Discovery, Semisynthesis, Antiparasitic and Cytotoxic Evaluation of 14-Membered Resorcylic Acid Lactones and Their Derivatives

Abstract

Ten antifouling 14-membered resorcylic acid lactones 1-10 were isolated previously with low or trace natural abundance from the zoanthid-derived Cochliobolus lunatus fungus. Further optimization of fermentation conditions led to the isolation of two major natural compounds 7 and 8 with multi-gram quantities. By one or two steps, we semisynthesized the six trace natural compounds 1-6 and a series of derivatives 11-27 of compounds 7 and 8 with high yields (65-95%). Compounds 11-13 showed strong antiplasmodial activity against Plasmodium falciparum with IC₅₀ values of 1.84, 8.36, and 6.95 μM, respectively. Very importantly, 11 and 12 were non-toxic with very safety and high therapeutic indices (CC₅₀/IC₅₀ > 180), and thus representing potential promising leads for antiplasmodial drug discovery. Furthermore, 11 was the only compound showed obvious antileishmanial activity against Leishmania donovani with an IC₅₀ value of 9.22 μM. Compounds 11 and 12 showed the values of IC₅₀ at 11.9 and 17.2 μM against neglected Chagas' disease causing Trypanosoma cruzi, respectively.

Figure 1

Chemical structures of natural compounds 1–10 and their derivatives 11–27.

Figure 2

HPLC profiles for the EtOAc extract of metabolites in the media Medium I and Medium II.

Figure 3

Example of one or two-step semisyntheses of compounds 1, 2, 6, 13, and 16.

Figure 4

Semisynthesis of compound 6 and chemical conversion of 6 to 3–5.

Figure 5

Chemical interconversion of compounds 3–6 in MeOH.

Figure 6

The structure-activity relationships of RALs.