Strasseriolides A–D, A Family of Antiplasmodial Macrolides Isolated from the Fungus Strasseria geniculata CF-247251

Abstract

A novel family of four potent antimalarial macrolides, strasseriolides A−D (1−4), has been isolated from cultures of Strasseria geniculata CF-247251, a fungal strain obtained from plant tissues. The structures of these compounds, including their absolute configurations, were elucidated by HRMS, NMR spectroscopy, and X-ray single-crystal diffraction. The four compounds gave respective IC 50 values of 9.810, 0.013, 0.123, and 0.128 μM against Plasmodium falciparum 3D7 parasites with no significant cytotoxicity against the HepG2 cell line.

Preclinical evaluation of strasseriolides A–D, potent antiplasmodial macrolides isolated from Strasseria geniculata CF-247,251

“…Considering the absence of in vivo toxicity of strasseriolides C and D to mice and their potent in vitro activity against Plasmodium falciparum parasites, strain 3D7, with IC 50 values of 0.123, and 0.128 µM, respectively [ 1 ], the two compounds were further investigated in preliminary in vivo efficacy experiments. Strasseriolide D significantly lowered parasitaemia in vivo, as indicated by the measurement of Arbitrary Luminescence Units in comparison to the control vehicle (1.25 × 10 5 ± 1.04 × 10 5 vs. 5.07 × 10 5 ± 3.08 × 10 5 , p < 0.01) (Fig.…”

“…A recently described novel family of four macrolides, strasseriolides A – D (Fig. 1 ), isolated from the fungus Strasseria geniculata CF-247,251, exhibits IC 50 values between 0.013 and 9.810 µM against Plasmodium falciparum strain 3D7 whole parasites and is active against chloroquine resistant P. falciparum strain Dd2 parasites [ 1 ]. The discovery of novel active compound(s) marks a key milestone in the early stages of the complex, capital-intensive drug discovery process [ 2 ].…”

“…This is especially important in the case of natural products since compounds from this source may have an unusually complex chemistry with peculiar and hidden pharmacokinetic challenges. Bearing these considerations in mind, the recently discovered antiplasmodial natural macrolides (strasseriolides A – D ) [ 1 ] were subjected to a series of preclinical evaluation experiments that included, in vitro cytotoxicity in immortalized THLE-2 liver cells, cardiotoxicity screening using the FluxOR™ potassium assay in hERG expressed HEK cells, drug-drug interaction and metabolic stability in liver microsomes, and in vivo toxicity, PK and efficacy studies in mice. The data obtained from these studies identified strasseriolide D as the most promising compound that merits further investigation.…”

Pipecolisporin, a Novel Cyclic Peptide with Antimalarial and Antitrypanosome Activities from a Wheat Endophytic Nigrospora oryzae

“…1 H-NMR (500 MHz, DMSO-d 6 ) spectrum of pipecolisporin (1); Figure S6. 13 Figure S12. Chromatographic profile of the standard amino acids present in pipecolisporin (1) derivatized with L-FDVA; Figure S13.…”

“…Although historically plants have been the main source of antiplasmodial natural products [8], many antimicrobial secondary metabolites from fungal endophytes have also been described as potential antiprotozoal agents. These include, among others, altenusin [9], xylariaquinone A [10], codinaeopsin [11], fusaripeptide A [12], strasseriolides A-D [13], leucinostatins [14], griseofulvin [15], or trichodermin [16]. Other interesting biological properties exhibited by endophytic metabolites include antifungal, anti-inflammatory, antiproliferative, or anticancer activities [17].…”