The fungistatic activity of ethylenic and acetylenic compounds; the fungistatic activity of tetraiodoethylene and related compounds

The high fungistatic activity of tetraiodoethylene has been investigated. Diiodo-acetylene, which like tetraiodoethylene is an unsaturated substance containing only carbon and iodine, has also been found to have a high antifungal action. The effect of replacing the iodine atoms in these compounds by hydrogen, bromine, and carboxyl and nitro groups has been studied. The high fungistatic activity of some iodoethylenic and iodoacetylenic compounds appears to be associated with the presence in the molecule of positive iodine.     

The fungistatic activity of ethylenic and acetylenic compounds; esters of halogenofumaric acids and acetylene dicarboxylic acid

A series of derivatives of acetylene dicarboxylic, halogenofumaric and related acids have been prepared and their fungistatic activities assessed. The lower halogeno- and thiocyanofumarates and acetylene dicarboxylates are highly fungistatic. The mode of action of these compounds is discussed.     

Relation between the molecular electrostatic potential and activity of some FF-MAS related sterol compounds

Follicular Fluid-Meiosis Activating Sterol (FF-MAS) is a compound important for maturation of gametes in mammals. Therefore, it may serve as a lead compound for a novel method of contraception. We studied the Molecular Electrostatic Potential of a series of active and inactive analogues of FF-MAS. We find that double bond configurations required for activity result in a local negative electrostatic potential which is larger as well as more dense compared to those of inactive molecules. We therefore hypothesize that the interaction energy of the double bond system of the MAS compounds with its receptor substantially contributes to the overall interaction energy. This notion is supported by interaction studies of the electrostatic potential originating from the double bonds in crystal structures of cholesterol and four MAS-derived Delta(8,14) structures synthesized and crystallized by us. In addition, we were able to derive a pharmacophore model that relates the local average ESP and its distance to the 3beta-OH oxygen atom to the activity of the molecules.     

Anti-HIV-1 protease activity of compounds from Boesenbergia pandurata

Searching for anti-HIV-1 protease (PR) inhibitors of Thai medicinal plants led to the isolation of a new cyclohexenyl chalcone named panduratin C (1) and chalcone derivatives (2-6) from the methanol extract of Boesenbergia pandurata rhizomes. The known compounds were identified to be panduratin A (2), hydroxypanduratin A (3), helichrysetin (4), 2',4',6'-trihydroxyhydrochalcone (5), and uvangoletin (6). The structures of all compounds were elucidated on the basis of chemical and spectroscopic methods. It was found that 3 possessed the most potent anti-HIV-1 PR activity with an IC50 value of 5.6 microM, followed by 2 (IC50 = 18.7 microM), whereas other compounds exhibited only mild activity. Structure-activity relationships of these compounds on anti-HIV-1 PR activity are summarized as follows: (1) hydroxyl moiety at position 4 conferred higher activity than methoxyl group; (2) prenylation of dihydrochalcone was essential for activity; (3) hydroxylation at position 4' reduced activity; and (4) introduction of double bond at C1' and C6' of chalcone gave higher activity. As regards active constituents contained in B. pandurata rhizomes, hydroxypanduratin A (3) and panduratin A (2) are active principles against HIV-1 PR.     

Effect of phenolic compounds on abscisic acid-induced stomatal movement: Structure – activity relationship

Application of abscisic acid (ABA) brings about stomatal closure within 30 min in epidermal peels of Vicia faba . A number of phenolic compounds antagonise the effect of ABA. Derivatives of benzoic acid, cinnamic acid, coumarin and flavonoids have been studied in order to establish structure – activity relationship. Derivatives of benzoic acid reverse the ABA effects. Coumarin, esculetin and three hydro derivatives of cinnamic acid fail to show the anti-ABA activity. Thus, the presence of parahydroxyl group and double bond in the side chain is necessary for anti-ABA activity.     

Fungistatic activity of different Indian soils againstFusarium udum Butler

Summary The fungistatic activity of different Indian soils againstF. udum, causing wilt disease of pigeon-pea, has been assessed in relation to soil pH and organic matter. Correlation co-efficient between soil characteristics and fungistasis has been calculated to evaluate relationship. High fungistatic activity was exhibited generally by the soils having low pH but high organic matter. The soils exhibiting high fungistatic activity againstF. udum have low incidence of wilt disease of pigeon-pea. There was no definite correlation between volatile and non-volatile fungistasis and, therefore, the origins of volatile and non-volatile fungistasis are different. In the usual biological limit pH had insignificant impact on fungistasis.     

