Structural Studies on 4,5‐Disubstituted 2‐Aminoimidazole‐Based Biofilm Modulators that Suppress Bacterial Resistance to β‐Lactams

A library of 4,5‐disubstituted 2‐aminoimidazole triazole amide (2‐AITA) conjugates has been successfully assembled. Upon biological screening, this class of small molecules was discovered as enhanced biofilm regulators through non‐microbicidal mechanisms against methicillin‐resistant Staphylococcus aureus (MRSA) and multidrug‐resistant Acinetobacter baumannii (MDRAB), with active concentrations in the low micromolar range. The library was also subjected to synergism and resensitization studies with β‐lactam antibiotics against MRSA. Lead compounds were identified that suppress the antibiotic resistance of MRSA by working synergistically with oxacillin, a β‐lactam antibiotic resistant to penicillinase. A further structure–activity relationship (SAR) study on the parent 2‐AITA compound delivered a 2‐aminoimidazole diamide (2‐AIDA) conjugate with significantly increased synergistic activity with oxacillin against MRSA, decreasing the MIC value of the β‐lactam antibiotic by 64‐fold. Increased anti‐biofilm activity did not necessarily lead to increased suppression of antibiotic resistance, which indicates that biofilm inhibition and resensitization are most likely occurring via distinct mechanisms.     

Synthesis and Evaluation of N‐Phenylpyrrolamides as DNA Gyrase B Inhibitors

ATP‐competitive inhibitors of DNA gyrase and topoisomerase IV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N‐phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from E. coli and Staphylococcus aureus. Antibacterial activities were studied against Gram‐positive and Gram‐negative bacterial strains. The most potent compound displayed an IC₅₀ of 47 nm against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 μm against the Gram‐positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux‐pump‐deficient E. coli strain (MIC=6.25 μm ) and against wild‐type E. coli in the presence of efflux pump inhibitor PAβN (MIC=3.13 μm ). Here we describe new findings regarding the structure–activity relationships of N‐phenylpyrrolamide DNA gyrase B inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds.     

Tribological behavior of polyamide 66‐based binary and ternary composites

Friction and wear characteristics of polyamide 66 (PA66) and the composites of organoclay modified by styrene–ethylene/butylene–styrene triblock copolymer grafted with 1.84 wt% of maleic anhydride (SEBS‐g‐MA) were studied using an Universal Micro Tribometer reciprocating friction and wear tester. The morphologies of the wear tracks of PA66 and the composites were observed using a scanning electron microscope. The results showed that plastic deformation induced by the traction of the harder steel ball occurred on the worn surfaces of PA66 and the composite which were reinforced by SEBS‐g‐MA copolymer. It was found that the average frictional coefficient and specific wear rate of PA66/SEBS‐g‐MA binary composite are lowest under the same conditions. This indicates that toughness and wear resistance of PA66 matrix are improved with the incorporation of SEBS‐g‐MA copolymer. POLYM. ENG. SCI., 2009. © 2009 Society of Plastics Engineers     

Diaryl‐Substituted Azolylthioacetamides: Inhibitor Discovery of New Delhi Metallo‐β‐Lactamase‐1 (NDM‐1)

The emergence and spread of antibiotic‐resistant pathogens is a global public health problem. Metallo‐β‐lactamases (MβLs) such as New Delhi MβL‐1 (NDM‐1) are principle contributors to the emergence of resistance because of their ability to hydrolyze almost all known β‐lactam antibiotics including penicillins, cephalosporins, and carbapenems. A clinical inhibitor of MBLs has not yet been found. In this study we developed eighteen new diaryl‐substituted azolylthioacetamides and found all of them to be inhibitors of the MβL L1 from Stenotrophomonas maltophilia (K_i<2 μM ), thirteen to be mixed inhibitors of NDM‐1 (K_i<7 μM ), and four to be broad‐spectrum inhibitors of all four tested MβLs CcrA from Bacteroides fragilis, NDM‐1 and ImiS from Aeromonas veronii, and L1 (K_i<52 μM ), which are representative of the B1a, B1b, B2, and B3 subclasses, respectively. Docking studies revealed that the azolylthioacetamides, which have the broadest inhibitory activity, coordinate to the Zn^II ion(s) preferentially via the triazole moiety, while other moieties interact mostly with the conserved active site residues Lys224 (CcrA, NDM‐1, and ImiS) or Ser221 (L1).     

