Discovery of 1,3,4-oxadiazoles with slow-action activity against Plasmodium falciparum malaria parasites

• Published in: European journal of medicinal chemistry Vol. 278; p. 116796
• Main Authors: Andrews, Katherine T., Fisher, Gillian M., Firmin, Meaghan, Liepa, Andris J., Wilson, Tony, Gardiner, James, Mohri, Yacine, Debele, Emmanuel, Rai, Anjana, Davey, Andrew K., Masurier, Antoine, Delion, Alix, Mouratidis, Alexandros A., Hutt, Oliver E., Forsyth, Craig M., Burrows, Jeremy N., Ryan, John H., Riches, Andrew G., Skinner-Adams, Tina S.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15.11.2024
• Subjects: Antimalarial drug discovery; malaria; P. falciparum 1,3,4-oxadiazoles; malaria; Antimalarial drug discovery; P. falciparum 1,3,4-oxadiazoles
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116796

To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 1 96 h IC50 550 nM; 3 96 h IC50 160 nM) with a different action to delayed-death slow-action drugs. A series of analogues were synthesized from thiotetrazoles and carbomoyl derivatives using Huisgen 1,3,4-oxadiazole synthesis followed by oxidation of the resultant thioethers to target sulfones. Structure activity relationship analysis of analogues identified compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC50 <40 nM; SI > 2500). Subsequent studies in mice with compound 1, which had the best microsomal stability of the compounds assessed (T1/2 >255 min), demonstrated rapid clearance and poor oral in vivo efficacy in a P. berghei murine malaria model. These data indicate that while N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines are a novel class of slow-acting antiplasmodial agents, the further development of this chemotype for malaria chemoprophylaxis will require pharmacokinetic profile improvements. [Display omitted] •New drugs are needed to achieve malaria eradication.•Novel 1,3,4-oxadiazoles with activity against malaria parasites were identified.•In vivo studies indicated that pharmacokinetic improvements are needed.