Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate

Molecules

Michael Eder de Oliveira⁴  Gisele Cenzi⁴  Renata Rachide Nunes⁴  Carla Regina Andrighetti²  Denia Mendes de Sousa Valadão²  Cláudia dos Reis³  Cláudia Maria Oliveira Simཞs³  Ricardo José Nunes¹  Moacyr Comar Júnior⁴  Alex Gutterres Taranto⁴  Bruno Antonio Marinho Sanchez²  Gustavo Henrique Ribeiro Viana⁴ 

[1] Departmento de Química-UFSC/Campus Universitário Trindade, CEP 88040-900, Florianópolis, SC, Brazil;Instituto de Ciências da Saúde-UFMT/Campus Sinop, CEP 78557-267, Sinop, MT, Brazil;Departmento de Ciências Farmacêuticas-UFSC/Campus Universitário Trindade, CEP 88040-900, Florianópolis, SC, Brazil;Centro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, Brazil

关键词: 4-methoxychalcone;    malaria;    ADMET properties;    LipE;   

DOI  :  10.3390/molecules181215276

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.