39978-18-2Relevant academic research and scientific papers
Experimental and computational evidence for stabilising parallel, offset π[C(O)N(H)NC]?π(phenyl) interactions in acetohydrazide derivatives
Cardoso, Laura N. F.,De Souza, Marcus V. N.,Tan, Sang Loon,Tiekink, Edward R. T.,Wardell, James L.,Wardell, Solange M. S. V.
, p. 962 - 974 (2022/02/16)
Parallel, offset π[C(O)N(H)NC]?π(phenyl) interactions are observed in the crystal of (2-thienyl)CH2CON(H)-NC(H)Ph, along with more conventional non-covalent interactions. All notable interactions were analysed using Hirshfeld surface analysis, NCI plots and QTAIM analysis. The π[C(O)N(H)NC]?π(phenyl) interactions, whereby the N(H) atom lies over the ring centroid and the N and C atoms on either side of the N(H) atom closely overlay the 1,3-carbon atoms of the phenyl ring, are shown to be attractive. Theory suggests the energy of association provided by the π[C(O)N(H)NC]?π(phenyl) interaction to the molecular packing to be about 15 kJ mol-1, a value similar to that provided by similarly oriented benzene and pyridine rings. A survey of related structures in the literature suggests that comparable interactions occur in approximately 5-6% of crystals where they can potentially occur. This journal is
4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors
Gavara, Laurent,Legru, Alice,Verdirosa, Federica,Sevaille, Laurent,Nauton, Lionel,Corsica, Giuseppina,Mercuri, Paola Sandra,Sannio, Filomena,Feller, Georges,Coulon, Rémi,De Luca, Filomena,Cerboni, Giulia,Tanfoni, Silvia,Chelini, Giulia,Galleni, Moreno,Docquier, Jean-Denis,Hernandez, Jean-Fran?ois
supporting information, (2021/06/15)
In Gram-negative bacteria, the major mechanism of resistance to β-lactam antibiotics is the production of one or several β-lactamases (BLs), including the highly worrying carbapenemases. Whereas inhibitors of these enzymes were recently marketed, they only target serine-carbapenemases (e.g. KPC-type), and no clinically useful inhibitor is available yet to neutralize the class of metallo-β-lactamases (MBLs). We are developing compounds based on the 1,2,4-triazole-3-thione scaffold, which binds to the di-zinc catalytic site of MBLs in an original fashion, and we previously reported its promising potential to yield broad-spectrum inhibitors. However, up to now only moderate antibiotic potentiation could be observed in microbiological assays and further exploration was needed to improve outer membrane penetration. Here, we synthesized and characterized a series of compounds possessing a diversely functionalized alkyl chain at the 4-position of the heterocycle. We found that the presence of a carboxylic group at the extremity of an alkyl chain yielded potent inhibitors of VIM-type enzymes with Ki values in the μM to sub-μM range, and that this alkyl chain had to be longer or equal to a propyl chain. This result confirmed the importance of a carboxylic function on the 4-substituent of 1,2,4-triazole-3-thione heterocycle. As observed in previous series, active compounds also preferentially contained phenyl, 2-hydroxy-5-methoxyphenyl, naphth-2-yl or m-biphenyl at position 5. However, none efficiently inhibited NDM-1 or IMP-1. Microbiological study on VIM-2-producing E. coli strains and on VIM-1/VIM-4-producing multidrug-resistant K. pneumoniae clinical isolates gave promising results, suggesting that the 1,2,4-triazole-3-thione scaffold worth continuing exploration to further improve penetration. Finally, docking experiments were performed to study the binding mode of alkanoic analogues in the active site of VIM-2.
A novel method for the synthesis of 1,2,4-triazole-derived heterocyclic compounds: enzyme inhibition and molecular docking studies
Riaz, Naheed,Iftikhar, Muhammad,Saleem, Muhammad,Aziz-ur-Rehman,Ahmed, Ishtiaq,Ashraf, Muhammad,Shahnawaz,Rehman, Jameel,al-Rashida, Mariya
, p. 1183 - 1200 (2020/01/31)
Two series of new N-aryl/aralkyl derivatives (9a–q) of 2-(4-ethyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide and N-aryl/aralkyl derivatives (10a–q) of 2-(4-phenyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide were synthesized. The methods included successive conversions of thiophen-2-acetic acid (a) into its respective ester, hydrazide and N-aryl/aralkyl 1,3,4-triazole. The target compounds (9a–q; 10a–q) were obtained by the reaction of N-aryl/aralkyl 1,3,4-triazole (5, 6) with various electrophiles, (8a–q), in N,N-dimethyl formamide (DMF) and sodium hydroxide at room temperature. The characterization of these compounds was done by FTIR, 1H-, 13C-NMR, EI-MS and HR-EI-MS spectral data. All compounds were evaluated for their enzyme inhibitory potentials against electric eel acetylcholinesterase, AChE (10f, 10d; IC50 values 32.26 ± 0.12, 45.72 ± 0.11?μM, respectively), equine butyrylcholinesterase, BChE (9d, 9l, 9b, 10d, 10h; IC50 values 12.52 ± 0.19, 12.52 ± 0.19, 21.72 ± 0.18, 23.62 ± 0.22, 24.52 ± 0.21?μM, respectively), jack bean urease (10i, 10n, 9e; IC50 values 7.27 ± 0.05, 7.35 ± 0.04, 8.79 ± 0.05?μM, respectively) and yeast α-glucosidase enzymes (9o, 10i; IC50 values 62.94 ± 0.19, and 69.46 ± 0.15?μM, respectively). The molecular docking studies supported these findings. This study provides cheaper bioactive triazole amides as promising future lead molecules.
