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.
Highlights
In 2010, there were an estimated 219 million cases of malaria, a global infectious disease, and it was responsible for 660,000 deaths [1]
The need for new antimalarial therapies has stimulated research into the search for synthetic molecules that are effective against acquired resistance to artemisinin derivatives and would result in promising antimalarial activity [4,5]
All compounds showed potency against the P. falciparum chloroquine-resistant clone W2, with IC50 values ranging from 1.96 μM
Summary
In 2010, there were an estimated 219 million cases of malaria, a global infectious disease, and it was responsible for 660,000 deaths [1]. The need for new antimalarial therapies has stimulated research into the search for synthetic molecules that are effective against acquired resistance to artemisinin derivatives and would result in promising antimalarial activity [4,5]. In this context, chalcones (1,3-diaryl-2-propen-1-ones), the bio-precursors of flavonoids, have been used as scaffolds for medicinal chemists for many years and chalcone analogs are associated with a broad range of biological activities, including antimalarial activity [6,7,8,9]. A recent strategy adopted in the search for new antimalarial drugs is the design of hybrids [13,14]
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