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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.

SUBMITTER: de Oliveira ME

PROVIDER: S-EPMC6269736 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Antimalarial activity of 4-metoxychalcones: docking studies as falcipain/plasmepsin inhibitors, ADMET and lipophilic efficiency analysis to identify a putative oral lead candidate.

de Oliveira Michael Eder ME Cenzi Gisele G Nunes Renata Rachide RR Andrighetti Carla Regina CR de Sousa Valadão Denia Mendes DM Dos Reis Cláudia C Simões Cláudia Maria Oliveira CM Nunes Ricardo José RJ Júnior Moacyr Comar MC Taranto Alex Gutterres AG Sanchez Bruno Antonio Marinho BA Viana Gustavo Henrique Ribeiro GH de Pilla Varotti Fernando F

Molecules (Basel, Switzerland) 20131210 12

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 ...[more]

PMID: 24335577

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Dataset Information

Antimalarial activity of 4-metoxychalcones: docking studies as falcipain/plasmepsin inhibitors, ADMET and lipophilic efficiency analysis to identify a putative oral lead candidate.

Publications

Antimalarial activity of 4-metoxychalcones: docking studies as falcipain/plasmepsin inhibitors, ADMET and lipophilic efficiency analysis to identify a putative oral lead candidate.

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