Synthesis and Evaluation of 1‐(1‐(Benzo[b]thiophen‐2‐yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP ( 1 , 1‐(1‐benzo[b]thiophen‐2‐yl‐cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (K_i=1 μM ) and biologically active against bloodstream T. brucei (EC₅₀=10 μM ), but with poor selectivity against mammalian MRC5 cells (EC₅₀=29 μM ). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed.     

Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis

Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione‐based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor (K_i=330 nM ) with an improved potency against T. brucei (EC₅₀=775 nM ).     

Binding to Large Enzyme Pockets: Small‐Molecule Inhibitors of Trypanothione Reductase

The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure‐based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small‐molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so‐called “mepacrine binding site”. The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi.     

Toward the Development of Dual‐Targeted Glyceraldehyde‐3‐phosphate Dehydrogenase/Trypanothione Reductase Inhibitors against Trypanosoma brucei and Trypanosoma cruzi

A significant improvement in the treatment of trypanosomiases has been achieved with the recent development of nifurtimox–eflornithine combination therapy (NECT). As an alternative to drug combinations and as a means to overcome most of the antitrypanosomatid drug discovery challenges, a multitarget drug design strategy has been envisaged. To begin testing this hypothesis, we designed and developed a series of quinone–coumarin hybrids against glyceraldehyde‐3‐phosphate dehydrogenase/trypanothione reductase (GAPDH/TR). These enzymes belong to metabolic pathways that are vital to Trypanosoma brucei and Trypanosoma cruzi, and have thus been considered promising drug targets. The synthesized molecules were characterized for their dual‐target antitrypanosomal profile, both in enzyme assays and in in vitro parasite cultures. The merged derivative 2‐{[3‐(3‐dimethylaminopropoxy)‐2‐oxo‐2H‐chromen‐7‐yl]oxy}anthracene‐1,4‐dione ( 10 ) showed an IC₅₀ value of 5.4 μM against TbGAPDH and a concomitant K_i value of 2.32 μM against TcTR. Notably, 2‐{4‐[6‐(2‐dimethylaminoethoxy)‐2‐oxo‐2H‐chromen‐3‐yl]phenoxy}anthracene‐1,4‐dione (compound 6 ) displayed a remarkable EC₅₀ value for T. brucei parasites (0.026 μM ) combined with a very low cytotoxicity toward mammalian L6 cells (7.95 μM ). This promising low toxicity of compound 6 might be at least partially due to the fact that it does not interfere with human glutathione reductase.     

Structure‐Based Design,Synthesis, and Evaluation of 2′‐(2‐Hydroxyethyl)‐2′‐deoxyadenosine and the 5′‐Diphosphate Derivative as Ribonucleotide Reductase Inhibitors

Analysis of the recently solved X‐ray crystal structures of Saccharomyces cerevisiae ribonucleotide reductase I (ScRnr1) in complex with effectors and substrates led to the discovery of a conserved water molecule located at the active site that interacted with the 2′‐hydroxy group of the nucleoside ribose. In this study 2′‐(2‐hydroxyethyl)‐2′‐deoxyadenosine 1 and the 5′‐diphosphate derivative 2 were designed and synthesized to see if the conserved water molecule could be displaced by a hydroxymethylene group, to generate novel RNR inhibitors as potential antitumor agents. Herein we report the synthesis of analogues 1 and 2 , and the co‐crystal structure of adenosine diphosphate analogue 2 bound to ScRnr1, which shows the conserved water molecule is displaced as hypothesized.     

A Novel Competitive Class of α‐Glucosidase Inhibitors: (E)‐1‐Phenyl‐3‐(4‐Styrylphenyl)Urea Derivatives

Competitive glycosidase inhibitors are generally sugar mimics that are costly and tedious to obtain because they require challenging and elongated chemical synthesis, which must be stereo‐ and regiocontrolled. Here, we show that readily accessible achiral (E)‐1‐phenyl‐3‐(4‐strylphenyl)ureas are potent competitive α‐glucosidase inhibitors. A systematic synthesis study shows that the 1‐phenyl moiety on the urea is critical for ensuring competitive inhibition, and substituents on both terminal phenyl groups contribute to inhibition potency. The most potent inhibitor, compound 12 (IC₅₀=8.4 μM , K_i=3.2 μM ), manifested a simple slow‐binding inhibition profile for α‐glucosidase with the kinetic parameters k₃=0.005256 μM ^?1 min^?1, k₄=0.003024 min^?1, and ${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$ =0.5753 μM .     

