Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate
Herein, we report the antimalarial activity of nine 4-methoxychalcone derivatives 1a–i and an initial analysis of their ADMET properties. All compounds showed potent activity against the P. falciparum chloroquine-resistant clone W2, with IC50 values ranging from 1.96 µM to 10.99 µM, with moderate or...
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doaj-57445ed3acb649258618cace9ed780c02020-11-24T23:12:00ZengMDPI AGMolecules1420-30492013-12-011812152761528710.3390/molecules181215276molecules181215276Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead CandidateMichael Eder de Oliveira0Gisele Cenzi1Renata Rachide Nunes2Carla Regina Andrighetti3Denia Mendes de Sousa Valadão4Cláudia dos Reis5Cláudia Maria Oliveira Simões6Ricardo José Nunes7Moacyr Comar Júnior8Alex Gutterres Taranto9Bruno Antonio Marinho Sanchez10Gustavo Henrique Ribeiro Viana11Fernando de Pilla Varotti12Centro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, BrazilCentro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, BrazilCentro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, BrazilInstituto de Ciências da Saúde-UFMT/Campus Sinop, CEP 78557-267, Sinop, MT, BrazilInstituto de Ciências da Saúde-UFMT/Campus Sinop, CEP 78557-267, Sinop, MT, BrazilDepartmento de Ciências Farmacêuticas-UFSC/Campus Universitário Trindade, CEP 88040-900, Florianópolis, SC, BrazilDepartmento de Ciências Farmacêuticas-UFSC/Campus Universitário Trindade, CEP 88040-900, Florianópolis, SC, BrazilDepartmento de Química-UFSC/Campus Universitário Trindade, CEP 88040-900, Florianópolis, SC, BrazilCentro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, BrazilCentro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, BrazilInstituto de Ciências da Saúde-UFMT/Campus Sinop, CEP 78557-267, Sinop, MT, BrazilCentro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, BrazilCentro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, BrazilHerein, we report the antimalarial activity of nine 4-methoxychalcone derivatives 1a–i and an initial analysis of their ADMET properties. All compounds showed potent activity against the P. falciparum chloroquine-resistant clone W2, with IC50 values ranging from 1.96 µM to 10.99 µM, with moderate or low cytotoxicity against the HeLa cell line. The compound 1a (IC50 = 2.06 µM) had the best selectivity index (9.0). All the sulfonamide 4-metychalcone derivatives synthesized had cLogP values between 2 and 5 (mean value 3.79) and molecular weights (MWs) below 500. The substitution of the pyrrolidine group in 1i by a morpholine group in 1a reduced the cLogP value from 3.05 in compound 1i to 2.34 in compound 1a. Indeed, compound 1a had the highest LipE value. The binding free energy of compound 1a showed it to be the most optimal chalcone derivative for plasmepsin-2 (−7.3 Kcal/mol). The physicochemical properties and LipE analysis of the dataset allowed us to establish that compound 1a is the highest quality compound of the series and a potential oral lead candidate.http://www.mdpi.com/1420-3049/18/12/152764-methoxychalconemalariaADMET propertiesLipE |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael Eder de Oliveira Gisele Cenzi Renata Rachide Nunes Carla Regina Andrighetti Denia Mendes de Sousa Valadão Cláudia dos Reis Cláudia Maria Oliveira Simões Ricardo José Nunes Moacyr Comar Júnior Alex Gutterres Taranto Bruno Antonio Marinho Sanchez Gustavo Henrique Ribeiro Viana Fernando de Pilla Varotti |
spellingShingle |
Michael Eder de Oliveira Gisele Cenzi Renata Rachide Nunes Carla Regina Andrighetti Denia Mendes de Sousa Valadão Cláudia dos Reis Cláudia Maria Oliveira Simões Ricardo José Nunes Moacyr Comar Júnior Alex Gutterres Taranto Bruno Antonio Marinho Sanchez Gustavo Henrique Ribeiro Viana Fernando de Pilla Varotti Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate Molecules 4-methoxychalcone malaria ADMET properties LipE |
author_facet |
Michael Eder de Oliveira Gisele Cenzi Renata Rachide Nunes Carla Regina Andrighetti Denia Mendes de Sousa Valadão Cláudia dos Reis Cláudia Maria Oliveira Simões Ricardo José Nunes Moacyr Comar Júnior Alex Gutterres Taranto Bruno Antonio Marinho Sanchez Gustavo Henrique Ribeiro Viana Fernando de Pilla Varotti |
author_sort |
Michael Eder de Oliveira |
title |
Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate |
title_short |
Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate |
title_full |
Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate |
title_fullStr |
Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate |
title_full_unstemmed |
Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate |
title_sort |
antimalarial activity of 4-metoxychalcones: docking studies as falcipain/plasmepsin inhibitors, admet and lipophilic efficiency analysis to identify a putative oral lead candidate |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2013-12-01 |
description |
Herein, we report the antimalarial activity of nine 4-methoxychalcone derivatives 1a–i and an initial analysis of their ADMET properties. All compounds showed potent activity against the P. falciparum chloroquine-resistant clone W2, with IC50 values ranging from 1.96 µM to 10.99 µM, with moderate or low cytotoxicity against the HeLa cell line. The compound 1a (IC50 = 2.06 µM) had the best selectivity index (9.0). All the sulfonamide 4-metychalcone derivatives synthesized had cLogP values between 2 and 5 (mean value 3.79) and molecular weights (MWs) below 500. The substitution of the pyrrolidine group in 1i by a morpholine group in 1a reduced the cLogP value from 3.05 in compound 1i to 2.34 in compound 1a. Indeed, compound 1a had the highest LipE value. The binding free energy of compound 1a showed it to be the most optimal chalcone derivative for plasmepsin-2 (−7.3 Kcal/mol). The physicochemical properties and LipE analysis of the dataset allowed us to establish that compound 1a is the highest quality compound of the series and a potential oral lead candidate. |
topic |
4-methoxychalcone malaria ADMET properties LipE |
url |
http://www.mdpi.com/1420-3049/18/12/15276 |
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