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

Andrews, K. T.; Fisher, G. M.; Firmin, M.; Liepa, A.; Wilson, T.; Gardiner, J.; Mohri, Y.; Rai, A.; Davey, A. K.; Masurier, A.; Delion, A.; Mouratidis, A. A.; Hutt, O.; Burrows, J. N.; Ryan, J. H.; Riches, A.; Skinner-Adams, T. S.

doi:10.1101/2023.03.09.531229

bioRxiv · 10.1101/2023.03.09.531229

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

Andrews, K. T.·Fisher, G. M.·Firmin, M.·Liepa, A.·Wilson, T.·Gardiner, J.·Mohri, Y.·Rai, A.·Davey, A. K.·Masurier, A.·Delion, A.·Mouratidis, A. A.·Hutt, O.·Burrows, J. N.·Ryan, J. H.·Riches, A.·Skinner-Adams, T. S.

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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 antiplas-modial chemotype (e.g., 1 96 h IC50 550 nM) with a different action to delayed-death slow-action drugs. Structure activity relationship analysis of analogues identified multiple 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 >2,500). However subsequent studies in mice with lead compound 1, which had the best microsomal stability of the compounds assessed, demonstrated rapid clearance (T1/2 <1.6 h) and poor oral in vivo efficacy. This indicates that improvements in the pharmacokinetic profile of N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines would be needed for the development of this chemotype for malaria chemoprophylaxis.

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Andrews, K. T., Fisher, G. M., Firmin, M., Liepa, A., Wilson, T., Gardiner, J., Mohri, Y., Rai, A., Davey, A. K., Masurier, A., Delion, A., Mouratidis, A. A., Hutt, O., Burrows, J. N., Ryan, J. H., Riches, A., Skinner-Adams, T. S.. 2023-03-10. Discovery of 1,3,4-oxadiazoles with slow-action activity against Plasmodium falciparum malaria parasites. https://doi.org/10.1101/2023.03.09.531229

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