Synthesis and photopolymerization of 4‐(1‐propenyl)oxybutyl acrylate

Hybrid monomer, 4‐(1‐propenyl)oxybutyl acrylate, with cationic and free radical polymerizable group was synthesized. Real‐time Fourier transform infrared spectroscopy (FTIR) was used to monitor the photopolymerization kinetics of the monomer. Photopolymerization processing conditions, such as light intensity, photoinitiator concentrations have been evaluated. It was found that hybrid monomer showed higher efficiency of photopolymerization in comparison with the blend system. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Synthesis and photopolymerization of 2‐(acryloyloxy)ethyl piperidine‐1‐carboxylate and 2‐(acryloyloxy)ethyl morpholone‐4‐carboxylate

Two low‐viscosity monomers, 2‐(acryloyloxy)ethyl piperidine‐1‐carboxylate (AEPC II) and 2‐(acryloyloxy)ethyl morpholone‐4‐carboxylate (AEMC), were synthesized with a non‐isocyanate route. The photopolymerization kinetics was monitored by real‐time infrared spectroscopy with a horizontal sample holder. The results indicated that AEPC II and AEMC had high ultraviolet curing rates and final double‐bond conversions, which could reach 90 and 95%, respectively. The glass‐transition temperatures of AEPC II/urethane acrylate resin (1/4 w/w), AEMC/urethane acrylate resin (1/4 w/w), and isobornyl acrylate/urethane acrylate resin (1/4 w/w) mixtures were 37.5, 45.6, and 57°C, respectively. The crosslink density of the AEMC/urethane acrylate resin (1/4 w/w) mixture was lower than that of the isobornyl acrylate/urethane acrylate resin (1/4 w/w) mixture. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Design and Synthesis of 4‐(2,4,5‐Trifluorophenyl)butane‐1,3‐diamines as Dipeptidyl Peptidase IV Inhibitors

The worldwide prevalence of diabetes has spurred numerous studies on the development of new antidiabetic medicines. As a result, dipeptidyl peptidase IV (DPP4) has been recognized as a validated target. In our efforts to discover new DPP4 inhibitors, we analyzed the complexed structures of DPP4 available in Protein Data Bank and designed a series of triazole compounds. After enzyme activity assays and crystallographic verification of the binding interaction patterns, we found that the triazole compounds can inhibit DPP4 with micromolar IC₅₀ values. Liver microsome stability and cytochrome P450 metabolic tests were performed on this series, revealing undesirable pharmacokinetic profiles for the triazole compounds. To overcome this liability, we substituted the triazole ring with an amide or urea group to produce a new series of DPP4 inhibitors. Based on its enzyme activity, metabolic stability, and selectivity over DPP8 and DPP9, we selected compound 21 r for further study of its in vivo effects in mice using an oral glucose tolerance test (OGTT). The results show that 21 r has efficacy similar to that of sitagliptin at a dose of 3 mg kg^?1. The crystal structure of 21 r bound to DPP4 also reveals that the trifluoromethyl group is directed toward a subpocket different from the subsite bound by sitagliptin, providing clues for the design of new DPP4 inhibitors.     

Synthesis and characterization of aromatic polyesters and copolyesters from 4,4′‐(1‐hydroxyphenylidene)diphenol and 4,4′‐(9‐fluorenylidene)diphenol

Two isophthalic polyesters from 4,4′‐(1‐hydroxyphenylidene)diphenol (BAP/ISO) and 4,4′‐(9‐fluorenylidene)diphenol (BF/ISO), and three different copolyesters containing 75, 50, and 25 mol % of BAP/ISO were synthesized by interfacial polycondensation. This preparation method yielded polymers and copolymers that produced flexible and transparent films when they were cast from solution. Proton NMR spectrometry studies showed that the isophthalic copolyesters were obtained as random copolymers with differences in comonomer composition no larger than 2.5 mol % with respect to the expected compositions. Wide‐angle X‐ray diffraction measurements indicated that all the polyesters and copolyesters were amorphous. The copolyesters showed amorphous patterns with maxima that fell between those of the polyesters. It was also found that thermal properties such as glass‐transition temperature, onset of decomposition temperature, thermal stability, dynamic mechanical storage modulus, and maximum on the α‐transition of the damping factor tan δ of BF/ISO were higher than those of BAP/ISO. The values of these thermal properties in the copolyesters fell between those of the polyesters and were dependent on the amounts of BF/ISO and BAP/ISO present in the copolyester in a linear fashion. Therefore, the thermal properties of a given copolyester can be predicted directly from the comonomers' composition. Overall, it shows that the interfacial polycondensation method is suitable to obtain these copolyesters in a controlled manner and that their properties can be tailored to be between those of the homopolyesters. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 2515–2522, 2002     

