Abstract
Marine natural products play critical roles in the chemical defense of many marine organisms and are essential, reputable sources of successful drug leads. Sixty-seven 14-membered resorcylic acid lactone derivatives 3–27 and 30–71 of the natural product zeaenol (1) isolated from the marine-derived fungus Cochliobolus lunatus were semisynthesized by chlorination, acylation, esterification, and acetalization in one to three steps. The structures of these new derivatives were established by HRESIMS and NMR techniques. All the compounds (1–71) were evaluated for their antialgal and antiplasmodial activities. Among them, 14 compounds displayed antifouling activities against adhesion of the fouling diatoms. In particular, 9 and 34 exhibited strong and selective inhibitory effects against the diatoms Navicula laevissima and Navicula exigua (EC50 = 6.67 and 8.55 μmol/L), respectively, which were similar in efficacy to those of the positive control SeaNine 211 (EC50 = 2.90 and 9.74 μmol/L). More importantly, 38, 39, and 69–71 showed potent antiplasmodial activities against Plasmodium falciparum with IC50 values ranging from 3.54 to 9.72 μmol/L. Very interestingly, the five antiplasmodial derivatives displayed non-toxicity in the cytotoxicity assays and the zebrafish embryos model, thus, representing potential promising antiplasmodial drug agents. The preliminary structure–activity relationships indicated that biphenyl substituent at C-2, acetonide at positions C-5′ and C-6′, and tri- or tetra-substituted of acyl groups increased the antiplasmodial activity. Therefore, combining evaluation of chemical ecology with pharmacological models will be implemented as a systematic strategy, not only for environmentally friendly antifoulants but also for structurally novel drugs.
Highlights
Marine natural products play critical roles in the chemical defense of many marine organisms and in some cases can influence the community structure of entire ecosystems (Bhadury et al 2006; Paul et al 2007)
14-Membered resorcylic acid lactones (RALs) are polyketide natural products with a 14-membered macrocyclic ring fused to a resorcylic acid residue (Jana and Nanda 2018)
Molecular mechanism studies revealed that cochliomycin A affected the cytochrome P450, glutathione S-transferase (GST), and NO/cGMP pathways, among which the NO/cGMP pathway was considered to play a key role in barnacle larval settlement (Wang et al 2016)
Summary
Marine natural products play critical roles in the chemical defense of many marine organisms and in some cases can influence the community structure of entire ecosystems (Bhadury et al 2006; Paul et al 2007). In our previous investigation for bioactive natural 14-membered RALs, cochliomycin A with the acetonide moiety, isolated from the marine-derived fungus Cochliobolus lunatus, showed significant antifouling activity against the larval settlement of the barnacle Balanus Amphitrite at the concentration of 1.2 μg/mL (Shao et al 2011). Total syntheses of paecilomycins E (Reddy et al 2019) and F, cochliomycin C, 6-epi-cochliomycin C (Kadari et al 2018), monocillin VII (Mallampudi et al 2019), 5′-hydroxyzearalenone, 5′β-hydroxyzearalenone (Thiraporn et al 2017), L-783290, L-783277 (Chakraborty et al 2020), paecilomycin B, 6′-epi-paecilomycin B (Ohba and Nakata 2018), zeaenol, and 7-epi-zeaenol (Doda et al 2019; Mohapatra et al 2014) were accomplished and reported Given their intriguing antifouling and antiplasmodial properties and attractive chemical structures, this family of macrolides has attracted a growing interest in the fields of medicinal chemistry and organic chemistry
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