐2‐yl)benzoic acid; IC₅₀=0.3±0.2 μm ], which was found to display considerable in vitro efficacy against the purified GyrB enzyme and potency against the H₃₇Rv strain of M. tuberculosis. Structural handles were also identified that will provide a suitable foundation for further optimization of these potent analogues.     

Effects of mixed solvents and PVDF types on performances of PVDF microporous membranes

Polyvinylidene fluoride (PVDF) microporous flat membranes were cast with different kinds of PVDFs and four mixed solvents [trimethyl phosphate (TMP)–N,N‐dimethylacetamide (DMAc), triethyl phosphate (TEP)–DMAc, tricresyl phosphate (TCP)–DMAc, and tri‐n‐butyl phosphate (TBP)–DMAc]. The effects of different commercial PVDFs (Solef® 1015, FR 904, Kynar 761, Kynar 741, Kynar 2801) on membrane morphologies and membrane performances of PVDF/TEP–DMAc/PEG200 system were investigated. The membrane morphologies were examined by scanning electron microscopy (SEM). The membrane performances in terms of pure water flux, rejection, porosity, and mean pore radius were measured. The membrane had the high flux of 143.0 ± 0.9 L m^?2 h^?1 when the content of TMP in the TMP–DMAc mixed solvent reached 60 wt %, which was 2.89 times that of the membrane cast with DMAc as single solvent and was 3.36 times that of the membrane cast with TMP as single solvent. Using mixed solvent with different solvent solubility parameters, different morphologies of PVDF microporous membranes were obtained. TMP–DMAc mixed solvent and TEP–DMAc mixed solvent indicated the stronger solvent power to PVDF due to the lower solubility parameter difference of 1.45 MPa^1/2 and the prepared membranes showed the faster precipitation rate and the higher flux. The less macrovoids of the membrane prepared with TEP (60 wt %)–DMAc (40 wt %) as mixed solvent contributed to the higher elongation ratio of 96.61% ± 0.41%. Therefore, using TEP(60 wt %)–DMAc (40 wt %) as mixed solvent, the casting solution had the better solvent power to PVDF, and the membrane possessed the excellent mechanical property. The microporous membranes prepared from casting solutions with different commercial PVDFs exhibited similar morphology, but the water flux increased with the increment of polymer solution viscosity. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Small-Molecule Inhibitors Targeting Sterol 14α-Demethylase (CYP51): Synthesis,Molecular Modelling and Evaluation Against Candida albicans

Fungal infections are a global issue affecting over 150 million people worldwide annually, with 750 000 of these caused by invasive Candida infections. Azole drugs are the frontline treatment against fungal infections; however, resistance to current azole antifungals in C. albicans poses a threat to public health. Two series of novel azole derivatives, short and extended derivatives, have been designed, synthesised and investigated for CYP51 inhibitory activity, binding affinity and minimum inhibitory concentration (MIC) against C. albicans strains. The short derivatives were more potent against the C. albicans strains (e. g., MIC 2-(4-chlorophenyl)-N-(2,4-dichlorobenzyl)-3-(1H-imidazol-1-yl)propanamide ( 5 f ) <0.03 μg/mL, N-(4-((4-chlorophenyl)sulfonamido)benzyl)-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propanamide ( 12 c ), 1 μg/mL, fluconazole 0.125 μg/mL) but both displayed comparable enzyme binding and inhibition ( 5 f K_d 62±17 nM, IC₅₀ 0.46 μM; 12 c K_d 43±18 nM, IC₅₀ 0.33 μM, fluconazole K_d 41±13 nM, IC₅₀ 0.31 μM, posaconazole K_d 43±11 nM, IC₅₀ 0.2 μM). The short series had poor selectivity for CaCYP51 over the human homologue, whereas the selectivity of the extended series, for example, compound 12 c , was higher (21.5-fold) than posaconazole (4.7-fold) based on K_d values, although posaconazole was more selective (615-fold) than 12 c (461-fold) based on IC₅₀ values. Based on inhibitory activity and selectivity profile, the extended series are the better of the two series for further development.     

