Synthesis, characterization and evaluation of prenylated chalcones ethers as promising antileishmanial compounds

• Published in: Molecular diversity Vol. 27; no. 5; pp. 2073 - 2092
• Main Authors: Hernández-Rivera, Jessica Lizbeth, Espinoza-Hicks, José C., Chacón-Vargas, Karla F., Carrillo-Campos, Javier, Sánchez-Torres, Luvia Enid, Camacho-Dávila, Alejandro A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2023; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Biosynthesis; Dehydrogenases; Drugs; Enzymes; Flavonoids; Life Sciences; Metabolism; Metabolites; Organic Chemistry; Original Article; Parasites; Parasitic diseases; Pharmaceutical industry; Pharmacy; Polymer Sciences; Protozoa; Selectivity index; Metabolic inhibition; prenylated chalcones; Structure–activity relationship; Molecular docking
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-022-10542-1

Drug therapy for leishmaniasis remains a major challenge as currently available drugs have limited efficacy, induce serious side-effects and are not accessible to everyone. Thus, the discovery of affordable drugs is urgently needed. Chalcones present a great potential as bioactive agents due to simple structure and functionalization capacity. The antileishmanial activity of different natural and synthetic chalcones have been reported. Here we report the synthesis of twenty-five novel prenylated chalcones that displayed antiparasitic activity in Leishmania mexicana. All the chalcones were evaluated at 5 µg/mL and eleven compounds exhibited a metabolic inhibition close to or exceeding 50%. Compounds 49 , 30 and 55 were the three most active with IC 50 values < 10 μM. These chalcones also showed the highest selectivity index (SI) values. Interestingly 49 and 55 possessing a substituent at a meta position in the B ring suggests that the substitution pattern influences antileishmanial activity. Additionally, a tridimensional model of fumarate reductase of L. mexicana was obtained by homology modeling. Docking studies suggest that prenylated chalcones could modulate fumarate reductase activity by binding with good affinity to two binding sites that are critical for the target. In conclusion, the novel prenylated chalcones could be considered as promising antileishmanial agents. Graphical abstract