Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold

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.

Screening a Natural Product-Based Library against Kinetoplastid Parasites

“…The significant difference in plasmodial activity between 3 and 7 may be due to the different thiazine regiochemistry and the lack of an ethylamine chain in 7 , compared to the natural product 3 ordifferences in the assay formats used. In vivo testing of thiaplakortone A in a mouse model of malaria infection did not suppress parasitemia with oral administration, possibly due to associated poor bioavailability [ 65 ].…”

1-(4-Hexylbenzoyl)-3-methylthiourea

“…The thiourea structure is similar to the urea, except that the S atom in thiourea replaces the O atom on urea. In previous studies, urea was widely used in drug discovery research, for example as anticancer [1,2], anti-tuberculosis [3,4], antimalarial [5,6] and analgesic [7]. Thiourea was also widely used in new drug discovery research, such as anticancer and antitumor [8][9][10][11][12], antibacterial, antimicrobial and anti-tuberculosis [13][14][15][16][17][18], soluble epoxide hydrolase (sEH) inhibitor [19] and antiviral [20].…”

Synthesis and Antiplasmodial Evaluation of Analogues Based on the Tricyclic Core of Thiaplakortones A–D

“…While in vivo toxicity effects for several of the synthetic compounds indicated potential liabilities associated with this structure class, the limited number of analogues investigated made it difficult to assess their true potential as antiplasmodial leads [ 2 ]. In order to more thoroughly explore this compound class a larger analogue library based on the thiaplakortone A scaffold was recently undertaken and reported [ 3 ]. This 38-membered library consisted of a series of amide and urea analogues based on the thiaplakortone A natural product scaffold.…”

“…This 38-membered library consisted of a series of amide and urea analogues based on the thiaplakortone A natural product scaffold. Several analogues showed potent in vitro P. falciparum growth inhibition (IC 50 < 500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast (NFF) cells (selectivity index >100) [ 3 ]. Furthermore, analogues 8 and 9 displayed good metabolic stability and solubility, and when administered subcutaneously to mice plasma concentrations remained >0.2 µM for 8 h. Analogues 8 and 9 were also well tolerated in mice after subcutaneous administration of 32 mg/kg twice daily for 4 d. In addition, using this dosing protocol blood stage P. berghei parasitemia was suppressed by 52% for 8 and 26% for 9 , relative to controls [ 3 ].…”

“…Several analogues showed potent in vitro P. falciparum growth inhibition (IC 50 < 500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast (NFF) cells (selectivity index >100) [ 3 ]. Furthermore, analogues 8 and 9 displayed good metabolic stability and solubility, and when administered subcutaneously to mice plasma concentrations remained >0.2 µM for 8 h. Analogues 8 and 9 were also well tolerated in mice after subcutaneous administration of 32 mg/kg twice daily for 4 d. In addition, using this dosing protocol blood stage P. berghei parasitemia was suppressed by 52% for 8 and 26% for 9 , relative to controls [ 3 ]. In order to further investigate the thiaplakortone core, we have recently undertaken synthetic studies that resulted in the removal of the ethylamine side-chain present in thiaplakortones A and B in order to determine the biological implications of the –CH 2 CH 2 NH 2 moiety.…”