Study of the role of iron in the anticryptococcal activity of human serum and fluconazole

Anticryptococcal activity of human serum and apotransferrin in RPMI 1640 was studied in vitro. The effects of varying concentrations of FeCl₃ on this activity was investigated. Possible synergy of serum and apotransferrin with fluconazole was also measured. The fungistatic activity of human serum, whether lyophilized, stored at 4 °C, fresh frozen or purchased from commercial sources vs. Cryptococcus neoformans was comparable. There was no significant loss of fungistatic activity after freezing and thawing the serum up to 10 times. The fungistatic activity of human serum was similar when tested in different tissue culture media with the exception of Medium 199. The addition of apotransferrin (2.0 or 0.2 mg/ml) to RPMI 1640 had an inhibitory effect on cryptococcal growth. This effect was reversed by 20 M of FeCl₃ at both apotransferrin concentrations. By contrast, addition of FeCl₃ to human serum and RPMI 1640 did not reverse inhibition of growth. Fluconazole synergized with the human serum preparations described, but not with pooled commercial serum, for fungicidal activity. Synergistic activity of fluconazole and human serum was not affected by the addition of FeCl₃. Apotransferrin did not show any synergistic fungicidal activity with fluconazole.     

Molecular docking analysis of bioactive compounds from Mollugo cerviana (L.) SER with DHFR for antifungal activity

Fungal infections have been increasing in recent years due to growing number of high-risk patients particularly immuno compromised hosts. Candida is the third- or fourth-most-common isolate in nosocomial bloodstream infections. The increase of fungal resistance to classical drugs, the treatment costs, and the fact that most available antifungal drugs have only fungistatic activity, justify the search for new strategies. Identification of therapeutic compounds from plants has been the centre of attraction ever since they were discovered. It is of interest to document the molecular docking analysis of bioactive compounds present in Mollugo cerviana (L.) SER with the DHFR protein target for antifungal activity. We show the optimal binding features of several compounds from the extract with in vivo and in vitro activities. Results of this showed that all compounds showed good antimicrobial activity and a very good antifungal activity against the target DHFR protein. So, these compounds may act as potential drug molecules after the experimental validation.     

Effect of alkyl side chain variation on the electron-transfer activity of ubiquinone derivatives

The effect of the alkyl side chain of the ubiquinone molecule on the electron-transfer activity of ubiquinone in mitochondrial succinate-cytochrome c reductase is studied by using synthetic ubiquinone derivatives that possess the basic ubiquinone structure of 2,3-dimethoxy-5-methyl-1,4-benzoquinone with different alkyl side chains at the 6-position. The alkyl side chains vary in chain length, degree of saturation, and location of double bonds. When a ubiquinone derivative is used as an electron acceptor for succinate-ubiquinone reductase, an alkyl side chain of six carbons is needed to obtain the maximum activity. However, when it serves as an electron donor for ubiquinol-cytochrome c reductase or as a mediator in succinate-cytochrome c reductase, an alkyl side chain of 10 carbons gives maximal efficiency. Introduction of one or two isolated double bonds into the alkyl side chain of the ubiquinone molecule has little effect on electron-transfer activity. However, a conjugated double bond system in the alkyl side chain drastically reduces electron-transfer efficiency. The effect of the conjugated double bond system on the electron-transferring efficiency of ubiquinone depends on its location in the alkyl side chain. When location is far from the benzoquinone ring, the effect is minimal. These observations together with the results obtained from photoaffinity-labeling studies lead us to conclude that flexibility in the portion of the alkyl side chain immediately adjacent to the benzoquinone ring is required for the electron-transfer activity of ubiquinone.     

Antifungal activity displayed by cereulide, the emetic toxin produced by Bacillus cereus

In this study, the fungistatic activity of Bacillus cereus cereulide-producing strains was demonstrated against nine fungal species. The role of cereulide was confirmed using plasmid-cured derivatives and ces knockout mutants. The fungistatic spectra of cereulide and valinomycin, a chemically related cyclododecadepsipeptide, were also compared and found to be similar but distinct.     

