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Various species of berries have been reported to contain several polyphenolic compounds, such as anthocyanins and flavonols, which are known to possess high antioxidant activity and may be beneficial for human health. To our knowledge, a thorough chemical analysis of polyphenolics in species of these plants native to Newfoundland, Canada has not been conducted. The primary objective of this study was to determine the polyphenolic compounds present in commercial extracts from Newfoundland berries, which included blueberries (V. angustifolium), lingonberries (V. vitis-idaea) and black currant (Ribes lacustre). Anthocyanin and flavonol glycosides in powdered extracts from Ribes lacustre and the Vaccinium species were identified using the high performance liquid chromatographic (HPLC) separation method with mass spectrometric (MS) detection. The identified compounds were extracted from dried berries by various solvents via ultrasonication followed by centrifugation. A reverse-phase analytical column was employed to identify the retention time of each chemical component before submission for LC–MS analysis. A total of 21 phenolic compounds were tentatively identified in the three species. Further, we tested the effects of the lingonberry extract for its ability to protect neurons and glia from trauma utilizing an in vitro model of cell injury. Surprisingly, these extracts provided complete protection from cell death in this model. These findings indicate the presence of a wide variety of anthocyanins and flavonols in berries that grow natively in Newfoundland. These powdered extracts maintain these compounds intact despite being processed from berry fruit, indicating their potential use as dietary supplements. In addition, these recent findings and previous data from our lab demonstrate the ability of compounds in berries to protect the nervous system from traumatic insults.

Chlorogenic acid is a well known natural product with important bioactivities. It contains an ester bond formed between the COOH of caffeic acid and the 3-OH of quinic acid. We synthesized a chlorogenic acid analogue, 3α-caffeoylquinic acid amide, using caffeic and quinic acids as starting materials. The caffeoylquinc acid amide was found to be much more stable than chlorogenic acid and showed anti-Hepatitis C virus (anti-HCV) activity with a potency similar to chlorogenic acid. The caffeoylquinc acid amide potently protected HepG2 cells against oxidative stress induced by tert-butyl hydroperoxide.

One-pot synthesis of (S)-2-(6-methoxynaphtalen-2-yl)propanoic acid, (S)-Naproxen using Preyssler and Keggin-type heteropolyacids as green and reusable catalysts A simple, clean and environmentally benign route to the enantioselective synthesis of (S)-2-(6-methoxynaphtalen-2-yl)propanoic acid, (S)-Naproxen 3 is described by using Preyssler heteropolyacid, H14[NaP5W30O110], as a green and reusable catalyst in water and in the presence of 1-(6-methoxynaphthalen-2-yl)propan-1-one 1, D-mannitol 2. The products were obtained in very good yields.

Alpha-glucosidases play important roles in the digestion of carbohydrates and biosynthesis of viral envelope glycoproteins. Inhibitors of alpha-glucosidase are promising candidates for the development of antitype II diabetics and anti-AIDS drugs. Here, we report the synthesis and alpha-glucosidase inhibitory activity of mono- and diketal/acetal derivatives of chlorogenic acid. The diketal derivatives showed more potent inhibitory activity than the monoketals. The 1,7-(5-nonanone) 3,4-(5-nonanone)-chlorogenic acid diketal showed remarkable inhibitory activity against alpha-glucosidases with potency better than that of 1-deoxynojirimycin hydrochloride. Four diasteremers of pelargonaldehyde diacetal and two of monoacetal derivatives of chlorogenic acid were synthesized in this study. They showed significant potent inhibition similar to or more potent than the ketal counterparts. Acetals with the alkyl chain oriented toward position 2 of chlorogenic acid showed more potent activity than those oriented toward position 6.

Derivatives of chlorogenic acid or its analogues were synthesized by coupling protected chlorogenic acid or its analogues with p-octyloxyaniline and selected amino acids. Most of the compounds exhibited significant potency against Cryptococcus neoformans and Candida species with low toxicity to brine shrimps. The 4,5-dihydroxyl groups in the quinic acid moiety were necessary for the activity and introduction of a free amino group increased the inhibitory activity against Aspergillus fumigatus.

Azolylalkylquinolines (AAQs) are a family of quinolines with varying degrees of cytotoxic activity (comparable or moderately superior to adriamycin in some cases) developed in the past decade in our group where their exact mode of action is still unclear. In this study the most probable DNA binding mode of AAQs was investigated employing a novel flexible ligand docking approach by using AutoDock 3.0. Forty-nine AAQs with known experimental inhibitory activity were docked onto d(CGCAAATTTGCG)(2), d(CGATCG)(2) and d(CGCG)(2) oligonucleotides retrieved from the Protein Data Bank (PDB IDs: 102D, 1D12 and 1D32, respectively) as the representatives of the three plausible models of interactions between chemotherapeutic agents and DNA (groove binding, groove binding plus intercalation and bisintercalation, respectively). Good correlation (r(2)=0.64) between calculated binding energies and experimental inhibitory activities was obtained using groove binding plus intercalation model for phenyl-azolylalkylquinoline (PAAQ) series. Our findings show that the most probable mode of action of PAAQs as DNA binding agents is via intercalation of quinolinic moiety between CG base pairs with linker chain and azole moiety binding to the minor groove.

