In vitro and in silico studies of antioxidant activity of 2-thiazolylhydrazone derivatives

In vitro and in silico studies of antioxidant activity of 2-thiazolylhydrazone derivatives

Accepted Manuscript In vitro and in silico studies of antioxidant activity of 2-thiazolylhydrazone derivatives Vinícius Gonçalves Maltarollo, Marina F...

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Accepted Manuscript In vitro and in silico studies of antioxidant activity of 2-thiazolylhydrazone derivatives Vinícius Gonçalves Maltarollo, Marina Ferrara de Resende, Thales Kronenberger, Cleudiomar Inácio Lino, Maria Clara Pinheiro Duarte Sampaio, Maira Galdino da Rocha Pitta, Moacyr Jesus Barreto de Melo Rêgo, Renata Adriana Labanca, Renata Barbosa de Oliveira PII:

S1093-3263(18)30451-0

DOI:

10.1016/j.jmgm.2018.10.007

Reference:

JMG 7245

To appear in:

Journal of Molecular Graphics and Modelling

Received Date: 8 June 2018 Revised Date:

17 September 2018

Accepted Date: 8 October 2018

Please cite this article as: Viní.Gonç. Maltarollo, M.F. de Resende, T. Kronenberger, Cleudiomar.Iná. Lino, M.C. Pinheiro Duarte Sampaio, M.G. da Rocha Pitta, M.J.B. de Melo Rêgo, R.A. Labanca, R.B. de Oliveira, In vitro and in silico studies of antioxidant activity of 2-thiazolylhydrazone derivatives, Journal of Molecular Graphics and Modelling (2018), doi: https://doi.org/10.1016/j.jmgm.2018.10.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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IN VITRO AND IN SILICO STUDIES OF ANTIOXIDANT ACTIVITY OF 2-

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THIAZOLYLHYDRAZONE DERIVATIVES

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Vinícius Gonçalves Maltarolloa#, Marina Ferrara de Resendeb#, Thales Kronenbergerc,

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Cleudiomar Inácio Linoa, Maria Clara Pinheiro Duarte Sampaiod, Maira Galdino da Rocha

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Pittad, Moacyr Jesus Barreto de Melo Rêgod, Renata Adriana Labancab, Renata Barbosa de

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Oliveiraa*

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a

Department of Pharmaceutical Products, Pharmacy Faculty, Federal University of

Minas Gerais, 6627 Antônio Carlos AVE, 31270-901, Belo Horizonte, Minas Gerais,

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Brazil.

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b

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Antônio Carlos AVE, 31270-901, Belo Horizonte, Minas Gerais, Brazil.

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c

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Strasse 14, Tübingen, DE 72076.

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d

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Therapeutical Aproaches, Federal University of Pernambuco, Prof. Moraes Rêgo AVE,

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50670-901, Recife, Pernambuco, Brazil.

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Department of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-

Laboratory of Immunomodulation

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# Vinícius G. Maltarollo and Marina F. de Resende contributed equally to this work.

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*Correspondence:

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R. B. Oliveira

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Av. Antônio Carlos 6627,

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31270-901, Belo Horizonte, Minas Gerais, Brazil

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E-mail: [email protected]

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and New

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Departament of Biochemistry,

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Department of Foods, Pharmacy Faculty, Federal University of Minas Gerais, 6627

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Abstract

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The antioxidant potential of a series of thiazolylhydrazone derivatives was investigated

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using three different methods namely DPPH, ABTS and FRAP assays. In general, the

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tested compounds showed higher or comparable activity to that of curcumin, used as

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positive control. Chemometric analyses demonstrated that the presence of hydrazone

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moiety is required for the activity of this class of compounds. From these results,

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compound 4 was identified as the most promising molecule and was then selected for

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further studies. The antiproliferative effect of compound 4 was evaluated, being active

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in three (T47D, MDA-MB-231 and SKMEL) of the six cancer cell lines tested, with

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IC50 values ranging from 15.9 to 31.3 µM. Compound 4 exhibited no detectable

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cytotoxic effect on peripheral blood mononuclear cells (PBMC) when tested at a

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concentration of 100 µM, demonstrating good selectivity. From these results, it is

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possible to infer that there is a correlation between antioxidant capacity and anticancer

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effects.

