Abstract
A series of amide (8–32, 40–45) and urea (33, 34, 36–39) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg(-1)), plasma concentrations remained above 0.2 μM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg(-1) twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for 8 and 26% for 33, relative to the vehicle control.
Highlights
Malaria is an infectious disease caused by parasites belonging to the genus Plasmodium and is a major health and economic problem globally
As the thiaplakortone scaffold contains a quinone motif we examined the activity of several of our more potent compounds, which included the synthesised natural products (1 and 2), along with the amide (8 and 16) and urea analogues (33 and 38) against an atovaquone-resistant P. falciparum line (C2B)
31 amide and 7 urea derivatives based on the thiaplakortone A tricyclic scaffold were synthesised and evaluated for their in vitro antimalarial activity and mammalian cell 1562 | Org
Summary
Malaria is an infectious disease caused by parasites belonging to the genus Plasmodium and is a major health and economic problem globally. The mechanism of action for atovaquone involves the inhibition of the cytochrome bc1 complex in Plasmodium parasites.17–19 As the thiaplakortone scaffold contains a quinone motif we examined the activity of several of our more potent compounds, which included the synthesised natural products (1 and 2), along with the amide (8 and 16) and urea analogues (33 and 38) against an atovaquone-resistant P. falciparum line (C2B).20–22 In vitro screening results using the C2B line showed that 1, 2, 8, 16, 33 and 38 had IC50 values of 52 ± 9.8, 377 ± 49, 324 ± 70, 286 ± 26, 383 ± 108, and 331 ± 124 nM, respectively.
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