2-Acetylthiophene

Synthesis and evaluation of novel substituted 1,2,3-triazolyldihydroquinolines as promising antitubercular agents.[Pubmed:30638877]

Bioorg Med Chem Lett. 2019 Feb 15;29(4):529-533.

A series of novel substituted 1,2,3-triazolyldihydroquinolines 6a-o was designed and synthesized from 2-Acetylthiophene in five-step reaction sequence involving modified Boltzmann-Rahtz reaction of beta-Enaminone; Vilsmeier-Haack chloroformylation using DMF/POCl3; Ohira-Bestmann homologation of aldehyde to alkyne as key steps. The reaction of alkyne 4 with various aryl azides in the presence of copper sulfate and sodium ascorbate resulted desired new 1,2,3-triazolyldihydroquinolines 6a-o in excellent yields. In vitro screening of new compounds for anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (Mtb), resulted in three derivatives 6a (MIC:1.56microg/mL) and 6d, 6l (MIC:3.12microg/mL) as promising antitubercular agents with lower cytotoxicity profiles.

DFT study of the interactions between thiophene-based corrosion inhibitors and an Fe4 cluster.[Pubmed:28801757]

J Mol Model. 2017 Aug 11;23(9):260.

Understanding the physicochemical properties of corrosion inhibitors and their chemical interactions with metal surfaces is crucial to the design of improved (i.e., more efficient) corrosion inhibitors. In this work, the physicochemical properties of six thiophene-based corrosion inhibitors (2-Acetylthiophene (AT), 2-formylthiophene (FT), thiophene (Th), 2-methyl-3-thiophenthiol (MTT), 2-pentylthiophene (PT), and 2-thenylthiol (TT)) were systematically studied by performing ab initio calculations at the MP2(full)/6-31G(2df,p) level of theory. Adsorption of the inhibitors on an iron surface was also modeled by investigating the interactions of these molecules with a tetrahedral Fe4 cluster using the B3LYP method and the 6-311G(d,p) basis set or the LanL2DZ basis set. The calculated results indicate that the nature of the substituent group present has a significant impact on the geometric and electronic structures of the thiophene-based molecules. The presence of an electron-donating group causes the electron density in the thiophene ring to increase, while the presence of an electron-withdrawing group has the opposite effect. Accordingly, the examined molecules were ranked in order of corrosion inhibition efficiency as follows: FT approximately AT < Th < PT < TT < MTT. The calculated binding energies demonstrated that the pi-1Fe and pi-3Fe interaction configurations dominated over the S-1Fe configuration for all the compounds. Natural bond orbital analysis revealed that all of the thiophene-based compounds donate electrons from the pi and sigma orbitals of high-electron-density regions such as C2-S1-C5 and C3-C4 or from two lone pairs on S1 to the Fe4 cluster. Although electron donation from the thiophene-based compounds is always the dominant electron transfer process during adsorption, the backdonation of electrons from the 3d orbital of iron to sigma*-antibonding orbitals of the thiophene compounds is also observed, especially in the case of pi-3Fe parallel adsorption. Graphical abstract Optimized geometry, HOMO and LUMO for the pi-3Fe interaction configuration of 2-pentylthiophene and Fe4 cluster.

Design and environmentally benign synthesis of novel thiophene appended pyrazole analogues as anti-inflammatory and radical scavenging agents: Crystallographic, in silico modeling, docking and SAR characterization.[Pubmed:28648923]

Bioorg Chem. 2017 Aug;73:109-120.

Oxidative-stress induces inflammatory diseases and infections caused by drug-resistant microbial strains are on the rise necessitating the discovery of novel small-molecules for intervention therapy. The current study presents an effective and new green protocol for the synthesis of thiophene-appended pyrazoles through 3+2 annulations method. Chalcones 3(a-g) were prepared from 5-chloro-2-Acetylthiophene and aromatic aldehydes by Claisen-Schmidt approach. The reaction of chalcones 3(a-g) with phenylhydrazine hydrochlorides 4(a-b) in acetic acid (30%) medium and also with freshly prepared citrus extract medium under reflux conditions produced the thiophene appended pyrazoles 5(a-l) in moderate yields. Structures of synthesized new pyrazoles were confirmed by spectral studies, elemental analysis and single crystal X-ray diffraction studies. Further, preliminary assessment of the anti-inflammatory properties of the compounds showed that, amongst the series, compounds 5d, 5e and 5l have excellent anti-inflammatory activities. Further, compounds 5c, 5d, 5g, and 5i exhibited excellent DPPH radical scavenging abilities in comparison with the standard ascorbic acid. Furthermore, using detailed structural modeling and docking efforts, combined with preliminary SAR, we show possible structural and chemical features on both the small-molecules and the protein that might contribute to the binding and inhibition.