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Keywords: antioxidant activity; 2-thiazolylhydrazone, chemometric; cytotoxic activity

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1. Introduction

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Thiazolylhydrazone derivatives are a class of compounds with a diverse spectrum of

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biological activity. Representative examples of this class of compounds were reported

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to exhibit anticancer, antibacterial, antifungal and antioxidant activities.1-6 According to

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Mei-Hsiu Shih and co-workers, the scavenging activity of 2-thiazolylhydrazones is

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related to the presence of N-H group in the hydrazone moiety, which has the ability to

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donate a hydrogen atom and to reduce the DPPH radical (Figure 1).6

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Figure 1 - Schematic representation of the reaction between DPPH radical and 2-

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thiazolylhydrazones derivatives

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There are several examples of chemometric techniques explaining antioxidant effects,

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especially for relevant chemical classes such as the flavonoids.7,8 Choudhary et al. used

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2D and 3D quantitative structure-activity relationship (QSAR) models to guide the

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synthesis of a series of chalcone derivatives, which were then evaluated on their

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antioxidant activity. It was suggested that the introduction of electron-releasing groups

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and bulky heteroatoms at specific positions of the benzylideneacetophenone nucleus

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increased the activity of the molecules.9 Another example resides in QSAR models

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employing a series of antioxidant curcumin derivatives, which reported that the higher

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ACCEPTED MANUSCRIPT activity could be attributed to their increased chemical stability. The chemical stability

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was suggested by the lower hardness, higher softness and higher highest occupied

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molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies

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gap for the molecules.10 Specifically, it was reported that hydrazine thiazole derivatives

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exhibit potent DPPH radical-scavenging activity, on levels comparable with that of

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vitamin E.11 This series was employed to generate descriptor-based quantitative

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structure-activity relationship and classification models, which showed that fragments

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bearing an aromatic carbon attached to three heteroatoms can contribute to explain the

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high antioxidant activity.12

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Based on the scavenging ability of this class of compounds, we evaluated the

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antioxidant activity of a series of 2-thiazolylhydrazones derivatives, previously

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synthesized in our laboratory.3 In addition, chemometric analyses were carried out to

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establish a relationship between the molecular and electronic properties with the

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antioxidant activity of these compounds. Since a correlation between antioxidant and

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anticancer activities has been reported,13-15 the compound with the most promising

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antioxidant activity was tested for cytotoxicity activity against different tumor cell lines.

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2. Materials and Methods

2.1 Chemometric analyses

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The 2-thiazolylhydrazones derivatives 1-9 employed in multivariate analyses had their

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3D structures determined by conformational analyses, using OMEGA 2.5.1.4

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software16,17 with MMFF94 force-field18. Compounds 8 and 9 were simulated by using

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R configuration for convention due the experimentally obtained compounds were

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racemic mixtures. Then, the lowest energy conformers were employed in quantum

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mechanics calculations, using the software Jaguar (v9.8 release 11)19 implemented in

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the Maestro (2017v4, Schrodinger, NY, USA) package. All molecules underwent

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geometry optimization calculations which were carried out with Density Functional

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Theory (DFT) method with B3LYP functional and 6-311g (d,p) basis.20-22 The absence

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of imaginary frequencies was used as a criterion to ensure that the optimized structures

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represented the minimum in the potential energy surface. Subsequently, electronic

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dipole moment, atomic charges derived from electrostatic potential and related

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properties, as well as the molecular surface area were calculated. Further,

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physicochemical and molecular properties as n-octanol/water partition coefficient

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(logP), molecular weight, number of hydrogen-bond acceptors and donors, topological

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polar surface area, number of rotatable bonds, and hybridization ratio were calculated

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with PaDEL descriptor software.23

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Hierarchical Cluster Analysis (HCA) studies were carried out using Euclidean distance

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as similarity measurement and average linking method and using values of experimental

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antioxidant activities. In order to select the variables that better represent antioxidant

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activity, the Pearson correlation coefficients between each independent variable and

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DPPH, ABTS and FRAP values were calculated. Variables having low correlation with

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experimental activities (R < 0.7), as well as high correlated variables, were not further

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pursued in the study. This decision aimed to reduce overfitting due to the inclusion of

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two properties related to the same physical phenomenon.24 The selected properties were

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autoscaled before PCA. Both HCA and Principal Component Analysis (PCA) were

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carried out with Chemoface 1.6 software.25

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2.2 Synthesis

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The 2-thiazolylhydrazones derivatives 1-7 were obtained by reaction between an

