Zinc(II) Complex with Pyrazolone-Based Hydrazones is Strongly Effective against Trypanosoma brucei Which Causes African Sleeping Sickness

Abstract

Two pyrazolone-based hydrazones H 2 L′ [in general, H 2 L′; in detail, H 2 L 1 = 5-methyl-2-phenyl-4-(2-phenyl-1-(2-(4-(trifluoromethyl)phenyl)hydrazineyl)ethyl)-2,4-dihydro-3 H -pyrazol-3-one, H 2 L 2 = ( Z )-5-methyl-2-phenyl-4-(2-phenyl-1-(2-(pyridin-2-yl)hydrazineyl)ethylidene)-2,4-dihydro-3 H -pyrazol-3-one] were reacted with Zn(II) and Cu(II) acceptors affording the complexes [Zn(HL 1 ) 2 (MeOH) 2 ], [Cu(HL 1 ) 2 ], and [M(HL 2 ) 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(HL 1 ) 2 (MeOH) 2 ], zinc is six-coordinated by the N,O-chelated (HL 1 ) ligand and other two oxygen atoms of coordinated methanol molecules, while [Cu(HL 1 ) 2 ] adopts a square planar geometry with the two (HL 1 ) ligands in anti-conformation. Finally, the [M(HL 2 ) 2 ] complexes are octahedral with the two (HL 2 ) 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, H 2 L 1 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 H 2 L 1 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.

Targeting the nucleotide metabolism of Trypanosoma brucei and other trypanosomatids

“…Attempts have also been made with improved versions of acivicin by designing analogues based on the crystal structure of T. brucei CTP synthetase, but 3-bromoacivicin is still the most selective analogue (Tamborini et al 2012 ). A possible alternative to the glutamine analogues could be to use pyrazolone-based hydrazones, which were recently discovered to strongly reduce CTP pools in the parasite indicating that CTP synthetase is a likely target (Marchetti et al 2022 ).…”

De-epimerizing DyKAT of β-lactones generated by isothiourea-catalysed enantioselective [2 + 2] cycloaddition

“…37 Building upon these principles and the growing impact of organocatalysis in the pharmaceutical industry, [38][39][40][41][42] in this manuscript an effective synthetic strategy for the preparation of functionalised b-hydroxy-b-pyrazolone amides in high dr and er (up to >95 : 5 dr, >99 : 1 er) is described. Given that nitrogencontaining heterocycles are incorporated into an array of biologically relevant compounds, [43][44][45][46] and with pyrazole derivatives a prevalent heterocycle of widespread relevance, [47][48][49][50][51][52] the generation of catalytic enantioselective methods that would lead to chiral pyrazolone heterocycle derivatives was targeted. [53][54][55][56] The developed process combines an isothiourea-mediated highly enantioselective formal [2 + 2]-cycloaddition of C(1)-ammonium enolates to generate diastereoisomeric spirocyclic b-lactones, coupled with a subsequent substrate-controlled DyKAT type III process where the absolute conguration at C(3) within the blactone is labile and that at C(4) is xed (Fig.…”

Design, Synthesis and Evaluation of a Series of Zinc(II) Complexes of Anthracene-Affixed Multifunctional Organic Assembly as Potential Antibacterial and Antibiofilm Agents against Methicillin-Resistant Staphylococcus aureus

“…Therefore, with the aim of reducing toxicity and irritation of free zinc­(II) ion, the organo-chelated zinc complexes come to great attention. , It is also strongly believed that the complexation of zinc­(II) with appropriately designed multifunctional organic assembly improves bioavailability, while affording the beneficial effect against microbial infections. Unfortunately, considerably few research studies on antibacterial zinc complexes have been explored. − …”