Effect of poly [styrene‐b‐(ethylene‐co‐butylene)‐b‐styrene] (SEBS) and maleic anhydride‐grafted SEBS triblock copolymers in immiscible blends of (polyamide‐6)/polycarbonate: Morphology‐mechanical properties relationships

The effects of using maleated poly[styrene‐b‐(ethylene‐co‐butylene)‐b‐styrene] triblock copolymer (SEBS‐g‐MAH) and unmodified SEBS (unSEBS) on the phase morphology and mechanical properties of immiscible polymer blends of polyamide‐6 (PA‐6) and polycarbonate (PC) are investigated. Different binary, ternary, and quaternary blends were prepared by using a Brabender® co‐rotating twin‐screw extruder. The weight ratio of unSEBS to SEBS‐g‐MAH was changed to probe the phase morphology and mechanical properties. The results revealed that the mechanical properties of (PA‐6)/PC/(unSEBS/SEBS‐g‐MAH) blends were considerably governed by the unSEBS to SEBS‐g‐MAH weight ratio. Morphological investigation based on the spreading coefficient concept confirmed the results of scanning electron microscopy, indicating encapsulation of unSEBS domains around the PC core‐forming component in the presence of reactive SEBS‐g‐MAH precursor. Moreover, larger unSEBS‐PC composite droplets appeared throughout PA‐6 matrix upon increasing the ratio of unSEBS to SEBS‐g‐MAH, until reaching a maximum value. In the case of the (PA‐6)/PC blend compatibilized with a 50/50 combination of unSEBS and SEBS‐g‐MAH, the highest mechanical properties, i.e., tensile strength, impact resistance, and strain at break, were achieved owing to compatibilizing effect of virgin and maleated SEBS constituents. J. VINYL ADDIT. TECHNOL., 21:245–252, 2015. © 2014 Society of Plastics Engineers     

α‐Keto Phenylamides as P1′‐Extended Proteasome Inhibitors

The major challenge for proteasome inhibitor design lies in achieving high selectivity for, and activity against, the target, which requires specific interactions with the active site. Novel ligands aim to overcome off‐target‐related side effects such as peripheral neuropathy, which is frequently observed in cancer patients treated with the FDA‐approved proteasome inhibitors bortezomib ( 1 ) or carfilzomib ( 2 ). A systematic comparison of electrophilic headgroups recently identified the class of α‐keto amides as promising for next generation drug development. On the basis of crystallographic knowledge, we were able to develop a structure–activity relationship (SAR)‐based approach for rational ligand design using an electronic parameter (Hammett’s σ) and in silico molecular modeling. This resulted in the tripeptidic α‐keto phenylamide BSc4999 [(S)‐3‐(benzyloxycarbonyl‐(S)‐leucyl‐(S)‐leucylamino)‐5‐methyl‐2‐oxo‐N‐(2,4‐dimethylphenyl)hexanamide, 6 a ], a highly potent (IC₅₀=38 nM ), cell‐permeable, and slowly reversible covalent inhibitor which targets both the primed and non‐primed sites of the proteasome’s substrate binding channel as a special criterion for selectivity. The improved inhibition potency and selectivity of this new α‐keto phenylamide makes it a promising candidate for targeting a wider range of tumor subtypes than commercially available proteasome inhibitors and presents a new candidate for future studies.     

