Chloride substitution on 2-hydroxy-3,4,6-trimethoxyphenylchalcones improves in vitro selectivity on Trypanosoma cruzi strain Y
Copyright © 2022 Elsevier B.V. All rights reserved..
Chagas disease is a disease that is emerging in North America and Europe countries. Benznidazole is the main drug available, but it has high toxicity and low efficacy in the chronic phase. In this way, researching new antichagasic agents is necessary. Thus, the aim of this study is to evaluate the effect of novel chalcones and the influence of chlorine substitutions on Trypanosoma cruzi and host cells. Unsubstituted (1), 4-chlorine substituted (2) and 2,4-chlorine substituted (3) chalcones were synthesized by Claisen-Schmidt condensation, characterized, and electrical distribution was assessed by Density Fuctional Theory (DFT). The host cells toxicity (LLC-MK2) was performed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) reduction assay. The effect on epimastigote (24, 48 and 72h), trypomastigote (24h) and amastigotes (24 h) was evaluated. Flow cytometry assays were performed with 7-Aminoactinomycin D (7-AAD) and Annexin-PE, Dichlorofluorescein diaceteate (DCFH-DA) and Rhodamine123 (Rho123). Finally, molecular docking predicted interactions between chalcones and cruzain (TcCr) and trypanothione reductase (TcTR). The toxicity on host cells was reduced almost twenty times on chlorine substituted molecules. On epimastigote and trypomastigote forms, all substances presented similar effects. After treatment with molecule 3, it was observed a decrease in infected cells and intracellular amastigotes. Their effect is related to necrotic events, increase of cytoplasmic Reactive Oxygen Species (ROS) and mitochondrial dysfunction. Also, this effect might be associated with involvement of TcCr and TcTR enzymes. Therefore, the results showed that chlorine substitution on chalcones reduces the host cell's toxicity without compromising the effect on Trypanosoma cruzi Y strain forms, and it occurs over membrane damage, oxidative stress and possible interactions with TcCr and TcTR.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:361 |
|---|---|
| Enthalten in: |
Chemico-biological interactions - 361(2022) vom: 01. Juli, Seite 109920 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Magalhães, Emanuel Paula [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
4R7X1O2820 |
|---|
| Anmerkungen: |
Date Completed 30.05.2022 Date Revised 30.05.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.cbi.2022.109920 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM339909013 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM339909013 | ||
| 003 | DE-627 | ||
| 005 | 20231226003938.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.cbi.2022.109920 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1132.xml |
| 035 | |a (DE-627)NLM339909013 | ||
| 035 | |a (NLM)35461787 | ||
| 035 | |a (PII)S0009-2797(22)00125-9 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Magalhães, Emanuel Paula |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Chloride substitution on 2-hydroxy-3,4,6-trimethoxyphenylchalcones improves in vitro selectivity on Trypanosoma cruzi strain Y |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 30.05.2022 | ||
| 500 | |a Date Revised 30.05.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier B.V. All rights reserved. | ||
| 520 | |a Chagas disease is a disease that is emerging in North America and Europe countries. Benznidazole is the main drug available, but it has high toxicity and low efficacy in the chronic phase. In this way, researching new antichagasic agents is necessary. Thus, the aim of this study is to evaluate the effect of novel chalcones and the influence of chlorine substitutions on Trypanosoma cruzi and host cells. Unsubstituted (1), 4-chlorine substituted (2) and 2,4-chlorine substituted (3) chalcones were synthesized by Claisen-Schmidt condensation, characterized, and electrical distribution was assessed by Density Fuctional Theory (DFT). The host cells toxicity (LLC-MK2) was performed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) reduction assay. The effect on epimastigote (24, 48 and 72h), trypomastigote (24h) and amastigotes (24 h) was evaluated. Flow cytometry assays were performed with 7-Aminoactinomycin D (7-AAD) and Annexin-PE, Dichlorofluorescein diaceteate (DCFH-DA) and Rhodamine123 (Rho123). Finally, molecular docking predicted interactions between chalcones and cruzain (TcCr) and trypanothione reductase (TcTR). The toxicity on host cells was reduced almost twenty times on chlorine substituted molecules. On epimastigote and trypomastigote forms, all substances presented similar effects. After treatment with molecule 3, it was observed a decrease in infected cells and intracellular amastigotes. Their effect is related to necrotic events, increase of cytoplasmic Reactive Oxygen Species (ROS) and mitochondrial dysfunction. Also, this effect might be associated with involvement of TcCr and TcTR enzymes. Therefore, the results showed that chlorine substitution on chalcones reduces the host cell's toxicity without compromising the effect on Trypanosoma cruzi Y strain forms, and it occurs over membrane damage, oxidative stress and possible interactions with TcCr and TcTR | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Chagas disease | |
| 650 | 4 | |a Chalcones | |
| 650 | 4 | |a Cruzain | |
| 650 | 4 | |a Trypanothione reductase | |
| 650 | 7 | |a Chalcones |2 NLM | |
| 650 | 7 | |a Chlorides |2 NLM | |
| 650 | 7 | |a Trypanocidal Agents |2 NLM | |
| 650 | 7 | |a Chlorine |2 NLM | |
| 650 | 7 | |a 4R7X1O2820 |2 NLM | |
| 650 | 7 | |a Chalcone |2 NLM | |
| 650 | 7 | |a 5S5A2Q39HX |2 NLM | |
| 700 | 1 | |a Gomes, Naiara Dutra Barroso |e verfasserin |4 aut | |
| 700 | 1 | |a Freitas, Tiago Araújo de |e verfasserin |4 aut | |
| 700 | 1 | |a Silva, Brenna Pinheiro |e verfasserin |4 aut | |
| 700 | 1 | |a Ribeiro, Lyanna Rodrigues |e verfasserin |4 aut | |
| 700 | 1 | |a Ameida-Neto, Francisco Wagner Queiroz |e verfasserin |4 aut | |
| 700 | 1 | |a Marinho, Márcia Machado |e verfasserin |4 aut | |
| 700 | 1 | |a Lima-Neto, Pedro de |e verfasserin |4 aut | |
| 700 | 1 | |a Marinho, Emmanuel Silva |e verfasserin |4 aut | |
| 700 | 1 | |a Santos, Hélcio Silva Dos |e verfasserin |4 aut | |
| 700 | 1 | |a Teixeira, Alexandre Magno Rodrigues |e verfasserin |4 aut | |
| 700 | 1 | |a Sampaio, Tiago Lima |e verfasserin |4 aut | |
| 700 | 1 | |a Menezes, Ramon Róseo Paula Pessoa Bezerra de |e verfasserin |4 aut | |
| 700 | 1 | |a Martins, Alice Maria Costa |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Chemico-biological interactions |d 1969 |g 361(2022) vom: 01. Juli, Seite 109920 |w (DE-627)NLM000001848 |x 1872-7786 |7 nnns |
| 773 | 1 | 8 | |g volume:361 |g year:2022 |g day:01 |g month:07 |g pages:109920 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.cbi.2022.109920 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 361 |j 2022 |b 01 |c 07 |h 109920 | ||