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aldehyde or ketone with thiosemicarbazide, followed by cyclization in the presence of

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substituted or unsubstituted 2-bromoacetophenone, as previously described by us.3 The

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starting ketones used in the synthesis of 8 and 9 were synthesized from cyclohexanone

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by base-catalyzed aldol reaction by adaptation of the method reported in the literature.26

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Synthesis

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2-[(2-(3-nitrophenyl)hydroxymethyl)cyclohexylidenehydrazo]-4-(4-

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chlorophenyl)thiazole (8)

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Using the procedure described in literature,3 8 was obtained as an orange solid in 99 %

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yield. Mp: 182.1-182.9 °C; IR (cm-1): 3376, 3037, 2936, 2857, 1619, 1536, 1348, 1479,

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1445, 737; 1H NMR (200 MHz, DMSO-d6), δ/ppm: 8.3 (1H, s); 8.2 (1H, d); 7.9-7.8

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(3H, m); 7.6-7.6(2H, m); 7.4 (2H, d); 7.3 (1H, s); 5.2 (1H, d); 2.6(2H, m); 1.7-1.2 (8H,

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C NMR (50 MHz, DMSO-d6), δ/ppm: 169,6, 156.8, 149.3, 147.4, 143.2, 132.8,

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m);

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132.5, 132.3, 128.4, 128.1, 126.5, 121.9, 121.4, 102.7, 74.2, 50.0, 30.0, 26.8, 24.7, 23,7;

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HRMS (m/z) 457.1096 [M+H]+, calcd457.1101 C22H22ClN4O3S+.

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Synthesis

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chlorophenyl)thiazole (9)

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Using the procedure described in literature,3 9 was obtained as a brown solid in 88%

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yield. Mp: 215.3-215.8 °C; IR (cm-1): 3393, 3102, 2939, 2854, 1577, 1567, 1473, 730;

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(1H, s), 5.1(1H, s), 5.0 (1H, m), 2.7 (1H, m), 2.2-1.3 (8H, m);

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DMSO-d6), δ/ppm: 170.2, 154.7 153.4, 149.0, 133.7, 131.7, 128.6, 127.1, 121.8, 104.1,

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70.3, 50.1, 27.3, 26.7, 25.9, 22.8; HRMS (m/z) 413.1197 [M+H]+, calcd413.1203

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C21H22ClN4OS+.

2-[(2-(pyridin-4-yl)hydroxymethyl)cyclohexylidenehydrazo]-4-(4-

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H NMR (200 MHz, DMSO-d6), δ/ppm: 8.4 (2H, m); 7.8 (2H, d), 7.4-7.3(4H, m), 7.0

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C NMR (50 MHz,

2.3 In vitro antioxidant activity

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DPPH radical scavenging assay

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The ability of synthetic compounds to scavenge 2,2-diphenyl-1-picrylhyadrazyl

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(DPPH•) radical was measured using the method described by Lue et al.27 with

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modifications by Bhullar et al.,28 in triplicate. The absorbance was measured at 515 nm

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on a spectrophotometer with automatic microplate reader (Molecular Devices, Versa

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Max Program, Sunnyvale, California, USA) and the percentage of DPPH that has

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reacted was calculated using the following formula:

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% antioxidant activity = ((Acontrol- Asample)/Acontrol)*100

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being A = absorbance at 515 nm.

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Curcumin and the Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid)

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were used as positive control.

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2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assay

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The ABTS•+ scavenging capacity was evaluated according to the method described by

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Re et al.29 with modifications,30 in triplicate. The absorbance was measured at 734 nm

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in a spectrophotometer with automatic microplate reader (Molecular Devices,

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VersaMaxProgram, Sunnyvale, California, USA). Curcumin and the Trolox were used

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as positive control. The amount of radical scavenged by the samples was calculated

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using the following formula, and the result was expressed in percentage of antioxidant

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activity:

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% antioxidant activity = ((Acontrol- Asample)/Acontrol)*100 being A = absorbance at 734 nm.

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Ferric reducing antioxidant power (FRAP) assay

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To assess the antioxidant capacity based on ferric reduction, the method described by

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Benzie and Strain31 was used with modifications,28,32 in triplicate. After reading the

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absorbance at 593 nm in a spectrophotometer with automatic microplate reader

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(Molecular Devices, VersaMaxProgram, Sunnyvale, California, USA), the antioxidant

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potentials of the analyzed compounds were calculated based on Trolox standards at

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concentrations of 50, 100, 150, 200, 250, 300 and 350 µM. The results were expressed

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as Trolox equivalentes, or TE, in µM Trolox/ 100 µM sample. Curcumin was also

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included in the assay as positive control.

