Synthesis of transfused oxacycles and evaluation against tuberculosis and Alzheimer's disease. CICLEIMER 2019

The biodiversity of the marine environment, both animal and plant, generates a vast number of metabolites of great interest, as they possess structural and bioactivity patterns not readily found in terrestrial products. In this respect, cyclic structures again occupy a prominent place, appearing in all their forms. Regarding size, cyclic structures can range from three members, the smallest possible size, to macrocycles of nine or more members, encompassing all sizes of small (four and five members) and medium-sized (six, seven, and eight members) cycles. In terms of functionality, oxygenated heterocycles and lactones are the most common functional groups. Among all these possibilities, medium-sized oxacycles, and particularly transfused oxacycle groups, are a very prevalent structural motif in marine secondary metabolites. Our research group has been working for several years on the idea of synthesizing transfused oxacyclic structures, with the aim of studying the relationship between structural complexity and the biological activities of these compounds. Starting from a low level of complexity and using synthetic tools developed by the group, such as iron salt-catalyzed Prins cyclization, we have successfully synthesized several examples of transfused compounds with tetrahydropyran-tetrahydropyran and tetrahydropyran-oxepan structures. The main objective and interest of this research lies in the generation of transfused oxacyclic compounds that possess therapeutic properties against diseases such as Alzheimer's and tuberculosis. To this end, we will increase the number of analogs for the transfused tetrahydropyran-tetrahydropyran and tetrahydropyran-oxepan systems. Specifically, we will modify the different functional groups to modulate pharmacokinetic and pharmacodynamic aspects. Once synthesized, their biological activities against Alzheimer's disease and tuberculosis will be tested. Furthermore, the effect of ring size changes will be explored, initially by generating tetrahydrofuran-oxepan derivatives. Finally, attempts will be made to obtain more complex derivatives containing three transfused oxacycles. After conducting the various in vitro biological assays, the compounds exhibiting the highest activity levels will be selected for subsequent in vivo assays to determine their therapeutic potential.

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ULL Team

• Daniel Alejandro Cruz Perdomo
• Miguel A. Ramírez Muño
• Celina E. García González