Synthesis of Cyclotetrapeptides Analogues to Natural Products as Herbicides.

The synthesis of cyclotetrapeptides analogues of the natural products tentoxin and versicotide D was achieved in good yield by solid phase peptide synthesis (SPPS) of their linear precursors and solution phase cyclization. All the cyclopeptides and several open precursors were evaluated as herbicides. Five cyclopeptides and five lineal peptides showed a significant inhibition (>70%) of Ryegrass seed's radicle growth at 67 µg/mL. The evaluation at lower concentrations (4−11 µM) indicates two cyclopeptides analogs of tentoxin, which present one (N-Methyl-d-Phe), and two N-MeAA (N-Methyl-Ala and N-Methyl-Phe), respectively, as the most active of them, showing remarkable phytotoxic activity. In two cases, the open precursors are as active as their corresponding cyclopeptide. However, many linear peptides are inactive and their cyclization derivatives showed herbicidal activity. In addition, two cyclopeptide analogues of versicotide D showed more improved activity than the natural product. The results indicate that the peptide sequence, the amino acid stereochemistry and the presence of N-methyl group have important influence on the phytotoxic activity. Moreover, several compounds could be considered as lead candidates in the development of bioherbicides.

Synthesis and antiplasmodial assessment of nitazoxanide and analogs as new antimalarial candidates.

During the last years, the progression to control malaria disease seems to be slowed and WHO (World Health Organization) reported a modeling analysis with the prediction of the increase in malaria morbidity and mortality in sub-Saharan Africa during the COVID-19 pandemic. A rapid way to the discovery of new drugs could be carried out by performing investigations to identify drugs based on repurposing of "old" drugs. The 5-nitrothiazole drug, Nitazoxanide was shown to be active against intestinal protozoa, human helminths, anaerobic bacteria, viruses, etc. In this work, Nitazoxanide and analogs were prepared using two methodologies and evaluated against P. falciparum 3D7. A bithiazole analog, showed attractive inhibitory activity with an EC50 value of 5.9 µM, low propensity to show toxic effect against HepG2 cells at 25 µM, and no cross-resistance with standard antimalarials.

Synthesis of Cyclopeptides Analogues of Natural Products and Evaluation as Herbicides and Inhibitors of Cyanobacteria.

Natural products derived from plants or microorganisms have been considered as eco-friendly herbicides with application in crop protection. Several natural cyclopeptides have been reported as herbicides, while others have been identified as inhibitors of cyanobacteria. In this work, the syntheses of cyclotetrapeptides and cyclopentapeptides analogues of natural products were successfully performed by solid-phase peptide synthesis of their linear precursor and solution-phase macrolactamization. Four of the obtained peptides and cyclopeptides present phytotoxicity with more than 70% of radicle growth inhibition at 67 µg/mL. In addition, evaluation of 20 peptides and cyclopeptides, as inhibitors of cyanobacteria, rendered five active compounds that reduced the concentration of microcystins in the culture medium.