Hit-to-lead optimization of 4,5-dihydrofuran-3-sulfonyl scaffold against Leishmania amazonensis. Effect of an aliphatic moiety

Eur J Med Chem. 2024 Oct 5:280:116935. doi: 10.1016/j.ejmech.2024.116935. Online ahead of print.

Abstract

In line with our objective of designing new antileishmanial compounds for oral use, we report the synthesis and biological evaluation in vitro of original 4,5-dihydrofuran derivatives bearing an amidoxime group. Previous optimization focused on position 3 of the dihydrofuran ring involving aromatic fragments, resulting in the identification of the compound (HIT) 4-(5-benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N'-hydroxybenzimidamide (IC50 = 5.4 ± 1.0 μM, L. amazonensis promastigote, IC50 = 7.9 ± 1.1 μM, L. amazonensis intracellular amastigote). In the present work, position 3 was substituted with an aliphatic moiety. This modification was guided by a ligand-based approach, given the unknown biological target or mechanism of action for this compound. The 4,5-dihydrofuran derivatives were synthesized using microwave-assisted manganese (III) acetate-based oxidative cyclization of linear β-keto-carboxylic and β-keto-sulfone substrates, overcoming synthetic challenges to obtain aliphatic derivatives of 4,5-dihydrofuran-3-carboxamides. Finally, an unexpected and interesting biological activity with the 4,5-dihydrofuran-3-carboxylate (IC50 < 5 μM) against the amastigote form is discussed.

Keywords: 4,5-Dihydrofuran; Amidoxime; Leishmaniasis; Pharmacomodulation.