Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones dihydro analogues and photodimers

摘要

Previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines A and B to be modest growth inhibitors of Mycobacterium tuberculosis and a range of tropical diseases including Plasmodium falciparum and Leishmania donovani. In an effort to expand the structure-activity relationship of this compound class towards. infectious diseases, a library of natural product and natural product-like 4-methoxy-6-styryl-pyran-2-ones and a subset of catalytically reduced examples were synthesised. In addition, the photochemical reactivity of several of the 4-methoxy-6-styryl-pyran-2-ones were investigated yielding head-to-head and head-to-tail cyclobutane dimers as well as examples of asymmetric aniba-dimer A-type dimers. All compounds were evaluated for cytotoxicity and activity against M. tuberculosis, P. falciparum, L. donovani, Trypanosoma brucei rhodesiense and T. cruzi. Of the styryl-pyranones, natural product >3 and non-natural styrene and naphthalene substituted examples >13, 18, 21, 22 and >23 exhibited antimalarial activity (IC50 < 10 μM) with selectivity indices (SI) > 10. Δ Dihydro analogues were typically less active or lacked selectivity. Head-to-head and head-to-tail photodimers >5 and >34 exhibited moderate IC50s of 2.3 to 17 μM towards several of the parasitic organisms, while the aniba-dimer-type asymmetric dimers >31 and >33 were identified as being moderately active towards P. falciparum (IC50 1.5 and 1.7 μM) with good selectivity (SI ∼ 80). The 4-tert-butyl aniba-dimer A analogue >33 also exhibited activity towards L. donovani (IC50 4.5 μM), suggesting further elaboration of this latter scaffold could lead to the identification of new leads for the dual treatment of malaria and leishmaniasis.