Synthesis of polyundecamethylene 2,6‐naphthalamide as semiaromatic polyamide‐containing naphthalene ring

A novel engineering plastic polyundecamethylene 2,6‐naphthalamide (PA11N) was prepared via a reaction of 2,6‐naphthalene dicarboxylic acid and 1,11‐undecanediamine through a three‐step procedure. The structure of synthesized PA11N was characterized by elemental analysis, Fourier transform infrared spectroscopy, and proton nuclear magnetic resonance (¹H‐NMR). The thermal behaviors were determined by differential scanning calorimetry, thermogravimetric analysis, and dynamic mechanical analysis. The solubility, water‐absorbing capacity, and mechanical properties of PA11N have also been investigated. Melting temperature (T_m), glass transition temperature (T_g), and decomposition temperature (T_d) of PA11N are 294, 139, and 493°C, respectively. The results show that the heat resistance and mechanical properties of PA11N are near to those of polynonamethylene terephthalamide, and PA11N is a promising heat‐resistant and processable engineering plastic. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Design of gem‐Difluoro‐bis‐Tetrahydrofuran as P2 Ligand for HIV‐1 Protease Inhibitors to Improve Brain Penetration: Synthesis,X‐ray Studies,and Biological Evaluation

The structure‐based design, synthesis, biological evaluation, and X‐ray structural studies of fluorine‐containing HIV‐1 protease inhibitors are described. The synthesis of both enantiomers of the gem‐difluoro‐bis‐THF ligands was carried out in a stereoselective manner using a Reformatskii–Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐methoxyphenyl)sulfonamido)‐1‐phenylbutan‐2‐yl) carbamate ( 3 ) and (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐aminophenyl)sulfonamido)phenylbutan‐2‐yl) carbamate ( 4 ), exhibited HIV‐1 protease inhibitory K_i values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC₅₀ values of 0.8 and 3.1 nM against the laboratory strain HIV‐1_LAI. The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood–brain barrier permeability in an in vitro model. A high‐resolution X‐ray structure of inhibitor 4 in complex with HIV‐1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV‐1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis‐THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom.     

Synthesis and Structure–Activity Relationship Studies of 2‐(1,3,4‐Oxadiazole‐2(3H)‐thione)‐3‐amino‐5‐arylthieno[2,3‐b]pyridines as Inhibitors of DRAK2

In recent years, DAPK‐related apoptosis‐inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small‐molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (K_d) value of 0.25 μM . Variation of the core scaffold and of the substitution pattern afforded a series of 5‐arylthieno[2,3‐b]pyridines with strong binding affinity (K_d=0.008 μM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC₅₀ value of 0.029 μM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors.     

A Structure‐Based Virtual Screening Approach toward the Discovery of Histone Deacetylase Inhibitors: Identification of Promising Zinc‐Chelating Groups

The inhibitors of histone deacetylases (HDACs) have drawn a great deal of attention due to their promising potential as small‐molecule therapeutics for the treatment of cancer. By means of virtual screening with docking simulations under consideration of the effects of ligand solvation, we were able to identify six novel HDAC inhibitors with IC₅₀ values ranging from 1 to 100 μM . These newly identified inhibitors are structurally diverse and have various chelating groups for the active site zinc ion, including N‐[1,3,4]thiadiazol‐2‐yl sulfonamide, N‐thiazol‐2‐yl sulfonamide, and hydroxamic acid moieties. The former two groups are included in many drugs in current clinical use and have not yet been reported as HDAC inhibitors. Therefore, they can be considered as new inhibitor scaffolds for the development of anticancer drugs by structure–activity relationship studies to improve the inhibitory activities against HDACs. Interactions with the HDAC1 active site residues responsible for stabilizing these new inhibitors are addressed in detail.     