Structure-activity relationships for unsaturated dialdehydes. 1. The mutagenic activity of 18 compounds in the Salmonella/microsome assay

A considerable number of terpenes that contain an "unsaturated dialdehyde" functionality, and possess various biological activities, such as antimicrobial activity, pungency, antifeedant activity, and/or mutagenicity, have been isolated from natural sources. However, large qualitative and quantitative activity differences have been observed for the natural unsaturated dialdehydes, and small structural changes (e.g., stereoisomerization) seem to dramatically affect the biological activity. As part of a general attempt to study structure-activity relationships for unsaturated dialdehydes, the activity of compounds 1-18 (Table 1) in the Salmonella/microsome assay (strains TA98, TA2637 and TA100) has been investigated. 10 of the compounds were found to possess direct-acting mutagenic activity, although the mutagenic potencies vary considerably in this group (from 430 to 0.32 revertants per nmole in the Salmonella strain TA2637). Some structural features that appear to moderate the activity are discussed. The necessity of an intact unsaturated dialdehyde functionality for the mutagenic activity of isovelleral (1) (see Scheme 1 for names, numbers, and chemical structures) in the Salmonella/microsome assay was demonstrated by chemical conversions: modification of either aldehyde group or reduction of the double bond led to loss of activity.     

Coupled-enzyme system for the determination of lipase activity

A new method for lipase activity determination is described, in which liberation of fatty acids by lipase-catalyzed hydrolysis is coupled to lipoxygenation. The second reaction forms hydroperoxy-fatty acids containing a conjugated double bond that are detected at 234 nm. The method is sensitive, cheap and easy to use when compared to a titration method.     

In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature

The echinocandins anidulafungin and micafungin and the triazole posaconazole are currently undergoing phase III clinical trials. Caspofungin and voriconazole have recently been licensed for the treatment of aspergillosis (both agents), other less common mould (voriconazole) and candidal (caspofungin) infections. This review summarizes the published in vitro data obtained by NCCLS or NCCLS modified methods on the in vitro fungistatic and fungicidal activities of these five agents for yeasts and moulds in comparison to the established agents, amphotericin B, fluconazole, itraconazole, and flucytosine. Among the yeasts, the echinocandins have less activity for Candida parapsilosis and Candida guilliermondii, no activity for Cryptococcus neoformans and Trichosporon spp., but good fungistatic and fungicidal activity in vivo and in vitro for most of the other Candida spp.; this fungicidal activity has been reported by minimum fungicidal concentrations (MFCs) or time kill curve results. The new triazoles exhibit good fungistatic activity (but not fungicidal) for most Candida spp., C. neoformans, and Trichosporon spp. For the Aspergillus spp. evaluated, the echinocandins have similar or better fungistatic activity than those of amphotericin B and the triazoles, but fungicidal activity has been demonstrated only with amphotericin B and the triazoles, with the exception of fluconazole. Most studies showed posaconazole and voriconazole minimum inhibitory concentrations (MICs) ranging from 0.25 to 8 microg/ml for non-solani Fusarium spp., while MIC and minimum effective concentration (MEC) endpoints of the echinocandins were >8 microg/ml. The fungistatic activity of the triazoles is also superior to that of the echinocandins for most of the dimorphic fungi and the Zygomycetes. However, micafungin has activity for the mould phase of most dimorphic fungi, but not for the parasitic or yeast phase of Paracoccidioides brasiliensis. The echinocandins appear to have variable and species dependent fungistatic activity for the dematiaceous fungi, but all agents have poor or no activity against most isolates of Scedosporium prolificans. Only amphotericin B exhibit good fungistatic activity against the Zygomycetes. The combination of caspofungin with some triazoles, amphotericin B or liposomal amphotericin B has been synergistic in vitro, in animal models and in patients. Breakpoints are not available for any mould and antifungal agent combination. In vitro/in vivo correlations should aid in the interpretation of these results, but standard testing conditions are needed for the echinocandins, especially for mould testing, to obtain reliable results.     

Prostaglandins and congeners XXIII (1). Synthesis of 15-deoxy-16-hydroxy-16-methylprostanglandins. The importance of the C13--C14 trans double bond for bronchodilator activity.

The synthesis and bronchodilator activity in the guinea pig of several 15-deoxy-16-hydroxy-16-methylprostaglandin analogs is described. The E2 (VIa) and E1 (VIb) analogs are potent bronchodilators comparable in activity to the natrual prostaglandins, but possessing a longer duration of effect. Replacement of the C13--C14 trans double bond by a cis double bond or an ethylene linkage causes a substantial diminishment of this activity.     