Apoptotic effect of chalcone derivatives of 2-acetylthiophene in human breast cancer cells.[Pubmed:27923159]

Pharmacol Rep. 2017 Feb;69(1):156-161.

BACKGROUND: A variety of chalcones have demonstrated cytotoxic activity toward several cancer cell lines. This study aimed to investigate the cytotoxicity of four chalcones derivatives of 2-Acetylthiophene in human breast cancer cell lines. METHODS: MCF-7 and MDA-MB-231 cells were treated with synthesized chalcones and the cytotoxicity was evaluated by tetrazolium dye (MTT), live/dead, and DAPI assays. RESULTS: Chalcones significantly decreased MCF-7 and MDA-MB-231 cells viability in vitro in a dose dependent manner. After 48h treatment, the IC50 values ranging from 5.52 to 34.23muM. Chalcone 3c displayed the highest cytotoxic activity from all the tested compounds. Cytotoxic effects of compounds were confirmed in the live/dead assay. In addition, DAPI staining revealed that these compounds induce death by apoptosis. CONCLUSION: The data speculate that chalcone derivatives of 2-Acetylthiophene may represent a source of therapeutic agents for human breast cancer.

Antimicrobial Activity of Some Novel Armed Thiophene Derivatives and Petra/Osiris/Molinspiration (POM) Analyses.[Pubmed:26901173]

Molecules. 2016 Feb 17;21(2). pii: molecules21020222.

Tetrasubstituted 2-Acetylthiophene derivative 5 was synthesized and then condensed with various nitrogen nucleophiles such as 5-amino-1,2,4-triazole, 2-aminobenzimidazole, aniline or p-chloroaniline to afford the corresponding iminothiophene derivatives 6-8a,b. Condensation of thiophene 5 with malononitrile as carbon nucleophile afforded compound 9, which underwent nucleophilic addition with DMF-DMA to afford compound 10. The newly synthesized products were characterized by elemental analysis, IR, MS, (1)H-(13)C-NMR and CHN analysis and then evaluated for their antimicrobial activity. Results of the in vitro antibacterial activity showed that thiophene derivative 7 was found to be more potent than the standard drug gentamicin against Pseudomonas aeruginosa. Some of these compounds showed potential antimicrobial activities. Molecular docking and Osiris/Molinspiration analyses show the crucial role and impact of substituents on bioactivity and indicate the unfavorable structural parameters in actual drug design: more substitution with electronic donor group doesn't guarantee more effective bioactivity. This study should greatly help in an intelligent and a controlled pharmacomodulation of antibiotics.

Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects.[Pubmed:26044365]

J Enzyme Inhib Med Chem. 2016 Aug;31(4):568-73.

In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by (1)H NMR, (13)CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4-methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4-bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2-Acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1-S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1-S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with Kis in the range of 1.79 +/- 0.22-2.73 +/- 0.08 nM against hCA I and in the range of 1.72 +/- 0.58-11.64 +/- 5.21 nM against hCA II, respectively.

Investigation of anion-pi interactions involving thiophene walls incorporated calix[4]pyrroles.[Pubmed:25574562]

J Org Chem. 2015 Feb 6;80(3):1746-53.

Thiophene containing "two-wall" aryl extended calix[4]pyrroles were synthesized for the first time, through acid catalyzed condensation of 2-Acetylthiophenes with pyrrole. Isomeric "two-walled" calix[4]pyrroles (8a-10a and 8b-10b) were obtained in satisfactory yields and their halide anion binding strengths were investigated in the solution phase by (1)H NMR and in the gas phase by computational methods and mass spectrometry. Change in the chemical shifts of thiophene -CH-protons during the course of NMR titrations entailed participation of the thiophene rings in anion binding; this fact was further substantiated by computational methods. The alpha,alpha-(cis)-isomers (8a, 9a, and 10a) showed strong binding toward F(-) and Cl(-) anions when compared to their isomeric alpha,beta-(trans)-isomer (8b, 9b, and 10b). In both isomers, binding with F(-) anion was found to be stronger than that with Cl(-) anion. Both the solution-phase and gas-phase results revealed that the thiophene rings stabilize the anions through anion-pi interactions.

Generation of a structurally diverse library through alkylation and ring closure reactions using 3-dimethylamino-1-(thiophen-2-yl)propan-1-one hydrochloride.[Pubmed:23841334]

Acta Chim Slov. 2013;60(1):70-80.