C6‐Unsubstituted Pyrazolo[3,4‐d]pyrimidines Are Dual Src/Abl Inhibitors Effective against Imatinib Mesylate Resistant Chronic Myeloid Leukemia Cell Lines

Docking simulations were used to predict the most favorable interaction between the T315I mutated form of Abl (invariably associated with resistance to the tyrosine kinase inhibitor imatinib mesylate, IM) and C6‐unsubstituted and substituted pyrazolo[3,4‐d]pyrimidines previously found to be dual Src/Abl inhibitors. Two C6‐unsubstituted ( 1 and 2 ) and eight C6‐substituted compounds ( 3 – 10 ) were selected and assayed for their effects on the Ba/F3 cell line transducing the wild‐type p210Bcr–Abl construct, which is IM‐sensitive, or three of the most common mutations associated with IM resistance in vivo (T315I, Y253F, and E255K), and driven to drug resistance by saturating doses of IL‐3 or by the expression of the Bcr–Abl construct coding for the p185 protein of acute lymphoblastic leukemia. Compounds 1 and 2 were active against all cell lines assayed (LD₅₀ range: 0.7–4.3 μM ), whereas C6‐substituted compounds exhibited lower activity (LD₅₀～8 μM for compound 3 toward the T315I mutant). Notably, 1 and 2 were also effective toward the T315I mutation, which is insensitive to dual Src/Abl inhibitors. The cytotoxic effects of 1 and 2 on IM‐sensitive and IM‐resistant Ba/F3 cells were attributable, at least in part, to their pro‐apoptotic activity. Taken together, such findings suggest that C6‐unsubstituted pyrazolo[3,4‐d]pyrimidines may represent useful inhibitors to target IM‐resistant chronic myeloid leukemia.     

The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram‐Negative Bacteria to β‐Lactams

The increasing incidence of inducible chromosomal AmpC β‐lactamases within the clinic is a growing concern because these enzymes deactivate a broad range of even the most recently developed β‐lactam antibiotics. As a result, new strategies are needed to block the action of this antibiotic resistance enzyme. Presented here is a strategy to combat the action of inducible AmpC by inhibiting the β‐glucosaminidase NagZ, which is an enzyme involved in regulating the induction of AmpC expression. A divergent route facilitating the rapid synthesis of a series of N‐acyl analogues of 2‐acetamido‐2‐deoxynojirimycin is reported here. Among these compounds are potent NagZ inhibitors that are selective against functionally related human enzymes. These compounds reduce minimum inhibitory concentration values for β‐lactams against a clinically relevant Gram‐negative bacterium bearing inducible chromosomal AmpC β‐lactamase, Pseudomonas aeruginosa. The structure of a NagZ–inhibitor complex provides insight into the molecular basis for inhibition by these compounds.     

Coloring effect of the organic hybrid of polyamide 6 and N,N′‐ethylene‐bis(tetrabromophthalimide)

Coloring study in organic hybrid of polyamide (PA6) and N,N′‐ethylene‐bis(tetrabromophthalimide) (EPT), where the chromophore was self‐assembled by hydrogen bonding formed between PA6 molecular chains and EPT compound, have been characterized by several techniques. CS930 double wavelength lamella scanner was employed to measure the change of color. The existence of hydrogen bonding in PA6/N‐N′‐ethylene‐bis (tetrabromophthalimide) (PA6EPT) was investigated with Fourier transform infrared (FTIR), the results of which were compared with that of PA6 with the same thermal history. FTIR spectra at room temperature revealed that there is essentially hydrogen bonding between PA6 and EPT. The crystallization behavior of PA6EPT affected by hydrogen bonding was studied by using FTIR. The temperature‐dependent behavior of both PA6 and PA6EPT was studied by temperature‐FTIR spectroscopy and differential scanning calorimetry (DSC). With temperature increasing, changes in sensitive, high‐resolution absorbance spectra are observed as dissolve‐volatilizing thin film. Temperature‐FTIR results showed that the hydrogen bonding in PA6EPT attenuated and dissociated considerably at a smaller rate than PA6, that is to say, hydrogen bonding in PA6EPT is more stable than that in PA6. DSC showed that the melting temperature of PA6EPT and PA6 are similar. However, the crystalline degree and crystalline temperature and melting enthalpy of PA6 and PA6EPT are different. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 104: 594–600, 2007     