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2.4 Cytotoxic activity

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Cells were seeded at a density of 1 x 104 cells/well in 96-well plates with flat bottom in

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the final volume of 100 µL. After 24 hours, cells were treated with RI83 at different

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concentrations (1 to 100 µM) for 72 hours at 37º C with 5% CO2. Then, 20 µL per well

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of (3-(4,5-dimethylthiazol-2-)-2,5-diphenyltetrazolium bromide (MTT) were added, for

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three hours later, followed by 130 µL of 20% SDS. The absorbance was measured 24

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hours later using ELx808 Microplate Reader (Biotek, USA) at a wavelength of 570 nm.

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Non-treated cells were used as negative control, DMSO (0.1%) as vehicle control and

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Doxorubicin as positive control. Experiments were performed three independent times

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in triplicate.

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2.5 Selectivity assay

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Peripheral blood mononuclear cells (PBMC) were obtained from whole blood of

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healthy volunteers (N = 3). All donors signed a consent form and the study was

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approved by Human Research Ethics Committee from Federal University of

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Pernambuco (CEP/CCS/UFPE-11006). Cells were isolated using a density-gradient

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method with Ficoll-Paque PLUS (GE Healthcare). At the end of the process, the cell

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serum, 10 mM HEPES and 200 U/mL streptomycin and penicillin. Briefly, cells were

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seeded in 96-well plates (5x105 cells per well) and treated with RI83 (1-100 µM) for 48

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hours. After incubation, steps were performed as previously described in cytotoxic

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activity topic. Selectivity index (SI) was calculated according to Islam et al (2016).33

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Compounds with high selectivity have SI value > 3.33

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3. Results and Discussion

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Antioxidant activity of the compounds 1-9 (Figure 2) was assessed in vitro by three

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different methods: 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay,

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2,2-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS•+) radical scavenging assay

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and ferric reducing antioxidant power (FRAP) assay. Curcumin and the Trolox, a water-

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soluble analog of vitamin E, were used as positive control. In these assays, it is

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observed that some 2-thiazolylhydrazones showed better or similar results than that of

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positive controls. The assays results are shown in Table 1.

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Figure 2 – Chemical structure of the 2-thiazolylhydrazones derivatives 1-9

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Table 1 – Comparison of the results obtained for the in vitro antioxidant assays: DPPH radical scavenging assay; ABTS radical cation scavenging assay and ferric reducing antioxidant power (FRAP) assay FRAP (µM TE*/ 100

DPPH (%)

ABTS (%)

Curcumin

40.1 ± 1.4f

30.2 ± 2.0a

102.5 ± 0.8a

Trolox

47.4 ± 1.5e

19.5 ± 0,9b

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f

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62.1 ± 2.3d 68.7 ± 2.1d

10.7 ± 0.7

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61.6 ± 1.8b

11.4 ± 1.5c

3

53.9 ± 1.9d

10.6 ± 1.7c

4

37.2 ± 2.4f

32.6 ± 1.9a

5

57.3 ± 0.4c

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16.1 ± 2.6g

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67.7 ± 1.3a

8

38.9 ± 0.9f

9

39.3 ± 0.4f

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38.3 ± 0.7

µM sample)

75.7 ± 0.8c

82.4 ± 0.9b

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Compound

62.9 ± 0.5d

22.7 ± 4.7b

28.9 ± 1.4g

9.8 ± 2.6c

53.8 ± 0.3f

18.3 ± 3.1b

64.1 ± 2.4d

9.1 ± 1.1c

58.6 ± 1.7e

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*TE = Trolox equivalents. Means followed by the same lower case letter in columns do

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not differ according to the Tukey’s test at 5% significance.