3-Dimethylamino-1-(thiophen-2-yl)propan-1-one hydrochloride (2), a ketonic Mannich base derived from 2-Acetylthiophene, was used as a starting material in different types of alkylation and ring closure reactions with a view to generate a structurally diverse library of compounds. Compound 2 reacts with S-alkylated dithiocarbamic acid salts and aryl mercaptans to produce dithiocarbamates and thioethers, respectively. The dimethylamino moiety in compound 2 was exchanged with various aliphatic secondary and aromatic primary and secondary amines, whereas monocyclic NH-azoles such as pyrazole, imidazole, 1,2,4-triazole, and tetrazole were N-alkylated by compound 2. Ketones, pyrrole and indoles have been the substrates subjected to C-alkylation reactions by compound 2. Ring closure reactions of compound 2 with a suitable bifunctional nucleophile yielded pyrazolines, pyridines, 2,3-dihydro-1,5-1H-benzodiazepines, 2,3-dihydro-1,5-1H-benzothiazepine, pyrimido[1,2-a]benzimidazole and 4-hydroxypiperidine derivatives.

Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9.[Pubmed:22329513]

Chem Res Toxicol. 2012 Apr 16;25(4):895-903.

The uricosuric diuretic agent tienilic acid (TA) is a thiophene-containing compound that is metabolized by P450 2C9 to 5-OH-TA. A reactive metabolite of TA also forms a covalent adduct to P450 2C9 that inactivates the enzyme and initiates immune-mediated hepatic injury in humans, purportedly through a thiophene-S-oxide intermediate. The 3-thenoyl regioisomer of TA, tienilic acid isomer (TAI), is chemically very similar and is reported to be oxidized by P450 2C9 to a thiophene-S-oxide, yet it is not a mechanism-based inactivator (MBI) of P450 2C9 and is reported to be an intrinsic hepatotoxin in rats. The goal of the work presented in this article was to identify the reactive metabolites of TA and TAI by the characterization of products derived from P450 2C9-mediated oxidation. In addition, in silico approaches were used to better understand both the mechanisms of oxidation of TA and TAI and/or the structural rearrangements of oxidized thiophene compounds. Incubation of TA with P450 2C9 and NADPH yielded the well-characterized 5-OH-TA metabolite as the major product. However, contrary to previous reports, it was found that TAI was oxidized to two different types of reactive intermediates that ultimately lead to two types of products, a pair of hydroxythiophene/thiolactone tautomers and an S-oxide dimer. Both TA and TAI incorporated (1)(8)O from (1)(8)O(2) into their respective hydroxythiophene/thiolactone metabolites indicating that these products are derived from an arene oxide pathway. Intrinsic reaction coordinate calculations of the rearrangement reactions of the model compound 2-Acetylthiophene-S-oxide showed that a 1,5-oxygen migration mechanism is energetically unfavorable and does not yield the 5-OH product but instead yields a six-membered oxathiine ring. Therefore, arene oxide formation and subsequent NIH-shift rearrangement remains the favored mechanism for formation of 5-OH-TA. This also implicates the arene oxide as the initiating factor in TA induced liver injury via covalent modification of P450 2C9. Finally, in silico modeling of P450 2C9 active site ligand interactions with TA using the catalytically active iron-oxo species revealed significant differences in the orientations of TA and TAI in the active site, which correlated well with experimental results showing that TA was oxidized only to a ring carbon hydroxylated product, whereas TAI formed both ring carbon hydroxylated products and an S-oxide.

Synthesis of some Mannich bases with dimethylamine and their hydrazones and evaluation of their cytotoxicity against Jurkat cells.[Pubmed:21827048]

Arzneimittelforschung. 2011;61(6):366-71.

1-Aryl-3-dimethylamino-1-propanone hydrochlorides type mono Mannich bases, D series, and corresponding hydrazone derivatives, K series, were synthesized and their cytotoxicity was tested against Jurkat cells (transformed human T-lymphocytes). The aryl part was changed as phenyl in D1 and K1, 4-methylphenyl in D2 and K2, 4-methoxyphenyl in D3 and K3, 4-hydroxyphenyl in D4 and K4, 4-chlorophenyl in D5 and K5, 3-methoxyphenyl in D6 and K6, 4-fluorophenyl in D7 and K7, 4-bromophenyl in D8 and K8, 3-hydroxyphenyl in D9 and K9, and 2-Acetylthiophene in D10 and K10. Of the compounds synthesized, K2, K3, K5, K6, K7, K8, K9, and K10 are reported for the first time. Cytotoxic activities of the D and K series were compared with each other to see alterations in bioactivity depending on the chemical structures in Jurkat cells. Cytotoxicities of the compounds synthesized were also compared with the reference compound, 5-fluorouracil (CAS 148-82-3). Mono Mannich bases, D1 (3.60 times), D2 (4.45 times), D3 (2.46 times), D4 (3.52 times), D5 (5.18 times), D6 (3.20 times), D7 (3.23 times), D8 (3.95 times), D9 (3.36 times) and D10 (3.99 times) had 2.46-5.18 times higher cytotoxic potency than the reference compound 5-fluorouracil against Jurkat cells, while hydrazones K1 (4.92 times), K2 (4.65 times), K3 (6.04 times), K4 (6.34 times), K5 (4.67 times), K6 (5.12 times), K7 (5.39 times), K8 (8.31 times), K9 (4.65 times) and K10 (8.65 times) had 4.65-8.65 times higher cytotoxic potency than the reference compound 5-fluorouracil against the same cell line. On the other hand, hydrazone compounds K1 (1.37 times), K3 (2.46 times), K4 (1.80 times), K6 (1.60 times), K7 (1.67 times), K8 (2.11 times), K9 (1.38 times), and K10 (2.17 times) had 1.37-2.46 times higher cytotoxic potency than their corresponding mono Mannich bases. The results of this study suggest that hydrazones were better compounds compared with the corresponding mono Mannich bases in terms of cytotoxicity, and they may serve as model compounds to develop new cytotoxic agents for further studies.