A novel serine racemase inhibitor suppresses neuronal over-activation in vivo
Mori, Hisashi,Wada, Ryogo,Takahara, Satoyuki,Horino, Yoshikazu,Izumi, Hironori,Ishimoto, Tetsuya,Yoshida, Tomoyuki,Mizuguchi, Mineyuki,Obita, Takayuki,Gouda, Hiroaki,Hirono, Shuichi,Toyooka, Naoki
, p. 3736 - 3745 (2017/06/13)
Serine racemase (SRR) is an enzyme that produces D-serine from L-serine. D-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and Aβ peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs’ over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states. In the previous study, we performed in silico screening to identify four compounds with inhibitory activities against recombinant SRR. Here, we synthesized 21 derivatives of candidate 1, one of four hit compounds, and performed screening by in vitro evaluations. The derivative 13J showed a significantly lower IC50 value in vitro, and suppressed neuronal over-activation in vivo.
Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S-Component of the Energy-Coupling Factor Transporter for Thiamine
Monjas, Leticia,Swier, Lotteke J. Y. M.,Setyawati, Inda,Slotboom, Dirk J.,Hirsch, Anna K. H.
supporting information, p. 1693 - 1696 (2017/10/27)
We applied dynamic combinatorial chemistry (DCC) to identify ligands of ThiT, the S-component of the energy-coupling factor (ECF) transporter for thiamine in Lactococcus lactis. We used a pre-equilibrated dynamic combinatorial library (DCL) and saturation-transfer difference (STD) NMR spectroscopy to identify ligands of ThiT. This is the first report in which DCC is used for fragment growing to an ill-defined pocket, and one of the first reports for its application with an integral membrane protein as target.
N-acylhydrazones containing thiophene nucleus: a new anticancer class
Cardoso, Laura N. F.,Nogueira, Thais C. M.,Rodrigues, Felipe A. R.,Oliveira, Augusto Cesar Arag?o,Luciano, Maria Claudiados Santos,Pessoa, Claudia,de Souza, Marcus V. N.
, p. 1605 - 1608 (2017/06/27)
In this study, we present a series of N-acylhydrazones containing thiophene nuclei as a new anticancer class. Fifty-seven compounds in this series were evaluated for their activity against four human cancer cell lines. Cytotoxicity (IC50) ranged from 0.82 to 12.90 μM. The compound (E)-N′-(2-hydroxy-3-methoxybenzylidene)thiophene-2-carbohydrazide displayed good cytotoxic activity in all cell lines (IC50 = 0.82–5.36 μM) and yielded the best result in this series; therefore, it is an important lead compound in this new class.
Azolylthioacetamides as a potent scaffold for the development of metallo-β-lactamase inhibitors
Xiang, Yang,Chang, Ya-Nan,Ge, Ying,Kang, Joon S.,Zhang, Yi-Lin,Liu, Xiao-Long,Oelschlaeger, Peter,Yang, Ke-Wu
supporting information, p. 5225 - 5229 (2017/11/13)
In an effort to develop new inhibitors of metallo-β-lactamases (MβLs), twenty-eight azolylthioacetamides were synthesized and assayed against MβLs. The obtained benzimidazolyl and benzioxazolyl substituted 1–19 specifically inhibited the enzyme ImiS, and 10 was found to be the most potent inhibitor of ImiS with an IC50 value of 15 nM. The nitrobenzimidazolyl substituted 20–28 specifically inhibited NDM-1, with 27 being the most potent inhibitor with an IC50 value of 170 nM. Further studies with 10, 11, and 27 revealed a mixed inhibition mode with competitive and uncompetitive inhibition constants in a similar range as the IC50 values. These inhibitors resulted in a 2–4-fold decrease in imipenem MIC values using E. coli cells producing ImiS or NDM-1. While the source of uncompetitive (possibly allosteric) inhibition remains unclear, docking studies indicate that 10 and 11 may interact orthosterically with Zn2 in the active site of CphA, while 27 could bridge the two Zn(II) ions in the active site of NDM-1 via its nitro group.
SERINE RACEMASE INHIBITOR
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Paragraph 0227; 0228; 0229; 0330, (2014/12/12)
A novel serine racemase inhibitor exhibits sufficient activity and specificity. The serine racemase inhibitor includes one or more compounds selected from compounds respectively represented by the following general formulas [MM_1], [DR_1], [DR'_1], [LW_1], and [ED_1] as an active ingredient.
Synthesis, experimental and theoretical study on the structure of some semicarbazides with potential antibacterial activity
Pitucha, Monika,Karczmarzyk, Zbigniew,Kosikowska, Urszula,Malm, Anna
scheme or table, p. 505 - 511 (2011/06/28)
A series of 1,4-disubstituted semicarbazide and 4,4'-bis[1-substituted semicarbazide]diphenyl-methane derivatives were synthesized to explore their antibacterial activity. New compounds were characterized by elemental analysis and spectroscopic data. In order to find the tautomeric equilibrium for the molecules energy calculations for each possible tautomeric form of model compound 2, and for the most antibacterially active compound 7 in the investigated series, were calculated for the gas phase at the RHF/SCF/6-31G** level of theory.
Triazole derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase-Structure-activity relationships and crystallographic analysis
Kirschberg, Thorsten A.,Balakrishnan, Mini,Huang, Wei,Hluhanich, Rebecca,Kutty, Nilima,Liclican, Albert C.,McColl, Damian J.,Squires, Neil H.,Lansdon, Eric B.
, p. 1131 - 1134 (2008/12/21)
A series of 3,4,5-trisubstituted 1,2,4-4H triazole derivatives was synthesized and investigated for HIV-1 reverse transcriptase inhibition. An X-ray structure with HIV-1 RT secured the binding mode and allowed the key interactions with the enzyme to be identified.
