Structure modification, antialgal, antiplasmodial, and toxic evaluations of a series of new marine-derived 14-membered resorcylic acid lactone derivatives

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.

Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms

“…Harzialactone A ( 117 ) had the ability to overcome the transmembrane barriers to reach the macrophage phagolysosome, where amastigotes grow, and showed moderate activity against L. amazonensis promastigotes (IC 50 = 5.25 μg/mL). In addition, another polyketone isolated from Cochliobolus lunatus by Xu et al [ 70 ] (Derivatives 103 – 111 , Acyl derivatives 69 – 71 ) showed moderate antiplasmodial activity ( Table 1 ). The structure–activity relationships showed that biphenyl substituents at C-2, acetone at C-5′ and C-6′, and triple or quadruple substitution of acyl groups increased antiplasmodium activity.…”

In Silico and In Vitro Antiviral Activity Evaluation of Prodigiosin from Serratia marcescens Against Enterovirus 71

“…Consistent with our findings, most of these compounds were suggested to interfere with the early stages of the viral replication cycle (in adsorption, penetration, and RNA replication), except matrine, which was shown to regulate host immune response (in vivo). Since highly efficacious natural compounds are extremely difficult to discover, structural modification and derivative synthesis may be considered to enhance their efficacy (Lin et al, 2022;Xu et al, 2022). Furthermore, Shang, Xu, and Yin (2013) reported that 6-amino acid peptide (LVLQTM) was capable of binding the active site and inhibiting 2A protease (Falah et al, 2012), metrifudil and N6-benzyladenosine inhibited 2C helicase (Arita et al, 2008), and rupintrivir inhibited 3C protease ( Kuo et al, 2008;Cui et al, 2011;Tan et al, 2016).…”

Targeted isolation of antitubercular cycloheptapeptides and an unusual pyrroloindoline-containing new analog, asperpyrroindotide A, using LC–MS/MS-based molecular networking

“…Marine natural products (MNPs) have been recognized as a potential source of structurally novel and biologically active compounds that have yielded interesting chemical entities for drug discovery (Hai et al 2021 ; Newman et al 2020 ; Voser et al 2022 ; Xu et al 2022 ). More than 30 thousand new MNPs have been isolated from different marine organisms over the last 60 years (Blunt et al 2018 ; Carroll et al 2021 ).…”