In Silico Analysis: Anti-Inflammatory and α-Glucosidase Inhibitory Activity of New α-Methylene-γ-Lactams

Abstract

The research about α-methylene-γ-lactams is scarce; however, their synthesis has emerged in recent years mainly because they are isosters of α-methylene-γ-lactones. This last kind of compound is structurally most common in some natural products' nuclei, like sesquiterpene lactones that show biological activity such as anti-inflammatory, anticancer, antibacterial, etc., effects. In this work, seven α-methylene-γ-lactams were evaluated by their inflammation and α-glucosidase inhibition. Thus, compounds 3-methylene-4-phenylpyrrolidin-2-one (1), 3-methylene-4-(p-tolyl)pyrrolidin-2-one (2), 4-(4-chlorophenyl)-3-methylenepyrrolidin-2-one (3), 4-(2-chlorophenyl)-3-methylenepyrrolidin-2-one (4), 5-ethyl-3-methylene-4-phenylpyrrolidin-2-one (5), 5-ethyl-3-methylene-4-(p-tolyl)pyrrolidin-2-one (6) and 4-(4-chlorophenyl)-5-ethyl-3-methylenepyrrolidin-2-one (7) were evaluated via in vitro α-glucosidase assay at 1 mM concentration. From this analysis, 7 exerts the best inhibitory effect on α-glucosidase compared with the vehicle, but it shows a low potency compared with the reference drug at the same dose. On the other side, inflammation edema was induced using TPA (12-O-tetradecanoylphorbol 13-acetate) on mouse ears; compounds 1-7 were tested at 10 µg/ear dose. As a result, 1, 3, and 5 show a better inhibition than indomethacin, at the same doses. This is a preliminary report about the biological activity of these new α-methylene-γ-lactams.

Keywords: anti-inflammatory; α-glucosidase; α-methylene-γ-lactams.

Figure 1

α-methylene-γ-lactams tested as α-glucosidases and inflammation inhibitors.

Figure 2

Percentage of edema inhibition of 1 (24.81 ± 1.11%), 2 (24.81 ± 7.56%), 3 (32.42 ± 5.97%), 4 (10.05 ± 1.06%), 5 (28.73 ± 1.71%), 6 (8.67 ± 0.79%), 7 (17.45 ± 5.21%), and Indomethacin (31.90 ± 0.06%). Dose: 10 µg/ear. Each group represents the mean ± SEM of n = 5, *** p < 0.05 vs. vehicle.

Figure 3

Inhibitory activity of 1 (33.91 ± 0.73%), 2 (28.80 ± 2.41%), 3 (30.31 ± 1.13%), 4 (29.37 ± 2.88%), 5 (38.88 ± 1.61%), 6 (36.36 ± 1.21%), 7 (50.68 ± 1.67%), and Acarbose (87.98 ± 1.86%) [1 mM] on α-glucosidase activity. Each group represents the mean ± SEM of n = 6, *** p < 0.05 vs. vehicle.