Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages

Natural products isolated from plants are considered an important source of prototypes for the development of new drugs against tropical neglected protozoan diseases [1]. As a continuation of our previous studies with Brazilian plants with antitrypanosomal activity [2], the n-hexane extract from leaves of Nectandra leucantha (Lauraceae) displayed in vitro activity against T. cruzi. This extract was analyzed by HPLC/HRESIMS and subjected to a bioactivity-guided fractionation to afford four related neolignans: dehydrodieugenol B (1), 1-(8-propenyl)-3-[3′-methoxy-1′-(8-propenyl)-phenoxy]-4,5-dimethoxybenzene (2), 1-[(7S)-hydroxy-8-propenyl]-3-[3′-methoxy-1′-(8′-propenyl)-phenoxy]-4-hydroxy-5-methoxybenzene (3), and 1-[(7S)-hydroxy-8-propenyl]-3-[3′-methoxy-1′-(8′-propenyl)-phenoxy]-4,5-dimethoxybenzene (4). Chemical structures were determined by analysis of NMR, IR, UV and HRESIMS data. Isolated compounds were tested against intracellular amastigotes and extracellular trypomastigotes of T. cruzi and for mammalian cytotoxicity. Neolignan 4 showed the higher selectivity index (SI) against trypomastigotes (> 5) and amastigotes (> 13) of T. cruzi. The investigation of the mechanism of action demonstrated that neolignan 4 caused substantial alteration of the plasma membrane permeability, together with mitochondrial dysfunctions in trypomastigote forms. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compounds were non-mutagenic, non-carcinogenic, non-genotoxic, weak hERG blockers, with acceptable volume of distribution (1.66 – 3.32 L/kg), and low rodent oral toxicity (LD₅₀ 810 – 2,200 mg/kg). Considering some clinical events of cerebral Chagas disease, compounds 1 – 4 also demonstrated favorable properties, such as blood-brain barrier penetration. Unfavorable properties were also predicted as high promiscuity for P450 isoforms, high plasma protein binding affinity (> 91%), and moderate-to-low oral bioavailability. Finally, none of the compounds was predicted as interference compounds (PAINS). Considering the promising chemical and biological properties of the isolated neolignans, these compounds could be used as starting points to develop new lead compounds for Chagas disease.

[1] Newman DJ, Cragg GM. J Nat Prod 2016; 79: 629 – 661.

[2] Grecco SS, Costa-Silva TA, Jerz G et al. Phytomedicine 2017; 15: 62 – 67.