Thiophene Carboxylate Research Articles

Synthesis, antidiabetic activity and in silico studies of benzo[b]thiophene based small molecule α-amylase inhibitors

Benzo[b]thiophene has been implicated as molecular framework in the drug discovery against broad spectrum of biological targets. In the antidiabetic drug regime, benzo[b]thiophene based SGLT2 and ALR2 inhibitors have been recently developed but their potential towards α-amylase inhibition remained unexplored to date. In this context, a series of novel small molecule benzo[b]thiophene-2-carboxylic acid derivatives (3a-p) was synthesized, characterized, and evaluated for antidiabetic activity as α-amylase inhibitors. We found that, all benzo[b]thiophene derivatives exhibited significant α-amylase inhibition with IC50 value ranging from 5.37 ± 0.25 μM to 29.89 ± 0.68 μM. The SAR studies showed benzo[b]thiophene carboxylate bearing bis(2-hydroxyethyl)amino group (3b) was most potent with IC50 of 5.37 ± 0.25 μM compared to standard drug Acarbose (IC50 = 6.40 ± 0.14 μM). Further, the enzyme inhibition mechanism study regarded 3b as competitive inhibitor of α-amylase with Ki value of 1.76 μM. A detailed in silico study was also performed in order to estimate binding properties, drug likeness and predict toxicity profile of these agents. It was demonstrated that novel small molecule benzo[b]thiophene derivative (3b) can effectively bind through H-bonding, hydrophobic and π-stacking interactions within α-amylase active site. Moreover, drug likeness and toxicity prediction studies suggested compound 3b as potential & safter α-amylase inhibitor. Overall, our present study disclosed a novel class of benzo[b]thiophene based α-amylase inhibitors and opened a template for further lead optimization and development.

Role of tetrel bonds in the supramolecular architecture of tetranuclear Pb(ii)[LL′thiophene carboxylate] complexes – an experimental and computational study

Experimental and theoretical study of tetrel bonds in the 3D crystal arrangement.

Arylation of halogenated thiophene carboxylate via Suzuki–Miyaura reaction: Anti-bacterial study against clinically isolated extensively drug resistant Escherichia coli sequence type 405 and computational investigation

In present study, Pd(0) catalysed Suzuki-Miyaura cross coupling reaction was used to synthesize 2,4-biarylphenyl-5-arylthiophene-2-carboxylate (7a–7f) and 2-aryl-4-chlorophenyl-5-arylthiophene-2-carboxylate derivatives (8a–8l) in moderate to good yields. While 2,4-dibromophenyl-5-bromothiophene-2-carboxylate (4) and 2-bromo-4-chlorophenyl-5-bromothiophene-2-carboxylate (5) were synthesized via Steglich esterification of 5-bromothiophene-2-carboxylic acid (1) with 2,4-dibromo phenol (2) and 2-bromo-4-chlorophenol (3) in the presence of N, N΄-dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP). 1 H and 13 C NMR were used to confirm all of the compounds. To screen out the most active lead compounds, binding interactions of all synthesized compounds with MurD and MurE Escherichia coli proteins were evaluated theoretically via molecular docking studies indicating the good binding affinities. DFT calculations were performed out by using DFT-B3LYP/3-21g and structural and reactivity parameters were calculated. Compounds 5, 8b, 8e, 8h , and 8j have demonstrated potential reactivities and charge distributions that indicate their efficiency towards biological targets. These chemicals were tested in vitro for antibacterial activity against Gram-negative bacteria ( Escherichia coli ) at different concentrations based on theoretical results. The total results were quite close to the theoretical predictions and compound 8j was found to be having the greatest potential value, strongest binding affinities, and a promising antibacterial agent with MIC value of 50 mg/ml against Escherichia coli.

Asymmetric Total Synthesis of Phomarol

Asymmetric Total Synthesis of Phomarol

Selective and Rapid Cell-Permeable Inhibitor of Human Caspase-3.

Individual roles and overlapping functionalities of 12 human caspases during apoptosis and other cellular processes remain poorly resolved primarily due to a lack of chemical tools. Here we present a new selective caspase-3 inhibitor, termed Ac-ATS010-KE, with rapid and irreversible binding kinetics. Relative to previously designed caspase-3-selective molecules that have tremendously abated inhibitory rates and thus limited use in biological settings, the improved kinetics of Ac-ATS010-KE permits its use in a cell-based capacity. We demonstrate that Ac-ATS010-KE prevents apoptosis with comparable efficacy to the general caspase inhibitor Ac-DEVD-KE and surprisingly does so without side-chain methylation. This observation is in contrast to the well-established peptide modification strategy typically employed for improving cellular permeability. Ac-ATS010-KE protects against extrinsic apoptosis, which demonstrates the utility of a thiophene carboxylate leaving group in biological settings, challenges the requisite neutralization of free carboxylic acids to improve cell permeability, and provides a tool-like compound to interrogate the role of caspase-3 in a variety of cellular processes.

