Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: Synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay

Oliveira, Jamerson Ferreira de; Lima, Talitha S.; Vendramini–Costa, Débora Barbosa; Pedrosa, Sybelle Christianne Batista de Lacerda; Lafayette, Elizabeth Almeida; Silva, Rosali Maria Ferreira da; Almeida, Sinara Mônica Vitalino de; Moura, Ricardo Olímpio de; Ruiz, Ana Lúcia Tasca Góis; Carvalho, João Ernesto de; Lima, Maria do Carmo Alves de

doi:10.1016/j.ejmech.2017.05.023

Cited by 66 publications

(13 citation statements)

References 62 publications

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“…DNA topoisomerase has been identified at a cellular target for a number of effective antitumor drugs. , Therefore, we used agarose gel electrophoresis to confirm whether Cu agents could inhibit the activity of DNA topoisomerase. It was obvious that 6b can inhibit the activity of both topoisomerase I (Topo I) and topoisomerase II (Topo II) (Figure A,D).…”

Section: Resultssupporting

confidence: 52%

Novel Brain-Tumor-Inhibiting Copper(II) Compound Based on a Human Serum Albumin (HSA)-Cell Penetrating Peptide Conjugate

Zhang

Gou

et al. 2019

J. Med. Chem.

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It is a great challenge to design drugs that penetrate the blood–brain barrier to inhibit brain tumor growth by acting against multiple targets and also improve their delivery efficacy and targeting ability to cancer cells. To overcome the above problems, we designed a multitarget metal agent for treating brain tumors based on an human serum albumin (HSA)-cell penetrating peptide conjugate. Thus, we rationally screened copper (Cu) and 2-acetyl-3-ethylpyrazine thiosemicarbazones to synthesize six compounds, and we investigated their structure–activity relationships and confirmed multiple mechanisms for brain glioma cells. The HSA–6b complex structure indicated that 6b binds to the IIA subdomain of HSA and His242 replaces the Br ligand in 6b in coordination with Cu2+. In vivo data suggested that both 6b and the HSA–6b–peptide conjugate penetrate the blood–brain barrier and inhibit brain tumor growth with few side effects. Furthermore, the HSA–peptide conjugate also improved the delivery efficacy and targeting ability of 6b in vivo.

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Section: Resultssupporting

confidence: 52%

Novel Brain-Tumor-Inhibiting Copper(II) Compound Based on a Human Serum Albumin (HSA)-Cell Penetrating Peptide Conjugate

Zhang

Gou

et al. 2019

J. Med. Chem.

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“…Several studies suggest that compounds with thiazolidinone core have a potent biological activity, such as anti-inflammatory, antibacterial, anticancer, antiviral, antiparasitic, among others [ 7 , 22 , 61 ]. Thiazolidinone could be considered an in vitro hit against T. gondii [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Protein targets of thiazolidinone derivatives in Toxoplasma gondii and insights into their binding to ROP18

et al. 2018

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BackgroundThiazolidinone derivatives show inhibitory activity (IC50) against the Toxoplasma gondii parasite, as well as high selectivity with high therapeutic index. To disclose the target proteins of the thiazolidinone core in this parasite, we explored in silico the active sites of different T. gondii proteins and estimated the binding-free energy of reported thiazolidinone molecules with inhibitory effect on invasion and replication of the parasite inside host cells. This enabled us to describe some of the most suitable structural characteristics to design a compound derived from the thiazolidinone core.ResultsThe best binding affinity was observed in the active site of kinase proteins, we selected the active site of the T. gondii ROP18 kinase, because it is an important factor for the virulence and survival of the parasite. We present the possible effect of a derivative of thiazolidinone core in the active site of T. gondii ROP18 and described some characteristics of substituent groups that could improve the affinity and specificity of compounds derived from the thiazolidinone core against T. gondii.ConclusionsThe results of our study suggest that compounds derived from the thiazolidinone core have a preference for protein kinases of T. gondii, being promising compounds for the development of new drugs with potential anti-toxoplasmosis activity. Our findings highlight the importance of use computational studies for the understanding of the action mechanism of compounds with biological activity.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5223-7) contains supplementary material, which is available to authorized users.

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“…As iron chelators, thiosemicarbazone derivatives have played an important role in organic and medicinal chemistry due to their promising biological activities, which include antiparasitic ( 22 ), anticancer ( 23 , 24 ), anticonvulsant ( 25 ), antiviral ( 26 ), antimicrobial ( 27 , 28 ), and antifungal ( 29 ) effects. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine), which exhibits anti-tumor activity, has entered phase II clinical trials and is expected to be used to treat many different types of cancer ( 30 ), and 4-(pyridine-2-yl)-N-([(8E)-5,6,7,8-tetrahydroquinolin-8-ylidene]amino) piperazine-1-carbothioamide (COTI-2) has been evaluated in phase Ib/IIa clinical trials for the treatment of gynecologic malignancies ( 31 ).…”

Section: Introductionmentioning

confidence: 99%

Selective Metal Chelation by a Thiosemicarbazone Derivative Interferes with Mitochondrial Respiration and Ribosome Biogenesis in Candida albicans

Duan

Xie

et al. 2022

Microbiol Spectr

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The increasing incidence of fungal infections and resistance to existing antifungals call for the development of broad-spectrum antifungals with novel mechanisms of action. In this study, we demonstrate that a thiosemicarbazone derivative 19ak selectively inhibits mitochondrial respiration mainly by retarding mitochondrial respiratory chain complex I activity through iron chelation and inhibits ribosome biogenesis mainly by disrupting intracellular zinc homeostasis in C. albicans .

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Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: Synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay

Cited by 66 publications

References 62 publications

Novel Brain-Tumor-Inhibiting Copper(II) Compound Based on a Human Serum Albumin (HSA)-Cell Penetrating Peptide Conjugate

Novel Brain-Tumor-Inhibiting Copper(II) Compound Based on a Human Serum Albumin (HSA)-Cell Penetrating Peptide Conjugate

Protein targets of thiazolidinone derivatives in Toxoplasma gondii and insights into their binding to ROP18

Selective Metal Chelation by a Thiosemicarbazone Derivative Interferes with Mitochondrial Respiration and Ribosome Biogenesis in Candida albicans

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