Synthesis and antifungal evaluation of 1-aryl-2-dimethyl- aminomethyl-2-propen-1-one hydrochlorides.[Pubmed:21642940]

Molecules. 2011 Jun 3;16(6):4660-71.

The development of resistance to current antifungal therapeutics drives the search for new effective agents. The fact that several acetophenone-derived Mannich bases had shown remarkable antifungal activities in our previous studies led us to design and synthesize some acetophenone-derived Mannich bases, 1-8 and 2-Acetylthiophene-derived Mannich base 9, 1-aryl-2-dimethylaminomethyl-2-propen-1-one hydrochloride, to evaluate their antifungal activities. The designed chemical structures have alpha,beta-unsaturated ketone moieties, which are responsible for the bioactivities of the Mannich bases. The aryl part was C(6)H(5)(1); 4-CH(3)C(6)H(4) (2); 4-CH(3)OC(6)H(4) (3); 4-ClC(6)H(4) (4); 4-FC(6)H(4) (5); 4-BrC(6)H(4) (6); 4-HOC(6)H(4) (7); 4-NO(2)C(6)H(4) (8); and C(4)H(3)S(2-yl) (9). In this study the designed compounds were synthesized by the conventional heating method and also by the microwave irradiation method to compare these methods in terms of reaction times and yields to find an optimum synthetic method, which can be applied for the synthesis of Mannich bases in further studies. Since there are limited number of studies reporting the synthesis of Mannich bases by microwave irradiation, this study may also contribute to the general literature on Mannich bases. Compound 7 was reported for the first time. Antifungal activities of all compounds and synthesis of the compounds by microwave irradiation were also reported for the first time by this study. Fungi (15 species) were used for antifungal activity test. Amphotericin B was tested as an antifungal reference compound. In conclusion, compounds 1-6, and 9, which had more potent (2-16 times) antifungal activity than the reference compound amphotericin B against some fungi, can be model compounds for further studies to develop new antifungal agents. In addition, microwave irradiation can be considered to reduce reaction period, while the conventional method can still be considered to obtain compounds with higher reaction yields in the synthesis of new Mannich bases.

Conformational preferences for some 5-substituted 2-acetylthiophenes through infrared spectroscopy and theoretical calculations.[Pubmed:21620762]

Spectrochim Acta A Mol Biomol Spectrosc. 2011 Sep;79(5):1071-6.

The s-cis-trans isomerisms of some derivatives of thiophene (2-acetyl, AT; 2-acetyl-5-bromo, ABT and 2-acetyl-5-chloro, ACT) were analyzed, using data from deconvolution of their carbonyl absorption bands in two solvents (CCl4 and CHCl3). These infrared data showed that the O,S-cis conformer largely predominates in the studied solvents and that the same occurs in the gas phase, as observed from theoretical calculations. The latter results were obtained using B3LYP/6-311++G(3df,3p) and MP2/6-311++G(3df,3p) levels of theory, with zero-point energy correction. Moreover, the use of the IEFPCM (Integral Equation Formalism Polarizable Continuum Model) to take into account the solvent effects, using the same levels of theory, confirmed the results observed from infrared data. Low temperature 13C NMR spectra in CS2/CD2Cl2 (-90 degrees C) and in acetone-d6 (-80 degrees C) did not show pairs of signals for each carbon, due to the known low energy barrier ( approximately 8 kcal mol(-1)) for the cis-trans interconversion. Data from NBO calculations show that the nO(2)-->sigmaS-C5* and nO(2)-->sigmaC2-C3* interactions occur only in the O,S-cis isomer and can explain its conformational preference.