Copper-mediated synthesis of N-vinyl ynamides from N-vinyl carbamates

Ynamides are versatile 3-atoms building blocks for organic synthesis as they participate in a variety of ionic, radical and pericyclic processes. Converting ynamides into 5-atom building blocks, such as the yet unreported N-vinyl ynamides, would open new avenues in this fascinating chemistry. We describe herein our efforts towards such goal and demonstrate that the cross-coupling between N-vinyl carbamates and bromo-alkynes using copper(I) thiophene carboxylate, 1,10-phenanthroline and tBuOK in DMSO is a reactive system with an improved profile compared to the classical ynamides syntheses. The advantages and limitations of this copper-mediated reaction are discussed.

1,3,5-Triazine(trithiophenylcarboxylate) esters form metastable monotropic nematic discotic liquid crystal phases

ABSTRACTConformationally flexible cores that generate large free volume when stacked and have an insufficient number of side-chains for filling the lateral space around each core have been proposed as design criteria for discotic liquid crystals that display nematic rather than columnar mesophases. Presented here are 1,3,5-triazines substituted with three thiophene carboxylate ester groups that fulfil these design criteria. Nine derivatives with linear, branched, and chiral ester chains were synthesised and their mesomorphism was studied by polarised optical microscopy, differential scanning calorimetry, and powder x-ray diffraction. Triazines with linear propyl to octyl chains display monotropic nematic discotic mesophases that crystallise within hours or days or when mechanically agitated. Packing structures for the nematic phases are proposed based on the single crystal structure of the ethyl ester. Their unusually slow nucleation and crystal growth can be attributed to the large number of possible low energy conformations that arise from the conformationally flexible core. Incorporation of racemic and chiral branched chains expectedly lowers the melting points of these derivatives but, unexpectedly, enhances nucleation and crystal growth well above the temperature ranges of their hypothetical nematic phases. Chiral nematic discotic mesophases were obtained for binary mixtures of derivatives with chiral branched and linear chains.

Eco‐Friendly Solvent‐Processed Fullerene‐Free Polymer Solar Cells with over 9.7% Efficiency and Long‐Term Performance Stability

AbstractA wide‐bandgap polymer, (poly[(2,6‐(4,8‐bis(5‐(2‐ethylhexyl)thiophen‐2‐yl)‐benzo[1,2‐b:4,5‐b′]dithiophene))‐alt‐(2,5‐(methyl thiophene carboxylate))]) (3MT‐Th), is synthesized to obtain a complementary broad range absorption when harmonized with 3,9‐bis(2‐methylene‐(3‐(1,1‐dicyanomethylene)‐indanone))‐5,5,11,11‐tetrakis(4‐hexylphenyl)‐dithieno[2,3‐d:2′,3′‐d′]‐s‐indaceno[1,2‐b:5,6‐b′]dithiophene (ITIC). The synthesized regiorandom 3MT‐Th polymer shows good solubility in nonhalogenated solvents. A film of 3MT‐Th:ITIC can be employed for forming an active layer in a polymer solar cell (PSC), with the blend solution containing toluene with 0.25% diphenylether as a nonhalogenated additive. The corresponding PSC devices display a power conversion efficiency of 9.73%. Moreover, the 3MT‐Th‐based PSCs exhibit excellent shelf‐life time of over 1000 h and are operationally stable under continuous light illumination. Therefore, methyl thiophene‐3‐carboxylate in 3MT‐Th is a promising new accepting unit for constructing p‐type polymers used for high‐performance nonfullerene‐type PSCs.

Rigid Peptide Scaffold‐Incorporated Structural Analogs of the Potent Antidepressant Peptide Drug Rapastinel (GLYX‐13)

AbstractAbstract:Rapastinel (GLYX‐13) is a natural amidated tetrapeptide (Thr‐Pro‐Pro‐Thr‐NH2)endowed with strong antidepressant property. Rapastinel shows considerable promise for treating drug‐resistant major depressive disorder (MDD), and is under clinical phase III development. Herein, we report the synthesis of a novel class of analogues of the potent antidepressant peptide drug rapastinel featuring rigid dipeptide scaffolds comprising proline (L/D) and amino thiophene carboxylates (Atc). Amino thiophene carboxylate is a conformationally constrained aromatic β‐amino acid, known to rigidify peptide backbones thereby limiting the conformational flexibility of peptides and improving proteolytic stability.

Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates.

Lomibuvir (1) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound 2, a molecule with comparable potency and an improved physicochemical profile relative to 1. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by 12f, provided 3-5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure-activity relationships, in vitro ADME characterization, and in vivo evaluation of this novel series are discussed.

Mycobacterium bovis Prevalence in Humans Does Not Differ between Regions in Burkina Faso

Background: In 1996, tuberculosis detection rate was higher in Oudalan (Sahel region) than in other provinces in Burkina Faso. Cattle breeding, a major activity of the local population, may favor exposure of humans to bovine tuberculosis. Objectives: (i) to isolate and identify M. bovis among new cases of tuberculosis with positive culture in the Sahel (Gorom-Gorom and Dori); the Center (Ouagadougou) and the Western (Bobo-Dioulasso) regions of the country; (ii) to investigate susceptibility of isolated strains to anti-tuberculosis. Methods: (i) collection of sputum from newly TB patients with a positive smear during a prospective study carried out in 1998 in the North, Central and Western region of the country and transferred at the Mycobacteriology Laboratory, (ii) optimization of operational procedures: (iii) mycobacteria strains's isolation on 3 different media (Loweinstein Jensen (LJ), LJ without glycerine and LJ supplemented with pyruvate; (iv) identification of the tuberculosis complex according to criteria such as: bacillus growth time, colony appearance, biochemical test results, bacilli growth with pyrazinamide or thiophene carboxylate hydrazide, or D-cycloserine; (v) performing antibiograms. Results: Among the isolated strains, M. bovis represented 6.2% (2/30) in Gorom-Gorom, 0% (0/18) in Dori, 2.6% (3/109) in Ouagadougou and 2.9% (2/65) in Bobo-Dioulasso. Sixty nine percent (31/45) of strains were susceptible to the main anti-tuberculosis drugs, 13 strains presented single or combined resistance and one strain was multidrug-resistant. Conclusion: We showed that M. bovis disease is prevalent in all the studied regions but at a relatively low rate. The transhumance of from the north to the west practiced by the breeders could explain why it was found M. bovis in a similar rate as in Ouagdougou and Bobo-Dioulasso where livestock activity is less intense than in Gorom-Gorom.

Synthesis of air-stable mixed bis-carboxylate titanocene complexes and their catalytic behaviors in cross-aldol and Mannich reactions

Tunable organometallic Lewis acid catalysts were developed by combining salicylic acid (H2-Sal) with benzoic acid (H-Ben), 4-fluorobenzoic acid (H-BenF) and 3-thiophenic acid (H-Th), as coligands for mixed bis-carboxylate titanocene complexes. Three air-stable complexes [Cp2Ti(η1-HSal)(η1-Ben)] (1), [Cp2Ti(η1-HSal)(η1-BenF)] (2) and [Cp2Ti[η1-HSal][(η1-Th)] (3) were prepared in high yields by the reaction of salicylato titanocene chelate with carboxylate ligands. The mixed bis-carboxylate titanocene complexes were fully characterized by physicochemical and spectroscopic methods. Single-crystal X-ray diffraction studies revealed Ti–O(H-Sal) bond distances in 1, 2 and 3 of 1.972(3), 1.9245(18) and 1.912(5) A, respectively, while the bond distances involving the coligands of 1, 2 and 3 are 1.908(3) A (Ti–OBen), 1.9296(19) A (Ti–OBenF) and 1.945(5) A (Ti–OTh), respectively. These bis-carboxylate titanocene complexes showed satisfactory activities and selectivities in Mannich and cross-aldol reactions. Notably, complex 3 bearing the labile thiophene carboxylate ligand gave high yields with a diastereomer ratio (d.r.) as high as 1:99 for the direct Mannich reactions of benzaldehyde, cyclohexanone and aniline. In cross-aldol reaction of benzaldehyde and cyclohexanone, 1 and 2 successfully catalyzed the formation of double-aldol products in up to 99 % yield.

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles.

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.