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DPPH and ABTS assay methods measures the DPPH and ABTS radical consumption

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rate by radical scavenger compounds. In DPPH assay, four compounds (2, 3, 5, and 7)

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showed superior antioxidant activity than both curcumin and Trolox, and other four (1,

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4, 8 and 9) showed similar antioxidant activity to that of curcumin. Regarding IC50

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values in DPPH radical scavenging assay, seven compounds showed lower values than

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that of curcumin (IC50 = 167.7 µM), being thus more active: 7 (IC50 = 97.1 µM), 3 (IC50

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= 110.6 µM), 9 (IC50 = 118.8 µM), 1 (IC50 = 126.0 µM), 2 (IC50 = 126.6 µM), 8 (IC50 =

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139.2 µM) and 5 (IC50 = 162.1 µM).

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In ABTS assay, only the compound 4 showed comparable activity to that of curcumin

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and compounds 4, 5, 6 and 8 exhibited higher or comparable scavenging potency than

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Trolox.

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tripyridyltriazine (FeIII-TPTZ) to ferrous-tripyridyltriazine (FeII-TPTZ), a blue-colored

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product. The results were expressed as Trolox equivalents (TE), in µM Trolox/ 100 µM

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sample. Unfortunately, in this assay, no compound showed greater activity than that of

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curcumin. However, among the compounds tested, the 2-thiazolylhydrazone 4 displayed

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the best result.

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After evaluation of antioxidant activity of the compounds, chemometric analyses were

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performed to correlate such activity with a set of chemical and electronic descriptors

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calculated from the molecular structure of the compounds. Initially, Hierarchical Cluster

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Analysis (HCA) were applied using DPPH, ABTS and FRAP antioxidant activity

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values to cluster compounds according to its antioxidant capacity. This step was

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performed due to the divergence of experimental results of the antioxidant activity.

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Compounds were separated into two major clusters (Figure 3A), the first cluster

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containing compound 6, which is the least active (according to DPPH and FRAP

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assays), selected as the dendrogram root, and compound 4 with the most antioxidant

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activity, according ABTS and FRAP assays. The second cluster grouped all the other

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molecules, which have a similar antioxidant profile.

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Figure 3. Dendrogram of HCA from antioxidant activities analysis (A); loadings plot

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from PCA analysis showing the importance of each property for each principal

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component (B) and; scores plot of the compound set from PCA using selected

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properties highlighting two clusters from the hierarchical cluster analysis (C).

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Subsequently, we searched for suitable calculated chemical or experimental properties,

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which could explain the difference in antioxidant ability, by employing a correlation

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matrix. Among the 39 calculated properties, only four (Table 2) were selected for

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further studies, based on correlation with biological activities: (1) HOMO energy; (2)

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ESP balance: distribution of atomic charges along the molecular surface; (3) atomic

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ESP charge in the sulphur atom and; (4) atomic ESP charge on the C1 atom.

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Table 2 - Calculated properties for dataset compounds. C1 (a.u.)

1

-0.22

0.25

-0.07

0.49

2

-0.19

0.24

-0.02

0.41

3

-0.20

0.24

-0.02

0.43

4

-0.22

0.24

-0.08

0.19

5

-0.21

0.25

-0.08

0.19

6

-0.22

0.19

-0.07

0.19

7

-0.20

0.24

-0.03

0.40

8

-0.22

0.25

-0.04

0.17

9

-0.22

0.25

0.00

0.35

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Cpd HOMO (a.u.) ESP balance S (a.u.)

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From loadings plot of PCA (Figure 3B), is possible to note that atomic charges on S

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and C1 atoms has the highest contributions to the first principal component, and ESP

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balance and HOMO energy has the highest contribution to the second PC. Is also

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possible to note that compounds 4 and 6 are separated from other along PC1 and all

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compounds are separated from compound 6 along PC2 (Figure 3C). Altogether, it is

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suggested that ESP balance and HOMO energy could explain the lack of activity of

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compound 6 and atomic charges on S and C1 atoms could explain the differences of the

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antioxidant profile of compound set. From raw calculated data, HOMO energies seem

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to be almost invariable (ranging from -0.22 to -0.19 atomic unities). However, when

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considering that all variables were auto-scaled before the chemometrics studies and its

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conversion for a usual unity as kcal/mol (-138.05 to -119.23 kcal/mol), it is noteworthy

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the large variation on electron donor ability of studied compounds.

