New heterobimetallic ferrocenyl derivatives are promising antitrypanosomal agents

Arce, Esteban Rodríguez; Putzu, Eugenia; Lapier, Michel; Maya, Juan Diego; Olea‐Azar, Claudio; Echeverría, Gustavo A.; Piro, Oscar E.; Medeiros, Andrea; Sardi, Florencia; Comini, Marcelo A.; Risi, Gastón; Salinas, Gustavo; Correia, Isabel; Pessoa, João Costa; Otero, Lucı́a; Gambino, Dinorah

doi:10.1039/c9dt01317b

Cited by 14 publications

(14 citation statements)

References 73 publications

(78 reference statements)

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“…Crizotinib ® [37], Donepezil ® [38], Risperidone ® [39], and Methyl phenidate ® [40] are the well-known examples of piperidinebased drugs (Figure 1). Likewise, thiosemicarbazones are emerging scaffolds of medicinal interest and their antimicrobial [41,42], anti-inflammatory [43], antioxidant [44,45], anticancer [46][47][48], anti-Alzheimer [49], and alpha-glucosidase inhibitory [50] activities have been reported in recent years.…”

Section: Introductionmentioning

confidence: 99%

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach

et al. 2021

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Alzheimer’s disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer’s heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 μM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 μM, respectively. Various informative structure–activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.

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Section: Introductionmentioning

confidence: 99%

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach

et al. 2021

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“…The most active and selective compound of the new series, [Pt(dppf)(TS3)] (PF 6 ), showed no in vivo toxicity in zebrafish embryos. All embryos were alive in the 1-100 μM concentration range examined, and no apparent toxicity was observed after 48 h of treatment (Rodríguez Arce et al, 2019).…”

Section: Ferrocenyl Derivativesmentioning

confidence: 91%

“…Their effect on some selected molecular targets was studied and omic studies were performed for the most promising pyridine-2-thiolato-1oxide (mpo) compounds. In general, the inclusion of the ferrocene moiety led to interesting effects on the biological profile of the compounds (Rodríguez Arce et al, 2015;Mosquillo et al, 2018a;Mosquillo et al, 2018b;Rivas et al, 2018;Rivas et al, 2019;Rodríguez Arce et al, 2019;Mosquillo et al, 2020;Rivas et al, 2021).…”

Section: Ferrocenyl Derivativesmentioning

confidence: 99%

Facing Diseases Caused by Trypanosomatid Parasites: Rational Design of Pd and Pt Complexes With Bioactive Ligands

Gambino

Otero

2022

Front. Chem.

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Human African Trypanosomiasis (HAT), Chagas disease or American Trypanosomiasis (CD), and leishmaniases are protozoan infections produced by trypanosomatid parasites belonging to the kinetoplastid order and they constitute an urgent global health problem. In fact, there is an urgent need of more efficient and less toxic chemotherapy for these diseases. Medicinal inorganic chemistry currently offers an attractive option for the rational design of new drugs and, in particular, antiparasitic ones. In this sense, one of the main strategies for the design of metal-based antiparasitic compounds has been the coordination of an organic ligand with known or potential biological activity, to a metal centre or an organometallic core. Classical metal coordination complexes or organometallic compounds could be designed as multifunctional agents joining, in a single molecule, different chemical species that could affect different parasitic targets. This review is focused on the rational design of palladium(II) and platinum(II) compounds with bioactive ligands as prospective drugs against trypanosomatid parasites that has been conducted by our group during the last 20 years.

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“…[25][26][27][28][29] These ligands, and many of their metallic compounds have shown featured antimicrobial, antiviral, antiparasitic, and antineoplastic activities. [28,30,31] TSCs can be functionalized with diverse bioactive or pharmacophoric groups and have been amply studied in medicinal chemistry [31,32] including clinical trials for multiple cancers (NCT02595879, NCT02688101, and NCT02433626). [19,33] Studies have shown that the anti-tumor activity of the thiosemicarbazones is due to their ability to act by multiple mechanisms of action, [34][35][36][37][38][39][40] such as inhibition of DNA synthesis, inhibition of cell proliferation, cell cycle, angiogenesis and metastasis, and modulation of signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

“….À ) which generates toxic reactive oxygen species (ROS). [51] Some of us have been involved in the development of thiosemicarbazones containing the 5-nitrofuryl moiety (HTSC) and their use as ligands to generate metal-based compounds (Pt, Pd, Ru and Re) with activity against Trypanosoma cruzi (parasite causing Chagas) [27][28][29]52] The mode of action observed for some of these compounds (e. g. the interaction with DNA and generation of reactive oxygen species) prompted the exploration of their antineoplastic activity, with Ru(II) compounds containing 5-nitrofuryl-TSC displaying relevant cytotoxicity. [53] We describe the synthesis and characterization of gold(I) compounds of the type [AuCl(HTSC)] incorporating thiosemicarbazones containing the 5-nitrofuryl motif.…”

Section: Introductionmentioning

confidence: 99%

5‐Nitrofuryl‐Containing Thiosemicarbazone Gold(I) Compounds: Synthesis, Stability Studies, and Anticancer Activity

Rodríguez‐Arce,

Gavrilov,

Alvite

et al. 2023

ChemPlusChem

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This work describes the synthesis of four gold(I) [AuClL] compounds containing chloro and biologically active protonated thiosemicarbazones based on 5‐nitrofuryl (L=HSTC). The stability of the compounds in dichloromethane, DMSO, and DMSO/culture media solutions was investigated by spectroscopy, cyclic voltammetry, and conductimetry, indicating the formation overtime of cationic monometallic [Au(HTSC)(DMSO)]± or [Au(HTSC)2]±, and/or dimeric species. Neutral [{Au(TSC)}2] species were obtained from one of the compounds in dichlomethane/n‐hexane solution and characterized by X‐ray crystallography revealing a Au−Au bond, and deprotonated thiosemicarbazone (TSC). The cytotoxicity of the gold compounds and thiosemicarbazone ligands was evaluated against selected cancer cell lines and compared to that of Auranofin. Studies of the most stable, cytotoxic, and selective compound on a renal cancer cell line (Caki‐1) demonstrated its relevant antimigratory and anti‐angiogenic properties, and preferential accumulation in the cell nuclei. Its mode of action seems to involve interaction with DNA, and subsequent cell death via apoptosis.

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New heterobimetallic ferrocenyl derivatives are promising antitrypanosomal agents

Abstract: New Pd and Pt ferrocenyl derivatives showed submicromolar activities on T. cruzi and T. brucei and high selectivities.

Cited by 14 publications

References 73 publications

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach

Facing Diseases Caused by Trypanosomatid Parasites: Rational Design of Pd and Pt Complexes With Bioactive Ligands

5‐Nitrofuryl‐Containing Thiosemicarbazone Gold(I) Compounds: Synthesis, Stability Studies, and Anticancer Activity

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