Exploration of a Library of 3,4‐(Methylenedioxy)aniline‐Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design,Synthesis, and Evaluation

A library of 3,4‐(methylenedioxy)aniline‐derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO‐B and AChE, with IC₅₀ values in the micro‐ or nanomolar ranges. Compound 16 , 1‐(2,6‐dichlorobenzylidene)‐4‐(benzo[1,3]dioxol‐5‐yl)semicarbazide presented a balanced multifunctional profile of MAO‐A (IC₅₀=4.52±0.032 μm ), MAO‐B (IC₅₀=0.059±0.002 μm ), and AChE (IC₅₀=0.0087±0.0002 μm ) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO‐A and MAO‐B, and mixed‐type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme–inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug‐like characteristics.     

Development of Cyclobutene‐ and Cyclobutane‐Functionalized Fatty Acids with Inhibitory Activity against Mycobacterium tuberculosis

Eleven fatty acid analogues incorporating four‐membered carbocycles (cyclobutenes, cyclobutanes, cyclobutanones, and cyclobutanols) were investigated for the ability to inhibit the growth of Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb). A number of the analogues displayed inhibitory activity against both mycobacterial species in minimal media. Several of the molecules displayed potent levels of inhibition against Mtb, with MIC values equal to or below those observed with the anti‐tuberculosis drugs D ‐cycloserine and isoniazid. In contrast, two of the analogues that display the greatest activity against Mtb failed to inhibit E. coli growth under either set of conditions. Thus, the active molecules identified herein may provide the basis for the development of anti‐mycobacterial agents against Mtb.     

New Insights into the Anti‐Inflammatory and Antioxidant Properties of Nitrated Phospholipids

Nitro‐fatty acids (NO₂‐FA) have been widely studied with regard to their identification, structural characterization, and biological actions. NO₂‐FA could also be present endogenously esterified to phospholipids (PL), and NO₂‐PL were already detected in cardiac mitochondria from diabetic rats and cardiomyoblasts subjected to starvation. However, the biological actions of NO₂‐PL have been overlooked. In this study, we evaluate the antioxidant and anti‐inflammatory potential of the nitrated 1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine (POPC) formed in vitro by incubation with NO₂BF₄, in a well‐recognized mimetic model of nitroxidative stress. Nitrated POPC showed anti‐radical ability to reduce both 2,2‐diphenyl‐1‐picrylhydrazyl radical (DPPH^?) (IC₂₀ = 225 ± 4 μg/mL; Trolox equivalent (TE) = 86 ± 6 μmol Trolox/g lipid) and 2,2′‐azino‐bis‐3‐ethylbenzothiazoline‐6‐sulfonic acid radical cation (ABTS^?+) (IC₅₀ = 124 ± 2 μg/mL; TE = 152 ± 9 μmol Trolox/g lipid). Also, higher lag times were achieved in oxygen radical absorbance capacity (ORAC) assay for nitrated POPC, indicating a faster reaction with oxygen‐derived radicals (TE = 1.03 ± 0.22 and TE = 1.30 ± 0.16 mmol Trolox/g lipid for nonmodified and nitrated POPC, respectively). Nitrated POPC showed the ability to inhibit lipid oxidation induced by the hydroxyl radical generated under Fenton reaction conditions, monitored by electrospray ionization (ESI) mass spectrometry (MS) using phosphatidylcholine (PtdCho) liposomes as a model of cell membrane. Nitrated POPC showed anti‐inflammatory potential, as assessed by the inhibition of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 macrophages activated by the Toll‐like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) in a well‐described in vitro model of inflammation. Altogether, this study provides new clues regarding the antioxidant and anti‐inflammatory potential of nitrated POPC, which should be explored in depth.     

Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum

Chagas disease and malaria are two neglected tropical diseases (NTDs) that prevail in tropical and subtropical regions in 149 countries. Chagas is also present in Europe, the US and Australia due to immigration of asymptomatic infected individuals. In the absence of an effective vaccine, the control of both diseases relies on chemotherapy. However, the emergence of parasite drug resistance is rendering currently available drugs obsolete. Hence, it is crucial to develop new molecules. Phthalimides, thiosemicarbazones, and 1,3-thiazoles have been used as scaffolds to obtain antiplasmodial and anti-Trypanosoma cruzi agents. Herein we present the synthesis of 24 phthalimido-thiosemicarbazones ( 3 a – x ) and 14 phthalimido-thiazoles ( 4 a – n ) and the corresponding biological activity against T. cruzi, Plasmodium falciparum, and cytotoxicity against mammalian cell lines. Some of these compounds showed potent inhibition of T. cruzi at low cytotoxic concentrations in RAW 264.7 cells. The most active compounds, 3 t (IC₅₀=3.60 μM), 3 h (IC₅₀=3.75 μM), and 4 j (IC₅₀=4.48 μM), were more active than the control drug benznidazole (IC₅₀=14.6 μM). Overall, the phthalimido-thiosemicarbazone derivatives were more potent than phthalimido-thiazole derivatives against T. cruzi. Flow cytometry assay data showed that compound 4 j was able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with compounds 3 h , 3 t , and 4 j at IC₅₀ concentrations promoted changes in the shape, flagella, and surface of the parasite body similar to those observed in benznidazole-treated cells. The compounds with the highest antimalarial activity were the phthalimido-thiazoles 4 l (IC₅₀=1.2 μM), 4 m (IC₅₀=1.7 μM), and 4 n (IC₅₀=2.4 μM). Together, these data revealed that phthalimido derivatives possess a dual antiparasitic profile with potential effects against T. cruzi and lead-like characteristics.     

Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine-2,5-dione Hybrids as Potential Antitumor Agents

In search of novel and effective antitumor agents, pyrazoline-substituted pyrrolidine-2,5-dione hybrids were designed, synthesized and evaluated in silico, in vitro and in vivo for anticancer efficacy. All the compounds exhibited remarkable cytotoxic effects in MCF7 and HT29 cells. The excellent antiproliferative activity toward MCF7 (IC₅₀=0.78±0.01 μM), HT29 (IC₅₀=0.92±0.15 μM) and K562 (IC₅₀=47.25±1.24 μM) cell lines, prompted us to further investigate the antitumor effects of the best compound S2 (1-(2-(3-(4-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione). In cell-cycle analysis, S2 was found to disrupt the growth phases with increased cell population in G₁/G₀ phase and decreased cell population in G₂/M phase. The excellent in vitro effects were also supported by inhibition of anti-apoptotic protein Bcl-2. In vivo tumor regression studies of S2 in HT29 xenograft nude mice, exhibited equivalent and promising tumor regression with maximum TGI, 66 % (i. p. route) and 60 % (oral route) at 50 mg kg⁻¹ dose by both the routes, indicating oral bioavailability and antitumor efficacy. These findings advocate that hybridization of pyrazoline and pyrrolidine-2,5-dioes holds promise for the development of more potent and less toxic anticancer agents.     

N‐Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α‐Mannosidase II

Inhibition of the biosynthesis of complex N‐glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi α‐mannosidase II (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co‐inhibition of lysosomal α‐mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N‐substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α‐mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (K_i=50–76 μm , as determined by enzyme assays) with a significant selectivity index of IC₅₀(LManII)/IC₅₀(GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC₅₀=92–200 μm ) and low cytotoxic activities in normal fibroblast cell lines (IC₅₀>200 μm ). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoiα1,2‐mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target α‐mannosidase.     

Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases

A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC₅₀ values in the micromolar range, with the majority of the compounds showing selectivity for the MAO-B isoform. N-[2-Oxo-1-(prop-2-ynyl)indolin-3-ylidene]benzo[d][1,3]dioxole-5-carbohydrazide ( 3 ) was identified as a lead AChE inhibitor with IC₅₀=0.052±0.006 μm . N-[(3E)-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-2H-1,3-benzodioxole-5-carbohydrazide ( 2 ) was the lead MAO-B inhibitor with IC₅₀=0.034±0.007 μm , and showed 50 times greater selectivity for MAO-B over MAO-A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO-B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents.     

