Candida inhibitory compounds

Xu, D. et al. 2007. Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albicans. PLoS Pathog. 3, e92. 

Compound 11 showed AChE inhibitory activity with an ICj, 19 pM. and weak antifimgal activity against Candida albicans with a minimum inhibitory concentration (MIC) value of 23 pg/ml. 

Antileukemic activity. Aucubin, in combination with caffeic acid, chlorogenic acid, ferulic acid, p-coumaric acid, and vanillic acid, exhibited weak antileukemic activity (inhibitory concentration [ICJjo 26-56 pg/ mL, international system of units 2-11) on human leukemia and lymphoma cell lines. Water-insoluble compounds, such as triterpenoids (oleanolic acid and ursolic acid), monotepene (linalool), and flavonoid (luteolin) produced strong activity " . Anti-nematodal activity. Water extract of the dried seed, at various concentrations, was active on Meloidogyne incognita Anti-yeast activity. Ethanol (80%) extract of the dried entire plant, on agar plate at a concentration of 1 mg/mL, was inactive on Candida albicans K... 

The enzyme was purified from Candida utilis in 1965 by Rosen et al. (8Q). Dried yeast was allowed to autolyze in phosphate buffer at pH 7.5 for 48 hr, and the enzyme was isolated in crystalline form from these autolysates by a procedure which included heating to 55° at pH 5.0, fractionation with ammonium sulfate, and purification on phospho-cellulose columns from which the enzyme was specifically eluted with malonate buffer containing 2.0 mM FDP. Crystallization was carried out by addition of ammonium sulfate in the presence of mM magnesium chloride. The Candida enzyme was more active than the mammalian FDPases at room temperature and pH 9.5 the crystalline protein catalyzed the hydrolysis of 83 /nnoles of FDP per minute per milligram of protein. The enzyme was completely inactive with other phosphate esters, including sedoheptulose diphosphate, ribulose diphosphate, and fructose 1- or fructose 6-phosphates. Nor was the activity of the enzyme inhibited by any of these compounds. Optimum activity was observed at concentrations of FDP between 0.05 and 0.5 mM higher concentrations of FDP (5 mM) were inhibitory. 

Bhandari et al. (56) modified a hit structure derived from the primary screening of various libraries (>300,000 compounds) on the zinc metalloenzyme phosphomannose isomerase from the yeast Candida albicans (CaPMI) to find enzyme inhibitors as jxitential antifungal agents. During primary screening only a 1296-member SP dipeptide pool library (Lll, Fig. 9.16) showed activity on the enzyme. Its deconvolution and analytical characterization led to the discovery of a by-product, derived from incomplete coupling, that showed activity on the enzyme. This compound (9.21, Fig. 9.16) showed a weak inhibitory activity on CaPMI (ICso = 40 xM) and was selected for further chemical profiling. 

It follows from the results that the antimicrobial properties of the studied pure compounds depend on their structure and substitution a. fraxetin (4), a 6-OMe-7,8-dihydroxycoumarin is a stronger inhibitor of S. aureus than esculetin (2), a 6,7- dihydroxycoumarin b. glucosidation decreases the inhibitory power of both types of dihydroxycoumarins c. the coumarins fraxin (3) and fraxetin (4) inhibit Candida species, while esculin (1) and esculetin (2) do not. 

Since the coumarin compounds show phosphodiesterase inhibitory activity, the observed change in the morphology of Candida albicans could be partly due to this property. Each Candida yeast cell can normally have a budding scar or the daughter cell still attached to it [319]. The possible cause of multibudding phenomenon could be PD inhibition. A similar observation was done in treatment with caffeine, which at the subinhibitory concentrations caused an increase in unusual modes of proliferation with signs of multiple budding in Candida albicans [320]. 

In the discovery of new antifungal compounds, Tsukuda and coworkers synthesized a nikkomycin analog library by Ugi condensation of uridine derivative 84, 59 carboxylic acids 85, 15 isocyanides 86, and an amino component attached to a Rink amide resin 87 (Figure 11.43). After cleavage from solid support, compounds 88 were tested for the enzyme inhibitory activity against Candida albicans chitin synthase 1. Among these derivatives, 246 samples exhibited more than 50% inhibition against this enzyme at a concentration of 10 tg/ml. 

Fluorocytosine - 5-Fluorocytosine is an antimetabolite of cytosine which is inhibitory to a limited number of saprophytic and parasitic fungi."" The relatively nontoxic compound is effective against experimental infections of Candida albicans and Cryntogoccus neoformans when administered orally or parenterally.o joy cTinical efficacy by oral therapy has been reported for systemic candidiasis and cryptococcosis with reversible side effects limited to a mild leukopenia, elevated transaminase levels, and a mild skin rash." > > After oral administration of 5-fluorocytosine-2i4C to rats, the known metabolites of 3 fluorouracil a-fluoro-0-ureido-propionic acid, urea, and CO2 were observed.In man the compound was recovered unchanged.Cultures of Cryptococcus neoformans collected prior to treatment were inhibited by 0 93-3"9 ig/ml, whereas cultures isolated 2-6 weeks after treatment were resistant to 1,000 ag/ml of 5-fluorocytoslne. 5... 

---