Discovery of Non‐ATP‐Competitive Inhibitors of Polo‐like Kinase 1

Polo‐like kinase 1 (Plk1) is an evolutionarily conserved serine/threonine kinase, and its N‐terminal kinase domain (KD) controls cell signaling through phosphorylation. Inhibitors of Plk1 are potential anticancer drugs. Most known Plk1 KD inhibitors are ATP‐competitive compounds, which may suffer from low selectivity. In this study we discovered novel non‐ATP‐competitive Plk1 KD inhibitors by virtual screening and experimental studies. Potential binding sites in Plk1 KD were identified by using the protein binding site detection program Cavity. The identified site was subjected to molecular‐docking‐based virtual screening. The activities of top‐ranking compounds were evaluated by in vitro enzyme assay with full‐length Plk1 and direct binding assay with Plk1 KD. Several compounds showed inhibitory activity, and the most potent was found to be 3‐((2‐oxo‐2‐(thiophen‐2‐yl)ethyl)thio)‐6‐(pyridin‐3‐ylmethyl)‐1,2,4‐triazin‐5(4H)‐one (compound 4 ) with an IC₅₀ value of 13.1±1.7 μm . Our work provides new insight into the design of kinase inhibitors that target non‐ATP binding sites.     

Chromophore‐Linked Substrate (CLS405): Probing Metallo‐β‐Lactamase Activity and Inhibition

Serine‐ and metallo‐β‐lactamases present a threat to the clinical use of nearly all β‐lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Efforts to develop metallo‐β‐lactamase (MBL) inhibitors require suitable screening platforms to allow the rapid determination of β‐lactamase activity and efficient inhibition. Unfortunately, the platforms currently available are not ideal for this purpose. Further progress in MBL inhibitor identification requires inexpensive and widely applicable assays. Herein the identification of an inexpensive and stable chromogenic substrate suitable for use in assays of clinically relevant MBLs is described. (6R,7R)‐3‐((4‐Nitrophenoxy)methyl)‐8‐oxo‐7‐(2‐phenylacetamido)‐5‐thia‐1‐azabicyclo[4.2.0]oct‐2‐ene‐2‐carboxylic acid 5,5‐dioxide (CLS405) was synthesised in a three‐step protocol. CLS405 was then characterised spectroscopically, and its stability and kinetic properties evaluated. With a Δλ_max value of 100 nm between the parent and hydrolysis product, a higher analytical accuracy is possible with CLS405 than with commonly used chromogenic substrates. The use of CLS405 in assays was validated by MBL activity measurements and inhibitor screening that resulted in the identification of N‐hydroxythiazoles as new inhibitor scaffolds for MBLs. Further evaluation of the identified N‐hydroxythiazoles against a panel of clinically relevant MBLs showed that they possess inhibitory activities in the mid‐ to low‐micromolar range. The findings of this study provide both a useful tool compound for further inhibitor identification, and novel scaffolds for the design of improved MBL inhibitors with potential as antibiotics against resistant strains of bacteria.     

Influence of imine‐carbon substituent in 6‐bromo‐2‐iminopyridine‐based cobalt(II) complexes on 1,3‐butadiene polymerization

6‐Bromo‐2‐iminopyridine cobalt(II) complexes bearing different imine‐carbon substituents ( Co1 – Co7 ) were synthesized and subsequently employed for 1,3‐butadiene polymerization. All the complexes were identified using Fourier transform infrared spectra and elemental analysis, and complexes Co1 and Co3 were further characterized using single‐crystal X‐ray diffraction analysis, demonstrating they adopted distorted trigonal bipyramidal and tetrahedral geometries, respectively. Activated by methylaluminoxane, these complexes exhibited high cis‐1,4 selectivity, and the activity was highly dependent on the substituent at the imine‐carbon position of the ligand. Addition of PPh₃ to the polymerization systems could enhance the catalytic activity and simultaneously switched the selectivity from cis‐1,4 to cis‐1,2 manner. On the basis of the obtained results, a plausible mechanism involving the regulation of selectivity and activity is proposed. © 2019 Society of Chemical Industry     