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The correlation between antioxidant activity and atomic charge properties34,35 and the

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molecular orbital energies36 was already proposed in the literature by chemometrics

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studies. The relevance of atomic charges of S and C1 atoms to antioxidant activity could

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be related to the stabilization of the formed radical as well as the orientation of a

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preferably oxidation site near thiazolylhydrazone moiety. The HOMO energy is an

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important electronic parameter for describing the antioxidant ability of a molecule

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ACCEPTED MANUSCRIPT because it is related to electron transfer reactions, in practical terms a compound with

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low values of HOMO energy has a weak electron donating ability, as well as a

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compound with high HOMO energy would is good electron-donor molecule.37-39 Then,

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a plot of HOMO for all compounds was analyzed in terms of the atomic contributions

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and we observed that this molecular orbital is mainly located at thiazolylhydrazone

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moiety as illustrated by three representative compounds of dataset (Figure 4). All these

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findings corroborate the proposed antioxidant mechanism would involve the hydrazone

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moiety.

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Figure 4. General structure of dataset compounds (A) and plot of HOMO of

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representative compounds of dataset (B, C and D).

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The results found in the present study are in agreement with those described by Mitra et

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al.12 These authors generated several QSAR models with different methods which its

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findings corroborate our results. From their work, the thiazolylhydrazone moiety as well

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as aromatic rings are described to be structurally important to antioxidant activity and;

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the hydrazine region has a molecular interaction field contour generate by a 3D-QSAR

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model (calculations derived from atomic partial charges) indicating its electrostatic

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importance for biological activity.12

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Based on the results obtained, compound 4 was considered the most promising hit for

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further studies. The cytotoxic activity of 4 was then evaluated on six cancer cell lines

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(T47D = human breast tumor; MDA-MB-231 = human breast adenocarcinoma; UACC

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= human melanoma; A375 = human melanoma; SKMEL = human melanoma; PANC =

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human pancreatic cancer cells). Peripheral blood mononuclear cells (PBMC) were used

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as models for healthy cells to evaluate the selectivity of compound 4. The results

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obtained are shown in Table 3.

Table 3 - Cytotoxicity of compound 4 on different cell lines. IC50 (µM) 25.3+0.3 15.9+2.4 >100 >100 31.3+4.0 >100 >100

SI* > 3.9 > 6.3 > 3.2 -

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Cell lines T47D MDA-MB-231 UACC A375 SKMEL PANC PBMC

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Compound 4 exhibited significant antiproliferative effects against both breast cancer

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cell lines, T47D and MDA-MB-231, and one of the melanoma cell lines (SKMEL)

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tested, with IC50 values ranging from 15.9 to 31.3 µM. In addition, it should be noted

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that 4 had no cytotoxic effect on non-malignant cells (PBMC), indicating good

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selectivity. In these experiments, doxorubicin, a chemotherapeutic drug, was used as

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positive control and showed IC50 values from 5 to 10 µM against all tumor cell lines

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tested. It is worth mentioning that doxorubicin exhibit significant toxicity on PBMC

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with IC50 value of 15.2 + 3.5 µM, displaying lower selectivity than 4.

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Although still controversial, some studies indicate the effectiveness of the use of

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antioxidants for the treatment of cancer. For example, antioxidant agents can lead to the

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death of cancer cells from ROS-induced survival signaling pathways.40 ROS are potent

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activators of nuclear factor κB (NF-κB), which plays a significant role in malignancy

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and cancer progression. Therefore, there is a correlation between ROS, NF-κB

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activation and tumor progression and compounds displaying antioxidant activity against

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free radicals may exert antitumor activity by modulating these pathways.15

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From these results, it is possible to infer that there is a correlation between antioxidant

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capacity and anticancer effects.

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ACCEPTED MANUSCRIPT 355

4. Conclusion

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In the current work, a promising antioxidant compound was identified from a series of

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2-thiazolylhydrazone derivatives. Compound 4 has been shown to have antioxidant and

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antitumor potential, being active on three cancer cell lines tested, with an acceptable

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selectivity index. The results obtained herein revealed compound 4 as a hit for the

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development of new drugs, whose mechanism of action is ascribed to their antioxidant

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properties.

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Acknowledgements

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The authors would like to thank OpenEye Scientific Software for OMEGA academic

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license. This work was supported by the Fundação de Amparo à Pesquisa de Minas

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Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Científico e Tecnológico

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(CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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ACCEPTED MANUSCRIPT • •

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Antioxidant potential of a series of thiazolylhydrazone derivatives was evaluated. Chemometric analyses showed that the hydrazone moiety is required for the activity. The results indicated the compound 4 as being the most promising one. The antiproliferative effect of compound 4 was also evaluated.