Amides of moronic acid and morolic acid with the tripeptides MAG and GAM targeting antimicrobial, antiviral and cytotoxic effects

Abstract

A series of amides of selected plant triterpenoids, moronic acid and morolic acid, with the tripeptides MAG and GAM, was designed and synthesized. Two required tripeptides 5 and 10 were synthesized by a step-wise chain elongation of the ethyl esters of either glycine or L-methionine at their N-terminus using Boc-protected amino acids in each step. The tripeptides 5 and 10 were used for the synthesis of 13–23, the derivatives of moronic acid (11) and morolic acid (12), to get a series of amide derivatives of the less frequently studied triterpenoids 11 and 12. The target compounds, and their intermediates, were subjected to an investigation of their antimicrobial, antiviral and cytotoxic activity. Selectivity of the pharmacological effects was found. Generally, the target compounds inhibited only the G⁺ microorganisms. Compound 16 inhibited Staphylococcus aureus (I = 99.6%; c = 62.5 μM) and Enterococcus faecalis (I = 85%; c = 250 μM). Several compounds showed moderate antiviral effects, both anti-HIV-1, 19 (EC₅₀ = 57.0 ± 4.1 μM, CC₅₀ > 100 μM), 20 (EC₅₀ = 17.8 ± 2.1 μM, CC₅₀ = 41.0 ± 5.2 μM) and 23 (EC₅₀ = 12.6 ± 0.82 μM, CC₅₀ = 38.0 ± 4.2 μM), and anti-HSV-1, 22 (EC₅₀ = 27.7 ± 3.5 μM, CC₅₀ > 100 μM) and 23 (EC₅₀ = 30.9 ± 3.3 μM, CC₅₀ > 100 μM). The target compounds showed no cytotoxicity in cancer cells, however, several of their intermediates were cytotoxic. Compound 21 showed cytotoxicity in HeLa (IC₅₀ = 7.9 ± 2.1 μM), G-361 (IC₅₀ = 8.0 ± 0.6 μM) and MCF7 (IC₅₀ = 8.6 ± 0.2 μM) cancer cell lines, while being non-toxic in normal fibroblasts (BJ; IC₅₀ > 50 μM).