A glycosylated tetramic acid, virgineone (1), was isolated from saprotrophic Lachnum virgineum. The antifungal activity of the fermentation extract of L. virgineum was characterized in the Candida ...albicans fitness test as distinguishable from other natural products tested. Bioassay-guided fractionation yielded 1, a tyrosine-derived tetramic acid with a C-22 oxygenated chain and a beta-mannose. It displayed broad-spectrum antifungal activity against Candida spp. and Aspergillus fumigatus with a MIC of 4 and 16 microg/mL, respectively. Virgineone was also identified in a number of Lachnum strains collected from diverse geographies and habitats.
Isometric tension recordings and patch clamp methods were combined to explore the functional effects and mechanisms of action of 8-daucene-3,4-diol (CAF603), a carotane sesquiterpene isolated from ...the fungus
Trichoderma virens. CAF603 (1–100
μM) inhibited the spontaneous motility of guinea pig's portal vein, duodenum and ileum, and the Ca
2+-induced tension of depolarized ileum strips. These effects were not antagonized by either iberiotoxin or glyburide. CAF603 increased the spontaneous motility of guinea pig detrusor muscle, but inhibited the contraction induced by high-KCl, depolarizing salines. CAF603 blocked L-type Ca
2+ channel currents of rabbit cardiac myocytes. It is proposed that Ca
2+-entry blockade accounts for the inhibitory effects of CAF603 on smooth muscle contractility, whereas the stimulation of spontaneous motility of detrusor muscle is ascribed to blockade of Ca
2+-activated K
+ (BK
Ca) channel currents. The latter interpretation is consistent with the allosteric modulation of charybdotoxin binding to BK
Ca in smooth muscle membranes Lee et al., 1995. J. Nat. Prod. 58, 1822–1828.
Paraherquamide was identified recently as a potent anthelmintic agent. In this paper we describe the identification and characterization of a specific, high-affinity paraherquamide binding site in a ...membrane preparation isolated from the free-living nematode, Caenorhabditis elegans. 3H Paraherquamide bound specifically to C. elegans membranes with an apparent dissociation constant, Kd, of 263 nM. A series of paraherquamide analogs were examined, and their relative affinity for the paraherquamide binding site correlated with their nematocidal activity. Phenothiazines were the only other class of anthelmintics tested which inhibited specific 3Hparaherquamide binding. These results suggest that the anthelmintic activity of paraherquamide and phenothiazine is mediated via an interaction with a common binding site.
A potent modulator of the Maxi-K channel, isolated from
Arthrinium phaeospermum, has been determined to be a carotane sesquiterpene by spectroscopic means. X-ray crystallographic studies demonstrated ...this compound as being identical to CAF-603, previously discovered as an antifungal agent.
A potent modulator of the Maxi-K channel, isolated from
Arthrinium phaeospermum, has been determined to be a carotane sesquiterpene by spectroscopic means. X-ray crystallographc studies demonstrated this compound as being identical to CAF-603, previously discovered as an antifungal agent.
Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new ...antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.
The investigation of endo and exo-aryl substitutions and the discovery of the tert-butyl group as a central scaffold on the novel class of FLAP inhibitors are reported.
A search for a suitable ...replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the ...discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure–activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as 13, 14, and 23. Among these leads, compound 14 possessed favorable pharmacokinetic properties and an off-target profile, which supported additional profiling in an exploratory rat toxicology study.
![[3H]paraherquamide binding ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0006-2952/small "[3H]paraherquamide binding to Caenorhabditis elegans. Studies on a potent new anthelmintic agent")
