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Molecules 2013, 18(12), 15276-15287; doi:10.3390/molecules181215276
Article

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

1, 1, 1, 2, 2, 3, 3, 4, 1, 1, 2, 1,*  and 1,*
1 Centro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, Brazil 2 Instituto de Ciências da Saúde-UFMT/Campus Sinop, CEP 78557-267, Sinop, MT, Brazil 3 Departmento de Ciências Farmacêuticas-UFSC/Campus Universitário Trindade, CEP 88040-900, Florianópolis, SC, Brazil 4 Departmento de Química-UFSC/Campus Universitário Trindade, CEP 88040-900, Florianópolis, SC, Brazil
* Authors to whom correspondence should be addressed.
Received: 20 September 2013 / Revised: 23 November 2013 / Accepted: 30 November 2013 / Published: 10 December 2013
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Herein, we report the antimalarial activity of nine 4-methoxychalcone derivatives 1ai 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.
Keywords: 4-methoxychalcone; malaria; ADMET properties; LipE 4-methoxychalcone; malaria; ADMET properties; LipE
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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de Oliveira, M.E.; Cenzi, G.; Nunes, R.R.; Andrighetti, C.R.; de Sousa Valadão, D.M.; dos Reis, C.; Simões, C.M.O.; Nunes, R.J.; Júnior, M.C.; Taranto, A.G.; Sanchez, B.A.M.; Viana, G.H.R.; de Pilla Varotti, F. Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate. Molecules 2013, 18, 15276-15287.

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