Synthesis, crystal structures and supramolecular architectures of square pyramidal Cu(II) complexes containing aromatic chelating N,N’-donor ligands

Design of new metal complexes is an interesting field for development of new functional molecular-based materials. In this process by the usage of mixed functional ligands one can precisely tune the physical and chemical properties of those metal complexes. However, it is difficult to obtain the desired complex in many cases for factors like different coordination abilities of the ligands and the types of anions have a great influence on the structure. A series of five copper(II) complexes [Cu(Bipy) (5-TPC) 2(H2O)] (1), [Cu(Phen) (5-TPC) 2(H2O)] (2), [Cu(NO3) (4,7-Phen) (5-TPC) (H2O)].H2O (3), [Cu(Bipy) 2(5-TPC)]2.(ClO4)2 (4), and [Cu2(Bipy)4(H2PO4)] (5) (where Bipy = 2,2'-bipyridine, Phen = 1,10-phenanthroline, 4,7-Phen = 4,7-hydroxy-1,10-phenanthroline, 5-TPC = 5-chloro-2- thiophene carboxylate) has been synthesized and characterised using single crystal X-ray diffraction studies. In all the compounds, the N,N’ ligand coordinates in a bidentate chelating manner and the copper has a square pyramidal geometry. Complexes (1,2) are expected to be isostructural due to similarity of the N.N’-chelating ligands used, but due to the difference in supramolecular architectures no similar unit cells were observed. This is important in crystal engineering point of view. Complexes (1–4) possess the neutral mononuclear and complex (5) possesses a dinuclear entity. These entities are connected by intermolecular interactions like X∙∙∙π, H∙∙∙X, (X = Cl) generating supramolecular architectures.

Influence of the Excited-State Charge-Transfer Character on the Exciton Dissociation in Donor–Acceptor Copolymers

We synthesize a polytriphenylamine homopolymer and two donor–acceptor copolymers (D–A-copolymers) based on triphenylamine (TPA) as donor in combination with two different acceptor moieties to study the effect of the acceptor unit on the excited-state charge-transfer characteristics (CT-characteristics) and charge separation. The two acceptor moieties are a dicyanovinyl group in the side chain and a thieno[3,4-b]thiophene carboxylate in the main chain. Absorption and photoluminescence studies show new CT-bands for both of the D–A-copolymers. Field-dependent charge extraction studies in bilayer solar cells indicate a stronger CT-character for the copolymer in which the acceptor group is less conjugated with the copolymer backbone. The D–A-copolymer carrying the acceptor unit in the main chain exhibits smaller excitonic CT-character and good conjugation leading to less-bound electron–hole pairs and a better charge separation. This fundamental study gives insight into the interdependence of conjugation, charge carrier mobility, and solar cell performance for two different D–A-copolymers.

Enantioselective Copper‐Catalyzed Conjugate Addition of Trimethylaluminum to β,γ‐Unsaturated α‐Ketoamides: Efficient Access to γ‐Methyl‐Substituted Carbonyl Compounds

Picture perfect: By using the reagent trimethylaluminium and β,γ-unsaturated α-ketoamides, 1,4-adducts were obtained with perfect 1,4-regioselectivity and good to excellent yields and ee values. The potential synthetic utility of the methodology was highlighted by preparation of γ-methyl-substituted carbonyls, key synthons to many natural products. binap=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, TC=thiophene carboxylate.

Synthesis and characterization of some new complexes of Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II) with 2,3 and 3,4- di-(2΄-thiophenoyloxy) aniline

A series of new complexes of the type [M(L1)Cl2] , [M(L2)Cl2] and [M΄(L1)(Th)2] where L1=2,3-di-(2΄-thiophenoyloxy) aniline, L2=3,4-di-(2΄-thiophenoyloxy)aniline, M=Co+2, Ni+2, Cu+2, Zn+2, Cd+2 and Hg+2, M΄= Ni+2, Cu+2, Zn+2 and Cd+2, Th=thiophene carboxylate. The complexes were prepared and characterized by molar conductance, IR, UV/vis spectra studies, magnetic measurements and metal content analysis. Conductivity data in DMF for complexes (1-12) and DMSO for complexes (13-16) showed that all complexes are non-electrolyte. Magnetic moment and electronic spectra indicate that some of the complexes contain a tetrahedral and the other have octahedral environment.

