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Puberulic acid (1)7, stipitatic acid (2)8 and viticolins A and B (3, 4) as novel natural products have been isolated from a culture broth of Penicillium viticola 9 FKI-4410 through our screening system and found to have promising antimalarial activity (Fig. 1)10, 11. In these highly-oxygenated 7-membered aromatic compounds, 1 shows the most potent antimalarial activity in vitro against the Plasmodium falciparum K1 (chloroquine-resistant) parasite strain (IC50 = 0.050 µM), as well as in vivo efficacy with 69% inhibition for a dose of 2 mg/kg × 4 through subcutaneous (s.c.) administration in 4-day suppressive test using a P. berghei-infected mouse model12. However, 1 exhibits toxicity in vivo, four out of five mice dying by day 3, after a s.c. dose of 5 mg/kg × 2 (day 0 and 1). While structually simple compounds such as tropone (5), tropolone (6) and hinokitiol (8), and natural 2 and 3 showed weaker activity than that of 1, 7-hydroxytropolone (7)13 was much more potent, exhibiting a >18-fold stronger IC50 value of 6.44 µM than that of 5. This observation suggested that the presence of more than three contiguous oxygen atoms in a compound might significantly affect antimalarial activity. These results stimulated us to undertake a structure-activity relationship (SAR) study based on the establishment of a total synthetic route, aiming to create new antimalarial candidates which retained potency but which were non-toxic. Furthermore, we expected that these compounds’ properties, especially low molecular weight and simple planar structures, could be invaluable for antimalarial drug leads with respect to ease of supply14, enabled by efficient and practical synthesis. Herein, we report the divergent synthesis of several related troponoids, including natural products, via utilization of the established total synthetic route of 1 15, and biological evaluation of their in vitro antimalarial activity and cytotoxicity.

要約:

Puberulic acid (1)は、Penicillium viticola FKI-4410の培養液から単離された新規天然物質であり、in vitroおよびin vivoで優れた抗マラリア活性を示した。しかし、マウスを用いたin vivo試験において、5 mg/kg を2回皮下投与したところ、5匹中4匹が3日目までに死亡するという毒性が観察された。この毒性が問題となるため、構造活性相関研究を行い、毒性が低く活性の高い新規抗マラリア薬の開発を目指すこととした。

[Antimalarial troponoids, puberulic acid and viticolins; divergent synthesis and structure-activity relationship studies | Scientific Reports](https://www.nature.com/articles/s41598-017-07718-3)

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