Silver‐Catalyzed Intramolecular Cyclization of o‐(1‐Alkynyl)benzamides: Efficient Synthesis of (1H)‐Isochromen‐1‐imines

An efficient avenue for the facile and atom‐economic synthesis of (1H)‐isochromen‐1‐imines has been developed, and a broad spectrum of substrates can participate in the process effectively to produce the desired products in good yields. Significantly, this is the first report of the synthesis of (1H)‐isochromen‐1‐imines that involves a silver(I)‐catalyzed, regiocontrolled intramolecular addition of the carbonyl group of the amide moiety towards an alkyne.     

1‐(1H‐Indol‐3‐yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors

The synthesis of 37 1‐(1H‐indol‐3‐yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti‐staphylococcal activity. By contrast, several of the compounds restored, in a concentration‐dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure–activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)‐N‐benzylidene‐2‐(tert‐butoxycarbonylamino)‐1‐(5‐iodo‐1H‐indol‐3‐yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA‐1199B strain when used at a concentration of 0.5 mg L ^?1. To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert‐butyl (2‐(3‐hydroxyureido)‐2‐(1H‐indol‐3‐yl)ethyl)carbamate, which is not toxic for human cells, was also found.     

1‐Arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines Histone Deacetylase Inhibitors Are Potent Cytokine Release Suppressors

A series of 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines ( 7 – 15 ) has been developed; the compounds exhibited potent histone deacetylase (HDAC) inhibitory activities. Notably, almost all of this series exhibited better HDAC‐inhibitory and antiproliferative activities than 3‐(1‐benzenesulfonyl‐1H‐indol‐5‐yl)‐N‐hydroxyacrylamide ( 6 ), as reported in a previous study. Among these compounds, 3‐[1‐(4‐methoxybenzenesulfonyl)‐2,3‐dihydro‐1H‐indol‐5‐yl]‐N‐hydroxyacrylamide ( 9 ) showed a two‐ to tenfold increase in activity compared to SAHA ( 1 ) in the suppression of lipopolysaccharide‐induced cytokine production. Compound 9 also caused a marked reduction in carrageenan‐induced acute inflammation in a rat model. Taken together, these data indicated that 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines HDAC inhibitors exhibit potent anti‐inflammatory activity.     

Synthesis and characterization of poly(ester‐ether‐imide)s derived from 5‐(4‐trimellitimidophenoxy)‐1‐trimellitimido naphthalene

A series of novel aromatic poly(ester‐ether‐imide)s with inherent viscosity values of 0.44–0.74 dL g^?1 were prepared by the diphenylchlorophosphate‐activated direct polycondensation of an imide ring‐containing diacid namely 5‐(4‐trimellitimidophenoxy)‐1‐trimellitimido naphthalene ( 1 ) with various aromatic dihydroxy compounds in the presence of pyridine and lithium chloride. Owing to comparison of the characterization data, an ester‐containing model compound ( 2 ) was also synthesized by the reaction of 1 with phenol. The model compound 2 and the resulted polymers were fully characterized by FT‐IR and NMR spectroscopy. The ultraviolet λ_max values of the poly(ester‐ether‐imide)s were also determined. The resulting polymers exhibited an excellent organosolubility in a variety of high polar solvents such as N,N‐dimethylacetamide, N,N‐dimethylformamide, dimethyl sulfoxide, and N‐methyl‐2‐pyrrolidone. They were soluble even in common less polar organic solvents such as pyridine, m‐cresol, and tetrahydrofuran on heating. Crystallinity of the polymers was estimated by means of wide‐angle X‐ray diffraction. The resulted polymers exhibited nearly an amorphous nature. From differential scanning calorimetry thermograms, the polymers showed glass‐transition temperatures between 221 and 245°C. Thermal behaviors of the obtained polymers were characterized by thermogravimetric analysis, and the 10% weight loss temperatures of the poly(ester‐ether‐imide)s were found to be over 410°C in nitrogen. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Synthesis and Evaluation of 3,4‐Dihydropyrimidin‐2(1H)‐ones as Sodium Iodide Symporter Inhibitors

