Synthesis and Structure–Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruzi

Abstract

Trypanosoma cruzi is the etiologic agent of Chagas disease, which affects over seven million people, especially in developing countries. Undesirable side effects are frequently associated with current therapies, which are typically ineffective in the treatment of all stages of the disease. Here, we report the first synthesis of the neolignan dehydrodieugenol B, a natural product recently shown to exhibit activity against T. cruzi. Using this strategy, a series of synthetic analogues were prepared to explore structure–activity relationships. The in vitro antiparasitic activities of these analogues revealed a wide tolerance of modifications and substituent deletions, with maintained or improved bioactivities against the amastigote forms of the parasite (50% inhibitory concentration (IC50) of 4–63 μM) and no mammalian toxicity (50% cytotoxic concentration (CC50) of >200 μM). Five of these analogues meet the Drugs for Neglected Disease Initiative (DNDi) “hit criteria” for Chagas disease. This work has enabled the identification of key structural features of the natural product and sites where scaffold modification is tolerated.

Discovery of New Hits as Antitrypanosomal Agents by In Silico and In Vitro Assays Using Neolignan-Inspired Natural Products from Nectandra leucantha

“…CoMFA and CoMSIA techniques employ probe atoms (in general, a positively charged sp 3 carbon) to obtain molecular interaction fields and a range of different similarity indices, respectively, that are related to the biological data [ 26 , 39 ]. To construct CoMFA and CoMSIA models, we used the molecular alignment based on the technique known as maximum common substructure (MCS) of the training molecules (grid spacing = 2 Å, and energy cut-off = 30 kcal/mol) [ 26 , 39 ]. To construct the CoMFA models, we calculated molecular interaction (steric and electrostatic) fields by using a probe atom from the Lennard–Jones and Coulomb potentials, respectively [ 26 ].…”

“…To construct CoMFA and CoMSIA models, we used the molecular alignment based on the technique known as maximum common substructure (MCS) of the training molecules (grid spacing = 2 Å, and energy cut-off = 30 kcal/mol) [ 26 , 39 ]. To construct the CoMFA models, we calculated molecular interaction (steric and electrostatic) fields by using a probe atom from the Lennard–Jones and Coulomb potentials, respectively [ 26 ]. Regarding the CoMSIA models, different similarity indices (steric, electrostatic, hydrophobic, H-bond donor, and H-bond acceptor) were obtained.…”

“…To select the best models, the values of q 2 LOO were analyzed and the selected models were also optimized using the option “region focus”. It is important to mention that the grid spacing was varied (1 to 4 Å), as well as the weight factor (from 0.3 to 1.5) [ 26 ].…”

“… 1 : IC 50 and CC 50 for compounds 9 – 33 and 36 – 50 were reported at references [ 8 , 10 , 26 ]; 2 : IC 50 , 50% inhibitory concentration against amastigote forms of T. cruzi ; 3 : CC 50 , 50% cytotoxic concentration in NCTC cells (ATCC, clone 929), NA, not active at 30 μM; 4 : SI: selectivity index (ratio CC 50 /IC 50 ); Bzd: benznidazole. …”

Virtual Screening Based on Ligand and Structure with in vitro Assessment of Neolignans against Trypanosoma cruzi

“…7 As neolignans are a diverse group of chemical structures present in several plant families and responsible for multiple biological activities, we chose to investigate the trypanomicidal potential of a set of neolignans. [8][9][10][11] Some studies [12][13][14] have reported the importance of neolignans as promising compounds in the treatment against T. cruzi.…”