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

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 (IC 50 = 5.4 ± 1.0 μM, L. amazonensis promastigote, IC 50 = 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 (IC 50 < 5 μM) against the amastigote form is discussed. • Vector-borne diseases such as leishmaniasis remain a global public health problem, exacerbated by climate change. New drugs designed for oral use are therefore needed. • In the absence of receptors or targeted mechanisms, the chemical similarity concept could be a source of reasonable hypotheses for developing new bioactive molecules. • Manganese-based oxidative cyclization of β-dicarbonyl compounds with terminal alkenes allowed us to synthesize a new series of dihydrofuran compounds. Among these, derivatives substituted by an ester moiety have excellent in vitro antileishmanial properties on amastigote strains.