Antiplasmodial activity of steroidal chalcones: evaluation of their effect on hemozoin synthesis and the new permeation pathway of Plasmodium falciparum‐infected erythrocyte membrane

Abstract

Chalcone derivatives on an estradiol framework were evaluated for their ability to inhibit the growth and development of the malaria parasite Plasmodium falciparum. Out of twelve steroidal chalcones and one indanone derivative studied, three were found to have 50% growth inhibitory concentration less than 5 lM and minimum inhibitory concentration for parasite development from ring to schizont stage as £20 lM with best activity for gallic acid-based chalcone derivative 1 as 2.07 and 10 lM, respectively. Two of the active derivatives 1 and 10 did not exhibit cytotoxicity against vero cells as evident by the good selectivity ratio. Study of structure-activity relationship indicated that increasing substitution in the benzoyl ringenhanced antiplasmodial activity. Hemozoin synthesis of the parasite remained unaffected by these derivatives. These derivatives were also investigated for their effect on parasite-induced new permeation pathway in the erythrocyte membrane by sorbitol-induced hemolysis, and four derivatives 1, 2, 9, and 10 exhibited significant inhibition (>70%) at 20 lM concentration. A positive correlation was also observed among the antiplasmodial activity and inhibition of new permeation pathway. These observations suggest that steroidal chalcones with selective activity for the parasite may be considered as antimalarial leads for further optimization and preclinical study.

In vitro anti-malarial efficacy of chalcones: cytotoxicity profile, mechanism of action and their effect on erythrocytes

“…Similar results were shown in the previous studies where different chalcone derivatives showed hindrance of plasmodial haemozoin formation in culture suggesting that these chalcones act on haemozoin formation pathways [52–54]. However, few studies reported that some do not interfere with haemozoin formation [55, 56]. This variation is mostly due to substitution on the ring A or B of the chalcones.…”

Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine‐Resistant Plasmodium falciparum

“…[15] According to the same authors, the ability of these NPPB derivatives to inhibit NPP improves with the length and lipophilicity of the hydrophobic tail. Chalcones like 11 are structurally related to the cinnamoyl moiety and were also reported as NPP inhibitors by Go et al [16] and Sisodia et al [17] In compounds 7, the heterocyclic core is linked to a butylcinnamoyl group that reasonably matches relevant structural factors described above, reinforcing the structural suitability of the compounds as NPP inhibitors. Heme seems to be a main target of compounds 7, which agrees with their structural similarity to chloroquine.…”

Anti-cancer activity oftrans-chalcone in osteosarcoma: Involvement of Sp1 and p53

“…Over the past ten years, there has been increasing attention to chalcones because they exhibit diverse biological activities. Naturally occurring chalcones, as well as synthetic chalcone analogues, have been demonstrated to have many biological effects, including anti‐inflammatory , anti‐malarial , anti‐fungal , and anti‐oxidant/anti‐cancer activities . Recent data suggest that chalcones also target a number of cancer signaling pathways, including tubulin polymerization, proteasomal pathway, cell cycle, apoptosis, receptors, and multidrug resistance transporters .…”