“Unnatural” natural products obtained by direct halogenation of crude plant extracts: the case study of Arrabidaea brachypoda

While natural products (NPs) continue to be a source of inspiration for drug development in a majority of cases these compounds should be derivatised to be drugable. It is also estimated that around 20 percent of all therapeutic small molecule drugs are halogenated.1 Carbon-halogen bond lead to a wide range of effects, including an increase in thermal and oxidative stability and an increased biological membrane permeability. In this context we have recently developed a strategy for the generic halogenation of plant extracts to build libraries of original halogenated NPs for the search of new antimicrobial agents [1]. First the halogenation (bromination) reaction was performed and optimized with a series of NP standards from different chemical classes [2]. Once the reaction was successfully achieved, selected plant extracts were submitted to the same generic bromination procedure.

In the present work, the bromination reaction was applied to the dichloromethane extract of Arrabidaea brachypoda's roots (250 mg). This plant extract contains unusual dimeric flavonoids possessing strong in vivo and in vitro activities against Trypanosoma cruzi. The reaction was monitored by UHPLC-TOF-HRMS. After 24hs significant modification of the metabolites profile were observed suggesting the formation of new halogenated products. In order to target the isolation of the halogenated NPs, the analytical metabolite profiling conditions were geometrically transferred to semi-preparative HPLC. Using this approach a series of 11 halogenated NP analogues were isolated in one step and fully characterized by NMR and HRESIMS analyses. A chemical space analysis of these unnatural natural NPs demonstrated that the physico-chemical parameters were strongly modified and thus lead chemical novelty. Evaluations of the biological activity of the isolated compounds against Trypanosoma cruzi is under way.

[1] Mendez L. et al., ACS Comb Sci, 2011. 13:200 – 204.

[2]Bernini R. et al, New Journal of Chemistry, 2015. 39:2980 – 2987.