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1.
Chembiochem ; 25(6): e202300696, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38146865

RESUMO

Pt(II) and Pd(II) coordinating N-donor ligands have been extensively studied as anticancer agents after the success of cisplatin. In this work, a novel bidentate N-donor ligand, the N-[[4-(phenylmethoxy)phenyl]methyl]-2-pyridinemethanamine, was designed to explore the antiparasitic, antiviral and antitumor activity of its Pt(II) and Pd(II) complexes. Chemical and spectroscopic characterization confirm the formation of [MLCl2 ] complexes, where M=Pt(II) and Pd(II). Single crystal X-ray diffraction confirmed a square-planar geometry for the Pd(II) complex. Spectroscopic characterization of the Pt(II) complex suggests a similar structure. 1 H NMR, 195 Pt NMR and HR-ESI-MS(+) analysis of DMSO solution of complexes indicated that both compounds exchange the chloride trans to the pyridine for a solvent molecule with different reaction rates. The ligand and the two complexes were tested for in vitro antitumoral, antileishmanial, and antiviral activity. The Pt(II) complex resulted in a GI50 of 10.5 µM against the NCI/ADR-RES (multidrug-resistant ovarian carcinoma) cell line. The ligand and the Pd(II) complex showed good anti-SARS-CoV-2 activity with around 65 % reduction in viral replication at a concentration of 50 µM.


Assuntos
Antineoplásicos , Complexos de Coordenação , Platina/farmacologia , Platina/química , Ligantes , Cisplatino , Antineoplásicos/farmacologia , Antineoplásicos/química , Antivirais/farmacologia , Paládio/farmacologia , Paládio/química , Cristalografia por Raios X , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Linhagem Celular Tumoral
2.
J Inorg Biochem ; 229: 111726, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35065320

RESUMO

Leishmania amazonensis and L. braziliensis are the main etiological agents of the American Tegumentary Leishmaniasis (ATL). Taking into account the limited effectiveness and high toxicity of the current drug arsenal to treat ATL, novel options are urgently needed. Inspired by the fact that gold-based compounds are promising candidates for antileishmanial drugs, we studied the biological action of a systematic series of six (1)-(6) symmetric Au(I) benzyl and aryl-N-heterocyclic carbenes. All compounds were active at low micromolar concentrations with 50% effective concentrations ranging from 1.57 to 8.30 µM against Leishmania promastigotes. The mesityl derivative (3) proved to be the best candidate from this series, with a selectivity index ~13 against both species. The results suggest an effect of the steric and electronic parameters of the N-substituent in the activity. Intracellular infections were drastically reduced after 24h of (2)-(5) incubation in terms of infection rate and amastigote burden. Further investigations showed that our compounds induced significant parasites' morphological alterations and membrane permeability. Also, (3) and (6) were able to reduce the residual activity of three Leishmania recombinant cysteine proteases, known as possible targets for Au(I) complexes. Our promising results open the possibility of exploring gold complexes as leishmanicidal molecules to be further screened in in vivo models of infection.


Assuntos
Imidazóis/farmacologia , Compostos Organoáuricos/farmacologia , Tripanossomicidas/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Feminino , Ouro/química , Imidazóis/síntese química , Leishmania braziliensis/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Organoáuricos/síntese química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química
3.
Trends Parasitol ; 37(8): 694-697, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34059455

RESUMO

Here we highlight coinfections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with ectoparasites, helminths, and protozoa, described in the literature, and the urgent need to understand the conditions of these associated pathologies. We emphasize the notion that such information is crucial for the continuity of measures that have been used for decades to control neglected parasitic diseases.


Assuntos
COVID-19 , Coinfecção , Doenças Parasitárias , Humanos , Doenças Negligenciadas/prevenção & controle , Doenças Parasitárias/prevenção & controle , SARS-CoV-2
4.
ChemMedChem ; 16(11): 1681-1695, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33615725

RESUMO

Leishmaniasis is one of the most neglected diseases worldwide and is considered a serious public health issue. The current therapeutic options have several disadvantages that make the search for new therapeutics urgent. Gold compounds are emerging as promising candidates based on encouraging in vitro and limited in vivo results for several AuI and AuIII complexes. The antiparasitic mechanisms of these molecules remain only partially understood. However, a few studies have proposed the trypanothione redox system as a target, similar to the mammalian thioredoxin system, pointed out as the main target for several gold compounds with significant antitumor activity. In this review, we present the current status of the investigation and design of gold compounds directed at treating leishmaniasis. In addition, we explore potential targets in Leishmania parasites beyond the trypanothione system, taking into account previous studies and structure modulation performed for gold-based compounds.


Assuntos
Antiprotozoários/farmacologia , Descoberta de Drogas , Glutationa/análogos & derivados , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Compostos Organoáuricos/farmacologia , Espermidina/análogos & derivados , Animais , Antiprotozoários/química , Glutationa/antagonistas & inibidores , Glutationa/metabolismo , Humanos , Leishmania/metabolismo , Leishmaniose/metabolismo , Compostos Organoáuricos/química , Oxirredução , Testes de Sensibilidade Parasitária , Espermidina/antagonistas & inibidores , Espermidina/metabolismo
5.
ChemMedChem ; 15(22): 2146-2150, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-32830445

RESUMO

A series of mononuclear coordination or organometallic AuI /AuIII complexes (1-9) have been comparatively studied in vitro for their antileishmanial activity against promastigotes and amastigotes, the clinically relevant parasite form, of Leishmania amazonensis and Leishmania braziliensis. One of the cationic AuI bis-N-heterocyclic carbenes (3) has low EC50 values (ca. 4 µM) in promastigotes cells and no toxicity in host macrophages. Together with two other AuIII complexes (6 and 7), the compound is also extremely effective in intracellular amastigotes from L. amazonensis. Initial mechanistic studies include an evaluation of the gold complexes' effect on L. amazonensis' plasma membrane integrity.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Compostos Organoáuricos/farmacologia , Animais , Antiprotozoários/química , Células Cultivadas , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Organoáuricos/química , Testes de Sensibilidade Parasitária
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