26029-04-9Relevant academic research and scientific papers
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.
Design, synthesis and molecular docking of new N-4-piperazinyl ciprofloxacin-triazole hybrids with potential antimicrobial activity
Mohammed, Hamada H.H.,Abdelhafez, El-Shimaa M.N.,Abbas, Samar H.,Moustafa, Gamal A.I.,Hauk, Glenn,Berger, James M.,Mitarai, Satoshi,Arai, Masayoshi,Abd El-Baky, Rehab M.,Abuo-Rahma, Gamal El-Din A.
, (2019/05/01)
New N-4-piperazinyl ciprofloxacin-triazole hybrids 6a-o were prepared and characterized. The in vitro antimycobacterial activity revealed that compound 6a experienced promising antimycobacterial activity against Mycobactrium smegmatis compared with the reference isoniazide (INH). Additionally, compound 6a exhibited broad spectrum antibacterial activity against all the tested strains either Gram-positive or Gram-negative bacteria compared with the reference ciprofloxacin. Also, compounds 6g and 6i displayed considerable antifungal activity compared with the reference ketoconazole. DNA cleavage assay of the highly active compounds 6c and 6h showed a good correlation between the Mycobactrium cleaved DNA gyrase assay and their in vitro antimycobactrial activity. Moreover, molecular modeling studies were done for the designed ciprofloxacin derivatives to predict their binding modes towards Topoisomerase II enzyme (PDB: 5bs8).
Construction of heterometallic and mixed-valence copper(I/II) chloride π-complexes with 1,2,4-triazole allyl-derivative
Hordiichuk, Oleh R.,Slyvka, Yurii I.,Kinzhybalo, Vasyl V.,Goreshnik, Evgeny A.,Bednarchuk, Tamara J.,Bednarchuk, Oleksandr,Jedryka, Jaros?aw,Kityk, Iwan,Mys'kiv, Marian G.
, (2019/07/19)
Copper(I) coordination compounds with allyl-derivatives of various heterocycles are an interesting subject of current research, however, the possibility of exploiting a second metal cation (i.e. obtaining heterobimetallic complexes) as a tool for crystal
New 1,2,4-triazole-Chalcone hybrids induce Caspase-3 dependent apoptosis in A549 human lung adenocarcinoma cells
Ahmed, Fatma F.,Abd El-Hafeez, Amer Ali,Abbas, Samar H.,Abdelhamid, Dalia,Abdel-Aziz, Mohamed
, p. 705 - 722 (2018/04/17)
A series of novel 1, 2, 4-triazole/chalcone hybrids was prepared and identified with different spectroscopic techniques. The prepared compounds showed remarkable cytotoxic activity against different cancer cell lines. Compounds 24, 25, 27, 41 and 47 had shown the highest cytotoxicity among the tested compounds against human lung adenocarcinoma A549 cells with IC50 ranging from 4.4 to 16.04 μM compared to cisplatin with IC50 of 15.3 μM. Flow cytometric analysis of the tested compounds showed an increase in the number of apoptotic cells in a dose-dependent manner. The further mechanistic study demonstrated that 1, 2, 4-triazole-chalcone hybrids induced apoptosis via increased level of proapoptotic protein Bax, release of cytochrome c from mitochondria and activation of caspase-3/8/9 proteins. However, general caspase inhibition by the pan-caspase inhibitor, z-VAD-fmk, significantly decreased the apoptosis induced by the tested hybrids, suggesting dependency of apoptosis on activation of the caspase-3 pathway.
Influence of apical ligands on Cu–(C[dbnd]C) interaction in Copper(I) halides (Cl?, Br?, I?) π-complexes with an 1,2,4-triazole allyl-derivative: Syntheses, crystal structures and NMR spectroscopy
Hordiichuk, Oleh R.,Kinzhybalo, Vasyl V.,Goreshnik, Evgeny A.,Slyvka, Yurii I.,Krawczyk, Marta S.,Mys'kiv, Marian G.
, p. 1 - 8 (2017/03/22)
New multifunctional 1,2,4-triazole based allyl-derivative as the ligand L (3-allylsulfanyl-4-allyl-5-phenyl-4H-1,2,4-triazole) revealed an ability to form stable binuclear copper(I) π-complexes. A series of related Cu(I) halides π-complexes, [Cu2/su
1,2,4-Triazole/oxime hybrids as new strategy for nitric oxide donors: Synthesis, anti-inflammatory, ulceroginicity and antiproliferative activities
Abuo-Rahma, Gamal El-Din A.A.,Abdel-Aziz, Mohamed,Beshr, Eman A.M.,Ali, Taha F.S.
, p. 185 - 198 (2014/01/06)
A series of novel nitric oxide (NO) donating triazole/oxime hybrids was prepared and evaluated for their anti-inflammatory activity and antiproliferative activity. Most of the tested compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared to indomethacin. Calculation of the ulcer indices and histopathological investigation indicated that the prepared NO-donating oximes exhibited less ulcerogenicity compared to their ketone intermediates and indomethacin. The NO-donating oximes 7i and 7k achieved remarkable cell growth inhibition activity against most of the tested cell lines. Compound 7k was found to be with high selectivity against CNS subpanel with selectivity ratio of 11.99 at GI 50 level.
New nitric oxide donating 1,2,4-triazole/oxime hybrids: Synthesis, investigation of anti-inflammatory, ulceroginic liability and antiproliferative activities
Abdel-Aziz, Mohamed,Abuo-Rahma, Gamal El-Din A.A.,Beshr, Eman A.M.,Ali, Taha F.S.
, p. 3839 - 3849 (2013/07/19)
A series of novel nitric oxide (NO) donating triazole/oxime hybrids was prepared and evaluated for their anti-inflammatory activity. Most of the tested compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared to indomethacin. Calculation of the ulcer indices and histopathological investigation indicated that the prepared NO-donating oximes exhibited less ulcerogenicity compared to their intermediate ketones and indomethacin. The NO-donating oxime 6i revealed significant activity against renal cancer A498 cell lines with 50.52 cell growth inhibition.
Synthesis and tuberculostatic activity of some 2-piperazinmethylene derivatives 1,2,4-triazole-3-thiones
Foks, Henryk,Janowiec, Mieczyslaw,Zwolska, Zofia,Augustynowicz-Kopec, Ewa
, p. 537 - 543 (2007/10/03)
The Mannich reaction's products of 1,2,4-triazole-3-thiones, substituted in position 4 (with ethyl, allyl, phenyl, Ph-4-Br) or 5 (with phenyl, Ph-4-OH, Ph-3,4,5-(OMe)3, 2-phenyl) were obtained. Their amino-components were 1-phenylpiperazine, 1-
Study of the products of iodocyclization of 4-allyl-5-phenyl-1,2,4- triazole-3-thione
Shmygarev,Kim
, p. 1077 - 1082 (2007/10/03)
The interaction of 4-allyl-5-phenyl-1,2,4-triazole-3-thione with iodine proceeds with the formation of a mixture of 6-iodomethyl-3-phenyl-5,6- dihydrothiazolo[2,3-c]-1,2,4-triazole and 6-iodo-3-phenyl-6,7-dihydro-5H-1,2,4- triazolo[3,4-b]-1,3-thiazine. The structures of the cyclization products obtained were established on the basis of the 1H NMR spectra of their dehydroiodinated derivatives. 6-Methyl-3-phenylthiazolo[2,3-c]-1,2,4-triazole, 3-phenyl-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine, and 3-phenyl-7H-1,2,4- triazolo[3,4-b]-1,3-thiazine are formed on eliminating HI from the cyclization products.
