title: Antimalarial activity of 4-metoxychalcones: docking studies as falcipain/plasmepsin inhibitors, ADMET and lipophilic efficiency analysis to identify a putative oral lead candidate.
abstract: 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.
authors: Michael Eder
authors: ME
authors: de Oliveira
authors: Gisele
authors: G
authors: Cenzi
authors: Renata Rachide
authors: RR
authors: Nunes
authors: Carla Regina
authors: CR
authors: Andrighetti
authors: Denia Mendes
authors: DM
authors: de Sousa Valadão
authors: Cláudia
authors: C
authors: Dos Reis
authors: Cláudia Maria Oliveira
authors: CM
authors: Simões
authors: Ricardo José
authors: RJ
authors: Nunes
authors: Moacyr Comar
authors: MC
authors: Júnior
authors: Alex Gutterres
authors: AG
authors: Taranto
authors: Bruno Antonio Marinho
authors: BA
authors: Sanchez
authors: Centro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, Brazil. viana@ufsj.edu.br.
authors: Gustavo Henrique Ribeiro
authors: GH
authors: Viana
authors: Centro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, Brazil. varotti@ufsj.edu.br.
authors: Fernando
authors: F
authors: de Pilla Varotti
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002599:Chalcone / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D008970:Molecular Weight; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D002599:Chalcone; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II