Article
Zinc(II) complex with pyrazolone-based hydrazones is strongly effective against Trypanosoma brucei, which causes African sleeping sickness
Author/s | Marchetti, Fabio
Tombesi, Alessia Di Nicola, Corrado Pettinari, Riccardo Verdicchio, Federico Crispini, Alessandra Scarpelli, Francesca Baldassarri, Cecilia Marangoni, Elisa Hofer, Anders Galindo del Pozo, Agustín ![]() ![]() ![]() ![]() ![]() ![]() ![]() Petrelli, Riccardo |
Department | Universidad de Sevilla. Departamento de Química Inorgánica |
Publication Date | 2022-08-15 |
Deposit Date | 2023-06-27 |
Published in |
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Abstract | Two pyrazolone-based hydrazones H2L′ [in general, H2L′; in detail, H2L1 = 5-methyl-2-phenyl-4-(2-phenyl-1-(2-(4-(trifluoromethyl)phenyl)hydrazineyl)ethyl)-2,4-dihydro-3H-pyrazol-3-one, H2L2 = (Z)-5-methyl-2-phenyl-4-(2-p ... Two pyrazolone-based hydrazones H2L′ [in general, H2L′; in detail, H2L1 = 5-methyl-2-phenyl-4-(2-phenyl-1-(2-(4-(trifluoromethyl)phenyl)hydrazineyl)ethyl)-2,4-dihydro-3H-pyrazol-3-one, H2L2 = (Z)-5-methyl-2-phenyl-4-(2-phenyl-1-(2-(pyridin-2-yl)hydrazineyl)ethylidene)-2,4-dihydro-3H-pyrazol-3-one] were reacted with Zn(II) and Cu(II) acceptors affording the complexes [Zn(HL1)2(MeOH)2], [Cu(HL1)2], and [M(HL2)2] (M = Cu or Zn). X-ray and DFT studies showed the free proligands to exist in the N–H,N–H tautomeric form and that in [Zn(HL1)2(MeOH)2], zinc is six-coordinated by the N,O-chelated (HL1) ligand and other two oxygen atoms of coordinated methanol molecules, while [Cu(HL1)2] adopts a square planar geometry with the two (HL1) ligands in anti-conformation. Finally, the [M(HL2)2] complexes are octahedral with the two (HL2) ligands acting as κ-O,N,N-donors in planar conformation. Both the proligands and metal complexes were tested against the parasite Trypanosoma brucei and Balb3T3 cells. The Zn(II) complexes were found to be very powerful, more than the starting proligands, while maintaining a good safety level. In detail, H2L1 and its Zn(II) complex have high selective index (55 and >100, respectively) against T. brucei compared to the mammalian Balb/3T3 reference cells. These results encouraged the researchers to investigate the mechanism of action of these compounds that have no structural relations with the already known drugs used against T. brucei. Interestingly, the analysis of NTP and dNTP pools in T. brucei treated by H2L1 and its Zn(II) complex showed that the drugs had a strong impact on the CTP pools, making it likely that CTP synthetase is the targeted enzyme. |
Funding agencies | Ministerio de Universidades e Investigación (MUR). Italia Partnership on Research and Innovation in the Mediterranean Area (PRIMA) Unión Europea Ministerio de Ciencia e Innovación (MICIN). España Consejo de Investigación Sueco Ministerio de Sanidad (MS). Italia |
Project ID. | PRIMA19_00246
![]() PGC2018-093443-B-I00 ![]() 2019- 01242 ![]() PRIN 2017CBNCYT_005 ![]() |
Citation | Marchetti, F., Tombesi, A., Di Nicola, C., Pettinari, R., Verdicchio, F., Crispini, A.,...,Petrelli, R. (2022). Zinc(II) complex with pyrazolone-based hydrazones is strongly effective against Trypanosoma brucei, which causes African sleeping sickness. Inorganic Chemistry, 61 (34), 13561-13575. https://doi.org/10.1021/acs.inorgchem.2c02201. |
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