Synthesis and evaluation of hybrid sulfonamide‐chalcones with potential antileishmanial activity

• Published in: Archiv der Pharmazie (Weinheim) 2024-03, Vol.357 (3), p.e2300440-n/a
• Main Authors: Oliveira, Nathalia S., Souza, Luana G., Almeida, Vitor M., Barreto, Arielly R. R., Carvalho‐Gondim, Felipe, Schaeffer, Edgar, Santos‐Filho, Osvaldo A., Rossi‐Bergmann, Bartira, Silva, Alcides J. M.
• Format: Article
• Language: English
• Subjects: amastigote; Animals; Antiprotozoal Agents - pharmacology; Chalcone - pharmacology; Chalcones - pharmacology; Enzymes; Leishmania amazonensis; Mice; molecular docking; molecular dynamics; Parasitic diseases; promastigote; Structure-Activity Relationship; Sulfanilamide; Sulfonamides - pharmacology
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202300440

Leishmaniasis is an emerging tropical infectious disease caused by a protozoan parasite of the genus Leishmania. In this work, the molecular hybridization between a trimethoxy chalcone and a sulfonamide group was used to generate a series of sulfonamide‐chalcones. A series of eight sulfonamide‐chalcone hybrids were made with good yields (up to 95%). These sulfonamide‐chalcones were tested against promastigotes of Leishmania amazonensis and cytotoxicity against mouse macrophages, which showed good antileishmanial activity with IC50 = 1.72–3.19 µM. Three of them (10c, 10g, and 10h) were also highly active against intracellular amastigotes and had a good selectivity index (SI > 9). Thus, those three compounds were docked in the cytosolic tryparedoxin peroxidase (cTXNPx) enzyme of the parasite, and molecular dynamics simulations were carried out. This enzyme was selected as a target protein for the sulfonamide‐chalcones due to the fact of the anterior report, which identified a strong and stable interaction between the chalcone NAT22 (6) and the cTXNPx. In addition, a prediction of the drug‐likeness, and the pharmacokinetic profile of all compounds were made, demonstrating a good profile of those chalcones. New sufonamide‐chalcones hybrids were designed, synthesized, and evaluated for antileishmanial activity. The activity for Leishmania amazonensis promastigotes was high (IC50 = 0.62–3.34 mM) with a selectivity index of up to 11.79, and the activity for the amastigote form of the parasite was better (IC50 = 0.40–1.29 mM). Molecular docking and molecular dynamics were carried out with the target enzyme, cytosolic tryparedoxin peroxidase.