2361-27-5Relevant articles and documents
Synthesis and amide imidic prototropic tautomerization in thiophene-2-carbohydrazide: XRD, DFT/HSA-computation, DNA-docking, TG and isoconversional kinetics via FWO and KAS models
Al-Zaqri, Nabil,Khatib, Tamer,Alsalme, Ali,Alharthi, Fahad A.,Zarrouk, Abdelkader,Warad, Ismail
, p. 2037 - 2048 (2020)
Thiophene-2-carbohydrazide as a novel small-molecule amide tautomer has been synthesized with an acceptable yield under microwave radiation (MW) conditions. The amide imidic thiophene-2-carbohydrazide prototropic tautomerization via single proton intramigration was computed using the DFT B3LYP/6-311G(d,p) level of theory. The endo-isomer amide structure of thiophene-2-carbohydrazide was proved by XRD and is considered to be the kinetically favored isomer. The DFT-structure parameters were compared to their corresponding XRD-experimental parameters. Several H-bond interactions were detected in the crystal lattice experimentally using the XRD-packing model then correlated to MEP and HSA calculations. The manual and calculated electronic parameters such as, frontier molecular orbital energies, excitation energy, absorption, dipole moment, DOS, GRD quantum parameters and TD-SCF/B3LYP were DFT computed. The thiophene-2-carbohydrazide isomers together with their prototropic (E)/(Z)-thiophene-2-carbohydrazonic acid tautomers were docked against 1BNA DNA. FWO and KAS isoconversional kinetic methods were applied, and the thermal behavior and estimated Ea-α relations were determined.
Novel phenolic Mannich base derivatives: synthesis, bioactivity, molecular docking, and ADME-Tox Studies
Tokal?, Feyzi Sinan,Taslimi, Parham,Demircio?lu, ?brahim Hakk?,?endil, K?v?lc?m,Tuzun, Burak,Gül?in, ?lhami
, p. 563 - 577 (2021/07/12)
In this study, it was aimed to synthesize novel molecules containing potential biological active phenolic Mannich base moiety and evaluate the inhibition properties against α-glycosidase (α-Gly) and acetylcholinesterase (AChE). For this purpose, phenolic aldehydes (1–3) were synthesized from 4-hydroxy-3-methoxy benzaldehyde (vanillin) according to the Mannich Reaction. Five different carboxylic acid hydrazides (4a-e) were synthesized from esters obtained from carboxylic acids. Fifteen Schiff base derivatives (5a-e, 6a-e, and 7a-e) were synthesized from the condensation reaction of compounds 1–3 with 4a-e. In this work, a series of novel Schiff bases from Phenolic Mannich bases (5a-e, 6a-e, and 7a-e) were tested toward α-Gly and AChE enzymes. Compounds 5a-e, 6a-e, and 7a-e showed Kis in ranging of 341.36 ± 31.84–904.76 ± 93.56?nM on AChE and 176.27 ± 22.87—621.77 ± 69.98?nM on α-glycosidase. Finally, novel compounds were found using molecular docking method to calculate the biological activity of these bases against many enzymes. The enzymes used in these calculations are acetylcholinesterase and α-glycosidase, respectively. Molecule 6b is more effective and active than other molecules with a docking score parameter value of ? 8.77 against AChE enzyme and 6d is more effective and active than other molecules with a docking score parameter value of ? 4.94 against α-Gly enzyme. After calculating the biological activities of novel compounds, ADME/T analysis parameters were examined to calculate the future drug use properties.
Effect of s–se bioisosteric exchange on affinity and intrinsic efficacy of novel n-acylhydrazone derivatives at the adenosine a2a receptor
Barreiro, Eliezer J.,No?l, Fran?ois G.,Pedreira, Júlia Galvez Bulh?es,Silva, Rafaela Ribeiro
, (2021/12/17)
In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new N-acylhydrazone (NAH) derivatives (3–8, 13, 14), analogues of the cardioactive compounds LASSBio-294 (1) and LASSBio-785 (2). NMR spectra analysis demonstrated a chemical shift variation of the iminic Csp2 of NAH S/Se-isosters, suggesting a stronger intramolecular chalcogen interaction for Se-derivatives. To investigate the pharmacological profile of these compounds at the adenosine A2A receptor (A2AR), we performed a previously validated functional binding assay. As expected for bioisosteres, the isosteric-S/Se replacement affected neither the affinity nor the intrinsic efficacy of our NAH derivatives (1–8). However, the N-methylated compounds (2, 6–8) presented a weak partial agonist profile at A2AR, contrary to the non-methylated counterparts (1, 3–5), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the N-methylation on intrinsic efficacy at A2AR, while meta-substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH-N-methylation and aromatic rings retroisosterism changed the intrinsic efficacy on A2AR, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.
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
, (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.
