Synthesis, Structure–Activity Relationships, and Parasitological Profiling of Brussonol Derivatives as New Plasmodium falciparum Inhibitors

Abstract

Malaria is a parasitic disease caused by protozoan parasites from the genus Plasmodium. Plasmodium falciparum is the most prevalent species worldwide and the causative agent of severe malaria. The spread of resistance to the currently available antimalarial therapy is a major concern. Therefore, it is imperative to discover and develop new antimalarial drugs, which not only treat the disease but also control the emerging resistance. Brussonol is an icetexane derivative and a member of a family of diterpenoids that have been isolated from several terrestrial plants. Here, the synthesis and antiplasmodial profiling of a series of brussonol derivatives are reported. The compounds showed inhibitory activities in the low micromolar range against a panel of sensitive and resistant P. falciparum strains (IC50s = 5–16 μM). Moreover, brussonol showed fast-acting in vitro inhibition and an additive inhibitory behavior when combined with the antimalarial artesunate (FICindex~1). The mode of action investigation indicated that brussonol increased the cytosolic calcium levels within the parasite. Hence, the discovery of brussonol as a new scaffold endowed with antiplasmodial activity will enable us to design derivatives with improved properties to deliver new lead candidates for malaria.

Discovery of brussonol analogs as lead candidates for malaria

“…These results suggest that the brussonol derivatives are fast-acting inhibitors of P. falciparum. Source: Adapted from BARBOSA et al 128 Similar results were obtained for compound 8 when assessing its speed-of-action (Figure 12a). Within 24 h of drug exposure, it was possible to visualize pyknotic nuclei in culture, and IC50 values for each assessed time were comparable (Figure 12b).…”

“…Detailed information on the synthetic routes and purification is found elsewhere. [127][128] The first step was the assessment of the in vitro inhibitory activity of synthesized compounds against P. falciparum (3D7 strain), and the evaluation of the cytotoxic effect on the human cell line HepG2. The collection of these data allowed the determination of the SI (Table 1).…”

“…Source: Adapted from BARBOSA et al 128 The concentration required to inhibit 50% of parasite's growth (IC50) is a crucial parameter to determine the potency of a compound. In the phenotypic screening for antiplasmodial activity evaluation, IC50 values of 10 µM are used as reference to select promising hit candidates.…”

“…Source: Adapted from Barbosa, et al 128 The next step was to evaluate the cytotoxic effect of compounds (IC50 3D7 < 10 µM) against a human hepatocellular cell line (HepG2). 8 out of 15 compounds had their CC50 values determined.…”

Special Issue “Drug Candidates for the Treatment of Infectious Diseases”

“…These compounds were discovered to demonstrate in vitro efficacy against both the erythrocytic stage of P. falciparum and the hepatic stage of P. berghei [ 23 ]. Barbosa and collaborators detailed the synthesis, SAR exploration, and assessment of brussonol derivatives active against P. falciparum , including resistant strains [ 24 ]. Argüello-García reported on the giardicidal effects of the neo-clerodane type diterpene named linearolactone.…”