A Concise Synthesis of Triazole Analogues of Lavendustin A via Click Chemistry Approach and Preliminary Evaluation of Their Antiparasitic Activity Against Trypanosoma cruzi

Abstract

Lavendustin A is a natural product isolated from the actinobacteria Streptomyces griseolavendus that presents a potent inhibitory activity on the Epidermal Growth Factor Receptor Protein Tyrosine Kinase (EGFR PTK). In addition, some of its analogues have also shown potent inhibitory activity against the polymerization of tubulin to microtubules, a pivotal process for the cell mitosis. From strategic structural modifications, two useful unprecedented alkynes bearing lavendustin A pharmacophoric subunit were rapidly accessed. Next, a set of novel triazole analogues of lavendustin A were synthesized in good yields employing CuI‐catalyzed azide‐alkyne cycloadditions (CuAAC) under mild conditions. Furthermore, preliminary evaluation of their biological activity against the epimastigote stage of Trypanosoma cruzi points towards promising trypanocidal properties.

Click chemistry: A fascinating, Nobel-winning method for the improvement of biological activity

“…As a result of their antiproliferative activity for the breast cancer stem cells, four triazole products exhibited much more potent activity than promising starting material Ironomycin. By following a similar approach, Carvalho et al [76] tried to get higher biological activity by modifying Lavendustin A, a natural product that presents strong tyrosine kinase inhibitory feature along with anticancer activity (Figure 7). Also, inspired by the antiproliferative and anti-infective activities of its synthetic derivatives, they searched for the antiprotozoal activity of ten triazole bioisosteric analogs of Lavendustin A.…”

“…Within the context of nucleic acid-based therapeutics, the researchers reported that viral loads and virus induced cytotoxicity were reduced by five-fold by their siRNA in cell lines challenged with SARS-CoV-2. Analogs of Betulin CuAAC Anticancer activity [73] Analogs of Solithromycin CuAAC Antibacterial activity [74] Analogs of Salinomycin CuAAC Antiproliferative activity against cancer stem cells [75] Analogs of Lavendustin A CuAAC Antiprotozoal/antiparasitic activity [76] siRNA-peptide conjugate through alkyne containing RNA and azido-peptide CuAAC Anti-SARS-CoV-2 activity [77] Derived from enolizable carbonyl compounds, primary amines and 4-nitrophenyl azide…”