γ‐Lactones from Persea americana and Persea fulva – in Vitro and in Silico Evaluation of Trypanosoma cruzi Activity

Abstract

In the present study, five known γ‐lactones (majoranolide B – 1, majorenolide – 2, majorynolide – 3, lincomolide D – 4, and isolinderanolide E – 5), as well as a new one (perseanolide – 6), were isolated from Persea fulva and P. americana. All isolated compounds exhibited potential activity against trypomastigote forms of Trypanosoma cruzi, whereas compounds 2 (EC50 of 4.8 μM) and 6 (EC50 of 3.6 μM) displayed superior activity than the positive control benznidazole (EC50 of 16.4 μM), with selectivity index (SI) values of 17.8 and >55.6, respectively (benznidazole, SI>12.2). Molecular docking studies were performed for 1–6 against six T. cruzi molecular targets. Using this approach, we observed that, even though perseanolide (6) showed favorable docking to several studied targets, the results were especially promising for hypoxanthine phosphoribosyl transferase (PDB 1TC1). As PDB 1TC1 is associated to the transference of a monophosphorylated ribose from phosphoribosylpyrophosphate (PRPP) in the ribonucleotide synthesis pathway, this interaction may affect the survival of T. cruzi in mammalian cells. The data herein also indicate that possible intermolecular interactions between 6 and PDB 1TC1 derive from (i) hydrogen bonds in the α,β‐unsaturated‐γ‐lactone unity and (ii) hydrophobic interactions in the long‐chain alkyl group. Based on our results, perseanolide (6), reported for the first time in this work, can auspiciously contribute to future works regarding new trypanocidal agents.

Chemistry and Bioactivity of the Genus Persea ‐ A Review

“…(2021) reported on the expressive activity of the compound majorenolide ( 52 ) against trypomastigote forms of T. cruzi , presenting EC 50 value of 4.8±0.7 μM (SI=17.8), higher than the standard drug benznidazole (EC 50 of 15.9±0.6 μM, SI>12.6). The influence of sp 2 hybridization on C‐11′ is also highlighted, since the compounds majoranolide B ( 54 ) and majorynolide ( 53 ), with sp 3 and sp hybridization on C‐11′, exhibited a reduced activity against the same parasite, with EC 50 values of 15.8±2.3 and 19.8±1.4 μM, respectively [33] . Majoranolide ( 51 ) exhibited moderate activity against the amastigote forms of T. cruzi , with EC 50 of 21.92±3.62 μM [32] …”

“…The influence of sp 2 hybridization on C-11' is also highlighted, since the compounds majoranolide B (54) and majorynolide (53), with sp 3 and sp hybridization on C-11', exhibited a reduced activity against the same parasite, with EC 50 values of 15.8 � 2.3 and 19.8 � 1.4 μM, respectively. [33] Majoranolide (51) exhibited moderate activity against the amastigote forms of T. cruzi, with EC 50 of 21.92 � 3.62 μM. [32] Compounds 51 to 54 were subjected to a cytotoxicity assay in C6 cells of mouse glioma, demonstrating cytotoxic action against this tumor cell.…”

“…Eighteen butanolides (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67) were isolated from Persea species (Figure 5), especially from P. americana, [33] P. indica, [50] P. major, [36,78] and P. fulva. [33,34] Majorano-( 51), majoreno-( 52), majoryno-( 53), and majoranolide B (54) were isolated from P. indica, [50] P. major [36,78] and P. fulva. [33,34] Additionally, Fraga et al (2020) established the absolute stereochemistry of C-5 of compound 54 as S. [21] Reis et al ( 2021) reported on the expressive activity of the compound majorenolide (52) against trypomastigote forms of T. cruzi, presenting EC 50 value of 4.8 � 0.7 μM (SI = 17.8), higher than the standard drug benznidazole (EC 50 of 15.9 � 0.6 μM, SI > 12.6).…”

“…Majorano‐ ( 51 ), majoreno‐ ( 52 ), majoryno‐ ( 53 ), and majoranolide B ( 54 ) were isolated from P. indica , [50] P. major [36,78] and P. fulva [33,34] . Additionally, Fraga et al.…”

“…Eighteen butanolides ( 51 – 67 ) were isolated from Persea species (Figure 5), especially from P. americana , [33] P. indica , [50] P. major , [36,78] and P. fulva [33,34] …”