N‐Benzyl‐4‐((heteroaryl)methyl)benzamides: A New Class of Direct NADH‐Dependent 2‐trans Enoyl–Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity

Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug‐sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug‐resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH‐dependent 2‐trans enoyl–acyl carrier protein reductase (InhA) inhibitors based on an N‐benzyl‐4‐((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG‐related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure–activity relationships. Furthermore, a co‐crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis.     

Terpendole E and its Derivative Inhibit STLC‐ and GSK‐1‐Resistant Eg5

Terpendole E is first natural product found to inhibit mitotic kinesin Eg5, but its inhibitory mechanism remains to be revealed. Here, we report the effects of terpendole E and 11ketopaspaline (a new natural terpendole E analogue) on the Eg5–microtubule interaction and in several Eg5 mutants. 11‐Ketopaspaline is a shunt product from terpendole E, and it shows potent inhibitory activity against the microtubule‐stimulated ATPase activity of Eg5. Unlike other Eg5 inhibitors, such as S‐trityl‐L ‐cysteine (STLC) and GSK‐1, both terpendole E and 11‐ketopaspaline only partially inhibited Eg5–microtubule interaction. Furthermore, terpendole E and 11‐ketopaspaline inhibited several Eg5 mutants that are resistant to STLC (Eg5^D130A, Eg5^L214A) or GSK‐1 (Eg5^I299F, Eg5^A356T), but with the same extent of inhibition against wild‐type Eg5. Because Eg5^D130A and Eg5^L214A show cross‐resistance to most known Eg5 inhibitors, which bind the L5 loop, these results suggest that terpendole E and its analogues have a different binding site and/or inhibitory mechanism to those for L5 loop‐binding type Eg5 inhibitors.     

Identification of Hck Inhibitors As Hits for the Development of Antileukemia and Anti‐HIV Agents

Hematopoietic cell kinase (Hck) is a member of the Src family of non‐receptor protein tyrosine kinases. High levels of Hck are associated with drug resistance in chronic myeloid leukemia. Furthermore, Hck activity has been connected with HIV‐1. Herein, structure‐based drug design efforts were aimed at identifying novel Hck inhibitors. First, an in‐house library of pyrazolo[3,4‐d]pyrimidine derivatives, which were previously shown to be dual Abl and c‐Src inhibitors, was analyzed by docking studies within the ATP binding site of Hck to select the best candidates to be tested in a cell‐free assay. Next, the same computational protocol was applied to screen a database of commercially available compounds. As a result, most of the selected compounds were found active against Hck, with K_i values ranging from 0.14 to 18.4 μM , confirming the suitability of the computational approach adopted. Furthermore, selected compounds showed an interesting antiproliferative activity profile against the human leukemia cell line KU‐812, and one compound was found to block HIV‐1 replication at sub‐toxic concentrations.     

Preparation and properties of compatibilized PVC/SMA‐g‐PA6 blends

The morphology and mechanical properties of PVC/SMA‐g‐PA6 blends were investigated in this paper. Graft to polymer SMA‐g‐PA6 was prepared via a solution graft reaction between SMA and PA6. FTIR test evidences the occurrence of the graft reaction between SMA and PA6. DSC analysis shows that SMA‐g‐PA6 has a lower melting point of 187°C, which may result in a decrease in crystallinity of PA6 and thus enable efficient blending of SMA‐g‐PA6 and PVC. Compatibilization was evidenced by the dramatic increase in mechanical properties, the smaller particle size and finer dispersion of PA6 in PVC matrix, and, further, a cocontinuous morphology at 16 wt % SMA‐g‐PA6 content. SMA‐g‐PA6 from the solution graft reaction can toughen and reinforce PVC material. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 432–439, 2004