Semisynthesis, Antiplasmodial Activity, and Mechanism of Action Studies of Isocoumarin Derivatives

Abstract

In this study, eight natural isocoumarins (1−8) were isolated from a marinederived Exserohilum sp. fungus. To explore their structure−activity relationship and discover potent antimalarial leads, a small library of 22 new derivatives (1a−1n, 2a, 3a−3c, 4a−4c, and 7a) were semisynthesized by varying the substituents of the aromatic ring and the aliphatic side chains. The natural compound (1) and three semisynthetic derivatives (1d, 1n, and 2a), possessing an all-cis stereochemistry, exhibited strong antiplasmodial activity with IC 50 values of 1.1, 0.8, 0.4, and 2.6 μM, respectively. Mechanism studies show that 1n inhibits hemozoin polymerization and decreases the mitochondrial membrane potential but also inhibits P. falciparum DNA gyrase. 1n not only combines different mechanisms of action but also exhibits a high therapeutic index (CC 50 /IC 50 = 675), high selectivity, and a notable drug-like profile.

Trends of antimalarial marine natural products: progresses, challenges and opportunities

“…The compound 290 is water-soluble and has a high oral utilization rate without toxicity and carcinogenicity, which meet the requirements of drug-like lead compounds. 129 Tunicate Didemnum sp. was the source of lepadins D–F ( 292–294 ) that contained the unprecedented decahydroquinoline skeleton with strong antitrypanosomal activities and inhibitory activities against two strains of P. falciparum with IC 50 values of 0.4–33.0 μM (artemisinin, IC 50 = 4 × 10 −3 to 0.01 μM).…”

Talaromarins A–F: Six New Isocoumarins from Mangrove-Derived Fungus Talaromyces flavus TGGP35

“…In summary, 23 secondary metabolites, including six new isocoumarin derivative talaromarins A-F (1-6) and 17 known analogues (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) were obtained from the mangrovederived fungus Talaromyces flavus TGGP35. Compounds 6-11, 17-19 and 22 exerted similar or better antioxidant activity than the positive control trolox (IC 50 = 0.29 mM), with IC 50 values ranging from 0.009 to 0.27 mM.…”

“…[3][4][5][6][7][8]. Among them, isocoumarins are lactone-type derivatives derived from the polyketide pathway [9,10], and they possess a wide range of pharmacological activities such as antibacterial 7-hydroxyoospolactone and parapholactone [11], anti-inflammatory (±)-prunomarin A [12], cytotoxic lunatinin [13], insecticidal peniciisocoumarins A and B, antiplasmodial monocerin [14], antioxidant and α-glucosidase inhibitory penicimarin N [15], brine shrimp (Artemia salina) lethal and broad-spectrum antimicrobial penicimarins G-K [16,17], penicoffrazins B and C [18].…”

Marine natural products

“…265 Aperorydine G was isolated as a first time MNP and its absolute configuration determined as 809 , 266 and (12 S )-12-hydroxymonocerin 810 was also isolated as a new MNP. 267 Triquinane (−)-asperaculin A has been synthesised in a 13 step process employing biodivergent Baeyer–Villiger oxidation, 268 and steroid-sterigmatocystin heterodimer asperversin A has been prepared by an 11 step asymmetric method. 269 Chromanone A was synthesised from pyrocatechol in two sequences, the shortest of which comprised five steps, 270 and cyclohexadepsipeptides exumolides A and B were prepared via a method utilising solid- and solution phases.…”