Molecular Simplification of Natural Products: Synthesis, Antibacterial Activity, and Molecular Docking Studies of Berberine Open Models

Abstract

Berberine, the main bioactive component of many medicinal plants belonging to various genera such as Berberis, Coptis, and Hydrastis is a multifunctional compound. Among the numerous interesting biological properties of berberine is broad antimicrobial activity including a range of Gram-positive and Gram-negative bacteria. With the aim of identifying berberine analogues possibly endowed with higher lead-likeness and easier synthetic access, the molecular simplification approach was applied to the secondary metabolite and a series of analogues were prepared and screened for their antimicrobial activity against Gram-positive and Gram-negative bacterial test species. Rewardingly, the berberine simplified analogues displayed 2–20-fold higher potency with respect to berberine. Since our berberine simplified analogues may be easily synthesized and are characterized by lower molecular weight than the parent compound, they are further functionalizable and should be more suitable for oral administration. Molecular docking simulations suggested FtsZ, a well-known protein involved in bacterial cell division, as a possible target.

A Comparative Study of the Inhibitory Action of Berberine Derivatives on the Recombinant Protein FtsZ of E. coli

“…Surprisingly, a different behaviour was observed for these compounds. Berberine and compounds 1a and 1f were predicted to interact with a binding site near the C terminus of the protein, whilst the analogues 1b – e were hosted in the protein active site within the GTP-binding pocket, thus suggesting a possible competitive inhibition mechanism on the GTPase activity of the protein [ 18 ].…”

“…The Minimal Inhibitory Concentrations (MICs) of both compounds were determined as the lowest concentration showing no visible growth after 24 h of incubation. The MIC values for 2g and 2h are reported in Table 4 , together with the most interesting compounds previously reported [ 18 ].…”

“…The highly conserved nature of the FtsZ protein among numerous prokaryotic species provides an opportunity for the development of broad-spectrum antibiotics [ 30 ]. Recently, molecular docking simulations predicted the binding of berberine analogues, either in the active site pocket, thus impairing the GTPase activity of the protein by a competitive inhibitory mechanism ( 1c , d ), or near the C-terminal region of the protein, leaving the active site free for GTP binding ( 1f ) [ 18 ].…”

“…In our previous study, molecular docking simulations suggested FtsZ as a possible target of berberine derivatives and analogues prepared according to the structural simplification approach [ 18 ]. In particular, 1c - and 1f -substituted berberine analogues showed greater potency than their parent compounds [ 19 ], indicating that appropriate modifications to the chemical structure of berberine might be instrumental to obtaining molecules with higher antimicrobial properties and FtsZ inhibitory capabilities.…”

Computational Evaluation of N-Based Transannular Interactions in Some Model Fused Medium-Sized Heterocyclic Systems and Implications for Drug Design

“…Ring-fused nitrogen heterocycles form important scaffolds in drug design and development [ 1 , 2 , 3 ]. Such compounds include many alkaloidal natural products, for example the bioactive protoberberine alkaloids such as berberine ( 1 ) [ 4 ] and coptisine ( 4 ) [ 5 ] and reduced derivatives like the dihydro- ( 2 and 5 ) [ 6 ] or tetrahydro-protoberberines ( 3 and 6 ) ( Figure 1 ) together with modified protoberberines [ 7 , 8 ] and [ 9 ] (pp. 65–68, 95–102).…”