Discovery and characterization of selective lipase-inhibiting polyheterocyclic derivatives: a combined in silico and in vitro study

Abstract

Background/aim: Obesity has become a global health crisis with an increasing prevalence, necessitating the search for effective therapies. Schiff base derivatives, known for their broad pharmacological activities, have gained attention as potential antiobesity agents. This study aimed to investigate the lipase inhibitory potential of novel Schiff base derivatives and assess their drug-like properties through in vitro assays and in silico methods.

Materials and methods: The lipase inhibitory activity of synthesized Schiff base derivatives was evaluated using in vitro assays, with IC₅₀ values determined for each compound. Additionally, in silico ADMET predictions (absorption, distribution, metabolism, excretion, and toxicity), molecular docking studies, and density functional theory (DFT) calculations were conducted to assess the pharmacokinetic properties and binding potential of the compounds to the lipase active site.

Results: The synthesized Schiff base derivatives demonstrated significant lipase inhibitory activity, with IC₅₀ values of 995.74 ± 0.010 μM (6) and 1985.51 ± 0.041 μM (2), comparable to the reference compound quercetin (843.06 ± 0.0007 μM). In silico ADMET analyses revealed that compounds 2 and 6 possess favorable pharmacokinetic properties and exhibit drug-like characteristics. Molecular docking studies showed robust binding interactions between these compounds and the lipase active site, which were further corroborated by DFT calculations that identified reactive regions and stable conformations. Among the compounds, compound 6 exhibited the most effective inhibition and interaction profile, indicating its potential as a lipase inhibitor. These findings underscore the potential of Schiff base derivatives as promising antiobesity agents.

Conclusion: The results of our study highlight the potential of Schiff base derivatives as promising candidates for antiobesity therapy, given their significant lipase inhibitory activity and favorable in silico predictions. Further research is needed to elucidate the precise mechanisms of action and assess the efficacy of these compounds in vivo.

Keywords: ADMET; Schiff base derivatives; in silico; in vitro; lipase inhibition; molecular docking.

Figure 1

The structure of the synthesized Schiff base derivatives 1–7.

Figure 2

Histogram of lipase inhibition percentages by Schiff base derivatives.

Figure 3

Inhibition curves and values of lipase by Schiff bases and quercetin.

Figure 4

Scan of the total energy of compounds 2 and 6 computed at B3LYP/6-31+G(d,p).

Figure 5

Computed RDG isosurface maps, scatter plots, Fukui functions, and dual descriptors of compounds 2 and 6 computed at B3LYP/6-31+G(d,p).

Figure 6

Best docking poses for the three compounds, 2, 6, and quercetin.