Inhibitory effects of resveratrol derivatives from dipterocarpaceae plants on tyrosinase activity

Stilbene derivatives, which are resveratrol (3,4',5-trihydroxy-trans-stilbene) oligomers ranging from monomer to tetramer, isolated from Dipterocarpaceae plants were tested for their inhibitory effects against murine tyrosinase activity. The structure-activity relationships obtained in this study suggest that the double bond in the stilbene skeleton is critical for the inhibition, and also that molecular size is important for inhibitory potency.     

A single amino acid determines the catalytic efficiency of two alkenal double bond reductases produced by the liverwort Plagiochasma appendiculatum

Alkenal double bond reductases (DBRs) catalyze the NADPH-dependent reduction of the α,β-unsaturated double bond of many secondary metabolites. Two alkenal double bond reductase genes PaDBR1 and PaDBR2 were isolated from the liverwort species Plagiochasma appendiculatum. Recombinant PaDBR2 protein had a higher catalytic activity than PaDBR1 with respect to the reduction of the double bond present in hydroxycinnamyl aldehydes. The residue at position 56 appeared to be responsible for this difference in enzyme activity. The functionality of a C56 to Y56 mutation in PaDBR1 was similar to that of PaDBR2. Further site-directed mutagenesis and structural modeling suggested that the phenol ring stacking between this residue and the substrate was an important determinant of catalytic efficiency.     

A novel surfactant nanoemulsion with a unique non-irritant topical antimicrobial activity against bacteria, enveloped viruses and fungi

A novel non-ionic surfactant nanoemulsion designated 8N8 has been tested for its biocidal activity. One percent 8N8 produced effective bactericidal activity against Bacillus cereus, Bacillus subtilis, Haemophilus influenzae, Neisseria gonorrhoeae, Streptococcus pneumoniae, and Vibrio cholerae in 15 minutes. In contrast, most enteric gram-negative bacteria were resistant to 8N8. One percent 8N8 was also virucidal within 15 minutes for all tested enveloped viruses, including Herpes simplex type 1, influenza A and vaccinia viruses. One percent 8N8 also demonstrated fungistatic activity on Candida albicans. The rapid and non-specific inactivation of vegetative bacteria and enveloped viruses, in addition to its fungistatic activity and low toxicity in experimental animals, makes 8N8 a potential candidate for use as a topical biocidal agent.     

Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group

A series of A-ring pyrrole derivatives of duocarmycin bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. New Seg-B analogues bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group containing double bond as spacer had lower peripheral blood toxicity than the derivatives bearing 5',6',7'-trimethoxyindole-2'-carboxyl group in Seg-B of the natural type. Moreover, most of them exhibited potent antitumor activity against in vivo murine tumor models.     

Synthesis and antimycotic activity of N-azolyl-2,4-dihydroxythiobenzamides

N-pyrazole and N-1,2,4-triazole derivatives of 2,4-dihydroxythiobenzamide prepared from sulfinyl-bis-(2,4-dihydroxythiobenzoyl) and commercially available azole amines were tested for their antimycotic activity. The chemical structure of compounds was confirmed by IR, 1H NMR, MS and elemental analysis. The MIC values against the reference strain Candida albicans ATCC 10231, azole-resistant clinical isolates of Candida albicans and non-Candida albicans species were determined for their potential activity in vitro. The compounds exhibited comparable or higher activity than itraconazole and fluconazole tested under the same experimental conditions. Pyrazoline derivatives showed higher activity than other analogues. The strongest fungistatic activity for N-(2,3-dimethyl-1-phenyl-1,2-dihydro-5-oxo-5H-pyrazol-4-yl)-2,4-dihydroxythiobenzamide was found with MIC values significantly lower than those for the studied drugs.     

The effect of corticosteroids on serum fungistatic activity

The direct impairment of a serum fungistatic factor has been postulated as a mechanism to account for the greater severity of cutaneous fungal disease in patients treated with corticosteroids.Trichophyton mentagrophytes andTrichophyton rubrum were grown on Mycosel® agar containing increasing concentrations of normal human sera and sera from patients with Cushing's syndrome and from those receiving high doses of prednisone. Fungistatic activity, observed as a retardation of the normal growth pattern, was not significantly different in any of the sera tested.