Polymer solar cells fabricated with 4,8-bis(2-ethylhexyloxy)benzo[1,2-b:4,5-b′]dithiophene and alkyl-substituted thiophene-3-carboxylate-containing conjugated polymers: Effect of alkyl side-chain in thiophene-3-carboxylate monomer on the device performance

Four alkyl-substituted thiophene-3-carboxylate containing donor–acceptor (D–A) copolymers were designed, synthesized, and characterized. Thiophene-3-carboxylate was used as a weak electron acceptor unit in the copolymers to provide a deeper highest occupied molecular orbital (HOMO) level for obtaining a higher open-circuit voltage in polymer solar cells (PSCs). The resulting bulk heterojunction PSCs, made of the copolymers and [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM), exhibited different short circuit currents (JSCs) and open-circuit voltages (VOCs), depending on the length of alkyl side-chain in the thiophene-3-carboxylate unit. Among all fabricated photovoltaic (PV) devices, PC2:PC71BM (1:1 wt. ratio) showed the highest efficiency with the highest JSC of 10.5 mA/cm2. Although PC5:PC71BM (1:1) displayed the highest VOC of 0.93 V, the device efficiency was observed to be poor, which is due to poor nanophase segregation. This comparison shows that the side-chain of thiophene carboxylate in these copolymers plays a very important role in the device efficiency.

Structural motifs in phenylbismuth heterocyclic carboxylates – secondary interactions leading to oligomers

The reaction of triphenylbismuth [BiPh(3)] with several heterocyclic carboxylic acids was explored. Seven crystalline compounds, [PhBi(2-O(2)C-3-(OH)C(5)H(3)N)(2)(2-O(2)C-3-(OH)C(5)H(3)NH)] (5), [(Bi(2-O(2)C-3-(OH)C(5)H(3)N)(4))(C(5)H(5)NH)(C(5)H(5)N)] (7), [PhBi(2-O(2)C-C(4)H(3)N(2))(2)(2-O(2)C-C(4)H(4)N(2))·H(2)O] (8), [PhBi(2-O(2)C-C(9)H(6)N)(2)·H(2)O] (9), [Ph(2)Bi(O(2)C-C(4)H(3)O)] (10), [Ph(2)Bi(O(2)C-C(4)H(3)S)] (11) and [PhBi(O(2)C-C(4)H(3)S)(2)](2) (12), were prepared by simple reactions using BiPh(3) and the corresponding acids, 3-hydroxypicolinic acid, pyrazine-2-carboxylic acid, quinoline-2-carboxylic (quinaldic) acid, furan-2-carboxylic acid and thiophene-2-carboxylic acid. Compound 5 primarily exhibits a coordination number of six with pentagonal pyramidal geometry at bismuth, but an additional weak Bi···O interaction in the direction of the lone pair of electrons is present. This feature leads to a weakly bound dimer. The use of pyridine as the solvent in a similar reaction, however, led to 7, in which all of the Bi-Ph bonds are cleaved. In this compound, bismuth exhibits a coordination number of eight and distorted dodecahedral geometry. In compound 8, the geometry around bismuth is primarily a pentagonal pyramid, however, clear-cut but weak secondary Bi···N interactions leading to a dimeric formulation are discernible in the structure. The quinaldate compound 9 exhibits a lower formal coordination number of five for bismuth, with square pyramidal geometry, but again two secondary Bi···O interactions for each bismuth in the direction of the lone pair lead to a dimer. A similar secondary Bi···O interaction involving furan oxygen is present in the furoate compound 10, which is a polymeric chain (one dimensional coordination polymer). Although the thiophene carboxylate 11 is also a polymeric chain, no Bi···S interactions are present. Unlike the previously reported tetrameric biscarboxylate [PhBi(2-O(2)C-C(5)H(3)N)(2)](4), the thiophene carboxylate [PhBi(O(2)C-C(4)H(3)S)(2)](2) (12) is a dimer considering only primary interactions. However, these dimers are arranged in such a way that there are secondary Bi···S interactions in the structure in the expected direction of the lone pair of electrons on bismuth. Thus, these studies suggest that the stereochemical activity (or inactivity) of the bismuth lone pair of electrons need to be judged more cautiously. TGA studies are consistent with the presence of Bi-Ph groups in all of the compounds, except 7, as indicated by their formulae.

Synthesis of 6-aryl-2′-deoxyuridine nucleosides via a Liebeskind cross-coupling methodology

Hitherto, the synthesis of 6-substituted 2′-deoxyuridine nucleoside analogues via Pd-catalyzed Suzuki cross-coupling reaction was hampered by the instability of the TIPDS-protected precursor 6-iodo-2′-deoxyuridine 1 in alkaline media due to cleavage of the glycosidic bond. Herein, the successful application of the Liebeskind reaction under base-free conditions is reported. This method comprises of the stoichiometric use of copper thiophene carboxylate (CuTC) as co-reagent at slightly elevated temperatures. Fluoride-mediated desilylation and Yoshikawa-phosphorylation afforded the nucleotide analogues 4b–c, 4e, and 4i.