Bioactive seven-membered oxacycles derived from a Diverted Total Synthesis (DTS) strategy Maria Victoria Sinka and Juan Ignacio Padrón Peña 1 Instituto de Productos Naturales y Agrobiología (IPNA-CSIC), Spain The concept of diverted total synthesis, which involves the systematic modification of natural products, is a potent approach for studying the mechanistic aspects of their biological activity. 1 Thus, because of the total synthesis of two laurexanes called (+)-isolaurepinnacin and (+)-neoisoprelaurefucin, 2 and taking advantage of the DTS strategy, we decided to evaluate these natural products and non-natural intermediates biologically (Figure 1).
Figure 1 . Lauroxane derivatives tested against different pathogenic microorganisms. The bioassays evaluated the efficacy of the tested compounds against two strains of amoebae ( Acanthamoeba castellanii Neff and Naegleria fowleri ) and three parasites ( Trypanosoma cruzi , Leishmania amazonensis , and Leishmania donovani ). These amoebae are responsible for causing two severe infectious diseases, granulomatous amoebic encephalitis, and primary amoebic meningoencephalitis, respectively, with a high mortality rate and limited therapeutic options available. The protozoan parasite Trypanosoma cruzi is responsible for Chagas disease, which is endemic in Latin America and is a zoonotic disease that affects several wild vertebrates and is transmitted to humans by insects (triatomines). Leishmaniasis is another significant tropical disease that is transmitted to humans by vectors. We have also collaborated to study cytotoxicity assays in three human cancer cell lines: U2OS (bone cancer), MOLT-4 (lymphoblastic leukemia), and HCT116 (colon cancer). Additionally, an antimicrobial investigation was conducted, involving various gram-positive bacteria ( S. aureus , M. luteus , E. faecium , B. cereus ) and gram- negative bacteria ( A. baumanii , E. cloacae , P . aeruginosa , K. oxytoca ), as well as the fungus C. neoformanns . Finally, due to external collaborations and the pandemic situation we have experienced, we have a lead compound that demonstrated effectiveness against the SARS-Cov-2 virus responsible for COVID-19. 3 Acknowledgments: This research was supported by the Ministerio de Ciencia e Innovación (MCIN), la Agencia Estatal de Investigación (AEI), and Fondo Europeo de Desarrollo Regional (FEDER). Grant PID2021-126747NB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe.” References 1. A. M. Szpilman, E. M. Carreira . Angew. Chem. Int. Ed. 2010 , 49 , 9592. 2. D. A. Cruz, V. Sinka, V. S. Martín, J. I. Padrón. J. Org. Chem . 2018 , 83 , 12632. 3. J. I. Padrón Peña, V. Sinka, R.Sanjuán Verdeguer, J. Dufloo, O. Schwartz. EP1641.1691. “Tri-substituted tetrahydrofurans and use thereof”. Spain, October 2021.
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© The Author(s), 2023
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