Biphasic Dose-Dependent G0/G1 and G2/M Cell-Cycle Arrest by Synthetic 2,3-Arylpyridylindole Derivatives in A549 Lung Cancer Cells

A collection of 2,3-arylpyridylindole derivatives were synthesized via the Larock heteroannulation and evaluated for their in vitro cytotoxic activity against A549 human lung cancer cells. Two derivatives expressed good cytotoxicity with IC₅₀ values of 1.18±0.25 μM and 0.87±0.10 μM and inhibited tubulin polymerization in vitro, with molecular docking studies suggesting the binding modes of the compounds in the colchicine binding site. Both derivatives have biphasic cell cycle arrest effects depending on their concentrations. At a lower concentration (0.5 μM), the two compounds induced G0/G1 cell cycle arrest by activating the JNK/p53/p21 pathway. At a higher concentration (2.0 μM), the two derivatives arrested the cell cycle at the G2/M phase via Akt signaling and inhibition of tubulin polymerization. Additional cytotoxic mechanisms of the two compounds involved the decreased expression of Bcl-2 and Mcl-1 antiapoptotic proteins through inhibition of the STAT3 and Akt signaling pathways.     

INH14, a Small-Molecule Urea Derivative,Inhibits the IKKα/β-Dependent TLR Inflammatory Response

N-(4-Ethylphenyl)-N′-phenylurea (INH14) is a fragment-like compound that inhibits the toll-like receptor 2 (TLR2)-mediated inflammatory activity and other inflammatory pathways (i.e., TLR4, TNF-R and IL-1R). In this study, we determined the molecular target of INH14. Overexpression of proteins that are part of the TLR2 pathway in cells treated with INH14 indicated that the target lay downstream of the complex TAK1/TAB1. Immunoblot assays showed that INH14 decreased IkBα degradation in cells activated by lipopeptide (TLR2 ligand). These data indicated the kinases IKKα and/or IKKβ as the targets of INH14, which was confirmed with kinase assays (IC₅₀ IKKα=8.97 μm ; IC₅₀ IKKβ=3.59 μm ). Furthermore, in vivo experiments showed that INH14 decreased TNFα formed after lipopeptide-induced inflammation, and treatment of ovarian cancer cells with INH14 led to a reduction of NF-kB constitutive activity and a reduction in the wound-closing ability of these cells. These results demonstrate that INH14 decreases NF-kB activation through the inhibition of IKKs. Optimization of INH14 could lead to potent inhibitors of IKKs that might be used as antiinflammatory drugs.     

Sulfonamide Inhibitors of β-Catenin Signaling as Anticancer Agents with Different Output on c-MYC

The Wnt/β-catenin pathway is often found deregulated in cancer. The aberrant accumulation of β-catenin in the cell nucleus results in the development of various malignancies. Specific drugs against this signaling pathway for clinical treatments have not been approved yet. Herein we report inhibitors of β-catenin signaling of potential therapeutic value as anticancer agents. Ethyl 4-((4-(trifluoromethyl)phenyl)sulfonamido)benzoate (compound 14 ) inhibits the effect on Wnt reporter with an IC₅₀ value of 7.0 μM, significantly reduces c-MYC levels, inhibits HCT116 colon cancer cell growth (IC₅₀ 20.2 μM), does not violate Lipinski and Veber rules, and shows predicted Caco-2 and MDCK cell permeability P_app>500 nm s⁻¹. Compound 14 seems to have potential for the development of new anticancer therapies.     

