Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin.

With drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the Plasmodium-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of Streptomyces strain PR3, a group of cyclodepsipeptides, including valinomycin, and a novel class of cyclic ethers were identified and elucidated. Further study revealed that the ethers were cyclic polypropylene glycol (cPPG) oligomers that had leached into the bacterial culture from an extraction resin. Molecular dynamics analysis suggests that these ethers are able to bind cations such as K+, NH4+ and Na+. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity in vitro. The IC50 of valinomycin against P. falciparum NF54 improved by 4-5-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 ± 0.77 ng/mL to 0.90 ± 0.2 ng/mL and 0.75 ± 0.08 ng/mL when dosed in the fixed ratios of 3:2 and 2:3 of valinomycin to cPPGs, respectively. Each fixed ratio combination displayed cytotoxicity (IC50) against the Chinese Hamster Ovary cell line of 57-65 µg/mL, which was lower than that of valinomycin (12.4 µg/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial.

Isolation, Characterization and Antiproliferative Activity of New Metabolites from the South African Endemic Red Algal Species Laurencia alfredensis.

The marine red algae of the genus Laurencia have been widely studied for their structurally diverse and biologically active secondary metabolites. We report here the natural product investigation of the organic extract of a newly identified South African endemic species, Laurencia alfredensis. A sequence of column chromatography, preparative TLC and normal phase HPLC resulted in the isolation of eleven compounds comprising three labdane-type diterpenes (1-3), four polyether triterpenes (4-7), three cholestane-type ecdysteroids (8-10) and a glycolipid (11). Compounds 1-3, 5-8 and 10 have not previously been reported, while compound 9 is reported here for the first time from a natural source and the known compound 11 isolated for the first time from the genus Laurencia. The structural elucidation and the relative configuration assignments of the compounds were accomplished by extensive use of 1D- and 2D-NMR, HR-ESI-MS, UV and IR spectroscopic techniques, while the absolute configuration of compound 1 was determined by single-crystal X-ray diffraction analysis. All compounds were evaluated against the MDA-MB-231 breast and HeLa cervical cancer cell lines. Compound 2 exhibited low micromolar antiproliferative activity (IC50 = 9.3 µM) against the triple negative breast carcinoma and compound 7 was similarly active (IC50 = 8.8 µM) against the cervical cancer cell line.

Antimicrobial and in silico studies of the triterpenoids of Dichapetalum albidum.

Here we report a new polyhydroxylated triterpene, 2ß,6ß,21α-trihydroxyfriedelan-3-one (4) isolated from the root and stem bark of Dichapetalum albidum A. Chev (Dichapetalaceae), along with six known triterpenoids (1-3, 5, 6, 8), sitosterol-3ß-O-D-glucopyranoside (9), a dipeptide (7), and a tyramine derivative of coumaric acid (10). Friedelan-3-one (2) showed an antimicrobial activity (IC50) of 11.40 µg/mL against Bacillus cereus, while friedelan-3α-ol (1) gave an IC50 of 13.07 µg/mL against Staphylococcus aureus with ampicillin reference standard of 19.52 µg/mL and 0.30 µg/mL respectively. 3ß-Acetyl tormentic acid (5) showed an IC50 of 12.50 µg/mL against Trypanosoma brucei brucei and sitosterol-3ß-O-d-glucopyranoside (9) showed an IC50 of 5.06 µg/mL against Leishmania donovani with respective reference standards of IC50 5.02 µg/mL for suramin and IC50 0.27 µg/mL for amphotericin B. Molecular docking of the isolated compounds on the enzyme glucose-6-phosphate dehydrogenase (G6PDH) suggested 3ß-acetyl tormentic acid (5) and sitosterol-3ß-O-D-glucopyranoside (9) as plausible inhibitors of the enzyme in accordance with the experimental biological results observed.

New dihydroxycucurbitacin D's from the Namib desert endemic plant Acanthosicyos horridus (!nara).

Acanthosicyos horridus Welw. ex Hook.f. (!nara) is a leafless, thorny, melon-producing plant endemic to the hyper-arid Namib Desert. The methanol crude extract prepared from the ripe fruits of !nara afforded the known dihydroxycucurbitacin 7ß-hydroxy-23,24-dihydrocucurbitacin D (1), along with four new congeners 7ß,15ß-dihydroxy-23,24-dihydrocucurbitacin D (2), 25-O-ß-glucopyranosyl-7ß-hydroxy-23,24-dihydrocucurbitacin D (3), 25-O-ß-glucopyranosyl-7ß-hydroxy-23,24-dihydroisocucurbitacin D (4) and 25-O-ß-glucopyranosyl-7ß-hydroxy-23,24-dihydro-3-epi-isocucurbitacin D (5). These compounds were isolated through a combination of preparative normal phase thin-layer chromatography (TLC) and semi-preparative reversed phase high performance liquid chromatography (HPLC). Their structures were established by comprehensive analysis of HR-ESI-MS data, 1D and 2D NMR spectroscopic data and by comparison with literature values of similar cucurbitacins. The five isolated compounds exhibited poor cytotoxic activity against the MDA-MB-231 breast cancer cell line. To the best of our knowledge, this is the first report of glycosylated cucurbitacins in Acanthosicyos horridus.