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

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

  • Eur J Med Chem. 2024 Nov 15:278:116796. doi: 10.1016/j.ejmech.2024.116796.
Katherine T Andrews 1,  Gillian M Fisher 2,  Meaghan Firmin 2,  Andris J Liepa 3,  Tony Wilson 3,  James Gardiner 3,  Yacine Mohri 3,  Emmanuel Debele 3,  Anjana Rai 2,  Andrew K Davey 4,  Antoine Masurier 3,  Alix Delion 3,  Alexandros A Mouratidis 3,  Oliver E Hutt 3,  Craig M Forsyth 5,  Jeremy N Burrows 6,  John H Ryan 7,  Andrew G Riches 8,  Tina S Skinner-Adams 9
Affiliations

Affiliations

  • 1 Institute for Biomedicine and Glycomics, Griffith University, Nathan, Queensland, 4111, Australia. Electronic address: k.andrews@griffith.edu.au.
  • 2 Institute for Biomedicine and Glycomics, Griffith University, Nathan, Queensland, 4111, Australia.
  • 3 Commonwealth Scientific and Industrial Research Organization, Biomedical Manufacturing, Clayton, Victoria, 3168, Australia.
  • 4 Griffith Health Group, Griffith University, Gold Coast, Queensland, 4222, Australia.
  • 5 School of Chemistry, Monash University, Clayton, Victoria, 3800, Australia.
  • 6 Medicines for Malaria Venture, Geneva, Switzerland.
  • 7 Commonwealth Scientific and Industrial Research Organization, Biomedical Manufacturing, Clayton, Victoria, 3168, Australia. Electronic address: jack.ryan@csiro.au.
  • 8 Commonwealth Scientific and Industrial Research Organization, Biomedical Manufacturing, Clayton, Victoria, 3168, Australia. Electronic address: andrew.riches@csiro.au.
  • 9 Institute for Biomedicine and Glycomics, Griffith University, Nathan, Queensland, 4111, Australia. Electronic address: t.skinner-adams@griffith.edu.au.
PMID: 39241483 DOI: 10.1016/j.ejmech.2024.116796
Abstract

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.

Keywords

Antimalarial drug discovery; P. falciparum 1,3,4-oxadiazoles; malaria.

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