Wavelength Dependence of the Aerosol Angstrom Exponent and Its Implications Over Delhi,India

The aerosol optical depth (AOD), Angstrom coefficients (α and β), and the second-order Angstrom exponent (α′) obtained by Microtops-II sun photometer have been analyzed in the spectral range 0.34–0.87 μm over the urban polluted city of Delhi, India for the period 2007–2008, aiming at investigating the physical and optical properties of aerosols. The average values of AOD at 500 nm, α and β (in the range 340–870 nm) are found to be 0.78 ± 0.32, 0.78 ± 0.28, and 0.45 ± 0.21, respectively, for the entire period of observations. The AOD data show significant curvature in the lnτ versus lnλ relationship suggesting different dominant aerosol types depending on season. In order to analyze further the curvature effect and the relative dominance of aerosol size, α has been calculated in three wavelength bands, i.e., shorter (0.34–0.50 μm), longer (0.675–0.87 μm), and broad (0.34–0.87 μm) during four seasons, summer (April–June), monsoon (July–September), winter (October–January), and spring (February–March) accompanied with calculations of α′, which quantifies the deviation of logarithmic behavior of AOD with lnλ. The α′ values are found to be positive and higher in the months of October–December and mostly negative in February and March, while close to zero values of α′ are found in April–August. These results indicate that winter season exhibits dominance of fine-mode aerosols while summer relatively higher concentration of coarse-mode particles. On the other hand, monsoon and spring seasons revealed the presence of mixed type, both fine- and coarse-mode aerosols over Delhi.     

Design and Efficient Synthesis of RalA Inhibitors Containing the Dihydro-α-carboline Scaffold

Ras-related protein RalA is a member of the Ras small GTPases superfamily. Its activation plays an important role in regulating tumor initiation, invasion, migration, and metastasis. In this study, we designed a new type of RalA inhibitor containing a dihydro-α-carboline scaffold. The structurally new dihydro-α-carboline derivatives could be efficiently synthesized in good yields through a newly developed three-component [3+2+1] cyclization reaction. Evaluation of the biological activity showed that some of the dihydro-α-carboline derivatives can inhibit RalA/B and proliferative activities of NSCLC cell lines. The 4-(pyridin-3-yl)-dihydro-α-carboline compound ( 3 o ) was found to be the most potent derivative, with IC₅₀ values of 0.43±0.03, 0.64±0.07, 0.93±0.10, and 1.54±0.15 μM against A549, H1299, H460, and H1975 cells, respectively. Mechanism investigation suggested that 3 o inhibits the RalA/B activation of A549, down-regulates Bcl-2, stimulates cytochrome c and PARP cleavage, and induces cell apoptosis. A molecular docking study revealed that 3 o can form stable hydrogen bonds with residues of RalA. Moreover, amide-π and alkyl-π interactions also contributed to the affinity between 3 o and RalA.     

Kinetics and crystal structure of isothermal crystallization of poly(lactic acid) plasticized with triphenyl phosphate

In this article, the spherulitic growth rate of neat and plasticized poly(lactic acid) (PLA) with triphenyl phosphate (TPP) was measured and analyzed in the temperature range of 104–142°C by polarizing optical microscopy. Neat PLA had the maximum value of 0.28 μm/s at 132°C, whereas plasticized PLA had higher value than that of neat PLA, but the temperature corresponding to the maximum value was shifted toward lower one with increasing TPP content. The isothermal crystallization kinetics of neat and plasticized PLA was also analyzed by differential scanning calorimetry and described by the Avrami equation. The results showed for neat PLA and its blends with various TPP contents, the average value of Avrami exponents n were close to around 2.5 at two crystallization temperatures of 113 and 128°C, the crystallization rate constant k was decreased, and the half‐life crystallization time t_1/2 was increased with TPP content. For neat PLA and its blend with 15 wt % TPP content, the average value of n was 2.0 and 2.3, respectively, the value of k was decreased, and the value of t_1/2 was increased with crystallization temperature (T_c). Further investigation into crystallization activation energy ΔE_a of neat PLA and its blend with 15 wt % TPP showed that ΔE_a of plasticized PLA was increased compared to neat PLA. It was verified by wide‐angle X‐ray diffraction that neat PLA and its blends containing various TPP contents crystallized isothermally in the temperature range of 113–128°C all form the α‐form crystal. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010