Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Abstract

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.

Aryl amino acetamides prevent the development ofPlasmodium falciparumrings via inhibition of the lipid transfer protein PfSTART1

“…This change also led to a small increase in human HepG2 cell activity (CC50 = 29 µM). This activity is consistent with that previously reported (Norcross et al, 2019). Replacing the phenolic group ( 3 ) in M-833 with an anilino group in W-991 resulted in a 20-fold improvement in parasite activity (EC50 = 150 nM), highlighting the preference for a secondary amine in that position.…”

“…To create more potent probes to investigate the target of M-833 as well as to explore the therapeutic potential of the compounds, we explored the structure activity relationship of the M-833 series. It was observed that M-833 shared structural similarities with the aminoacetamide compound 2 (Norcross et al, 2019) (Fig 3A), which is developed from a Tres Cantos Antimalarial Set (TCAMS) hit. The structural similarities include a substituted aryl sulfonamide, acetamide core and aryl amido substitution in both series.…”

“…Compound 2 was assessed for activity against M-833 resistant populations and was shown to be cross-resistant (Fig 3B), indicating compound 2 is likely to have the same molecular target as M-833. In the optimisation of M-833 it was found that there was crossover with the structure activity relationship between the two structurally related hit compounds (Norcross et al, 2019). Installation of a gem-dimethyl on the alpha position of the acetamide generated the compound W-991 (WEHI-991), resulting in a 20-fold improvement in parasite activity (EC50 = 7 nM) (Fig 3A).…”

Male contraceptive development: A medicinal chemistry perspective

“…Information on the target and ideally structural information would have helped to overcome these roadblocks. [34] Phenotypic screening of natural products has identified numerous first-in class therapies, for the treatment of cancer and anti-infectives. [35] Chemical optimisation of natural product leads can be inherently challenging due to synthetic complexity but may be necessary to improve the ADMET properties.…”

QSAR studies on benzothiophene derivatives as Plasmodium falciparum N‐myristoyltransferase inhibitors: Molecular insights into affinity and selectivity

“…In contrast, the lack of structural information about the molecular target and the need for complicated downstream target deconvolution methodologies make the optimization process and the discovery of the mode of action very challenging (Gilbert, Leroy, & Frearson, 2011). Nevertheless, this approach has been successful, and over the last decade, the majority of the lead and drug candidates were discovered this way, even if the exact mechanism of action remains unknown (Aguiar et al, 2018;Fagundez et al, 2019;Gonring-Salarini et al, 2019;Krake et al, 2017;Martelli et al, 2019;Martinez et al, 2018;Norcross et al, 2016Norcross et al, , 2019Okada-junior et al, 2018;Parra et al, 2018;Pereira et al, 2017).…”