The sodium iodide symporter (NIS) is responsible for the accumulation of iodide in the thyroid gland. This transport process is involved in numerous thyroid dysfunctions and is the basis for human contamination in the case of exposure to radioactive iodine species. 4‐Aryl‐3,4‐dihydropyrimidin‐2(1H)‐ones were recently discovered by high‐throughput screening as the first NIS inhibitors. Described herein are the synthesis and evaluation of 115 derivatives with structural modifications at five key positions on the pyrimidone core. This study provides extensive structure–activity relationships for this new class of inhibitors that will serve as a basis for further development of compounds with in vivo efficacy and adequate pharmacokinetic properties. In addition, the SAR investigation provided a more potent compound, which exhibits an IC₅₀ value of 3.2 nM in a rat thyroid cell line (FRTL5).     

High cis‐1,4 polyisoprene or cis‐1,4/3,4 binary polyisoprene synthesized using 2‐(benzimidazolyl)‐6‐(1‐(arylimino)ethyl)pyridine cobalt(II) dichlorides

Polyisoprene (PI) with a high content of cis‐1,4 (up to 95%) or cis‐1,4/3,4 binary structures was synthesized using a cobalt system in toluene. The cobalt system, which exhibited high activities (up to 3.50 × 10⁶ g PI (mol Co)^?1 h^?1), contained a series of 2‐(benzimidazolyl)‐6‐(1‐(arylimino)ethyl)pyridine cobalt(II) dichlorides activated with ethylaluminium sesquichloride. The nature of the ligands and the reaction conditions significantly affected both the catalytic performance of the cobalt complexes as well as the structures of the resultant PI. The stereospecific polymerization of isoprene could be tuned via changing either the co‐catalyst or solvent: for example, increased content of 3,4 PI (up to 36.6%) was achievable in heptane in the presence of diethylaluminium chloride. Sequence distribution analysis by ¹³C NMR spectroscopy indicated that most 3,4 units occurred randomly in the PI chains. © 2013 Society of Chemical Industry     

Synthesis and characterization of conducting copolymer of Trans‐1‐(4‐methyl‐3′‐thienyl)‐2‐(ferrocenyl)ethene with EDOT

Ferrocene‐substituted conducting polymer namely poly(trans‐1‐(4‐methyl‐3′‐thienyl)‐2‐(ferrocenyl)ethene‐co‐3,4‐ethylenedioxythiophene) [P(MTFE‐co‐EDOT)] was synthesized and its electrochromic properties were studied. Monomer, MTFE, was obtained using 2‐(ferrocenyl)ethene and 3‐methyl‐4‐bromothiophene. The structure of monomer was determined via Fourier transform infrared spectroscopy (FTIR), ¹H‐NMR, and ¹³C‐NMR techniques. The copolymer was synthesized using this monomer and EDOT. The resulting copolymer P(MTFE‐co‐EDOT) was characterized by cyclic voltammetry, FTIR, scanning electron microscopy, atomic force microscopy, and UV–vis spectroscopy. The conductivity measurements of copolymer and PEDOT were accomplished by the four‐probe technique. Although poly(trans‐1‐(4‐methyl‐3′‐thienyl)‐2‐(ferrocenyl)ethene) [P(MTFE)] reveals no electrochromic activity, its copolymer with EDOT has two different colors (violet and gray). Band gap (E_g) and λ_max of P(MTFE‐co‐EDOT) were determined. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Synthesis of 1‐Amino‐3‐(trimethylsilyl)allenes by Organocuprate Addition to 3‐(Trimethylsilyl)propyne Iminium Salts

1‐Dialkylamino‐3‐(trimethylsilyl)allenes 2a—q were obtained by conjugate addition of alkyl, vinyl, aryl, hetaryl, and silyl groups, via the respective organocuprates, to 3‐(trimethylsilyl)propyne iminium triflates 1a—d . Similarly, 2‐vinylidene‐2,3‐dihydro‐1,3‐benzothiazoles 4a,b were synthesized from semicyclic propyne iminium triflates 3a,b and a di‐tert‐butyl cuprate.