Ursolic acid and 2α-hydroxyursolic acid isolated from apple peels were found to show growth inhibitory activity against four tumor cell lines, HL-60, BGC, Bel-7402 and Hela. Structural modifications were performed on the C-3, C-28 and C-11 positions of ursolic acid and the cytotoxicity of the derivatives was evaluated. The SAR revealed that the triterpenes possessing two hydrogen-bond forming groups (an H-donor and a carbonyl group) at positions 3 and 28 exhibit cytotoxic activity. The configuration at C-3 was found to be important for the activity. Introduction of an amino group increased the cytotoxicity greatly. A 3β-amino derivative was 20 times more potent than the parent ursolic acid. The 28-aminoalkyl dimer compounds showed selective cytotoxicity.

Several new and known 2-(4-substituted phenyl)-3(2H)-isothiazolone derivatives with or without chloro substituent at C-5 position were synthesized and their in vitro antibacterial activity against selected Gram-negative and Gram-positive bacteria were evaluated using agar dilution method. Most of compounds exhibited moderate to high activities against tested microorganisms, and in comparison with the reference drugs some compounds showed comparable or higher activities. In contrast to results of the previous studies, some 5-chloro derivatives showed lower or comparable activities against some tested microorganism, in comparison with analogues without C-5 substitution. In general, most of the compounds bearing electron withdrawing group at 4-position of the phenyl ring were more active against Gram-positive and most of those having piperazine derivatives were more active against Gram-negative bacteria.

The functions and biosynthesis of sterols have been effective targets for fungal control in different areas, including pharmaceutical and agricultural applications. Fungi are among the organisms that synthesize sterols, principally ergosterol. In this paper, the effect of dibutyryl-cAMP (db-cAMP) on ergosterol level and the interaction of drugs that would change the concentration of cAMP with antifungal drugs have been investigated. Sterols were extracted from Candida albicans, and ergosterol was measured using the gas chromatography method. The interaction of different agents was measured by the broth dilution method. It was found that phosphodiesterase inhibitors reverse the inhibitory activity of azole antifungal drugs. Evaluating the ergosterol level of C. albicans incubated with db-cAMP revealed that it increased ergosterol level. Further experiments provided evidence attributing the observed interaction between azoles and phosphodiesterase inhibitors to the relationship between ergosterol and cAMP. The possible significance of this interaction includes potentiation of antifungal activity of drugs by manipulating the cAMP level.Key words: ergosterol, cAMP, phosphodiesterase inhibitor, antifungal.

The constituents and antifungal activity of Diplotaenia damavandica, a rare native plant growing in Iran, were investigated. A methanolic extract of D. damavandica was obtained. The fractionation and isolation of the components was performed using column chromatography and HPLC. Bioassayguided isolation of the extract led to the purification of four coumarin compounds, angelicin, libanorin, psoralen and auraptene. The antifungal activity against Candida albicans, Cryptococcus neoformans and Cladosporium cucumerinum was tested. The cytotoxicity of the fractions against the human KB cell line was evaluated. We conclude that the main antifungal component of D. damavandica is an angular furanocoumarin. The antifungal activity and low cytotoxicity of angelicin make it a potentially useful target for further research.

The increasing clinical importance of drug-resistant fungal pathogens has lent additional urgency to microbiological and antifungal research. Various thiazolo(or 1,2,3-thiadiazolo)thiosemicarbazides (2a-2e), 3-thiono-1,4-dihydrotriazolothiazoles-(or 1,2,3-thiadiazoles) (3a-3e), their related substituted thio-4H-1,2,4-triazoles (4a-4p) and sulfones (5a-5o) were synthesized. Most of the compounds tested for antifungal activity exhibited significant effects against Cryptococcus neoofrmans and Sacchromyces cerevisiae at MIC ranges of 0.53 to 12.5 micrograms/mL, whereas their activities were moderate against Candida albicans and weak against Aspergillus fumigatus. At 10 ppm concentration, all compounds showed low toxicity on brine shrimps (higher than 80% survival), except compounds 4c and 2c. At 100 ppm concentration most of the compounds showed toxicity except compounds 2b, 2e, 3c, 3d, 3e, and 4e. Compounds 4b, 4c, and 4h showed in vitro cytotoxicity against Kbalb cell lines and compounds 4c and 4g against 143B cell lines at 0.1 mM concentration.

The pharmacokinetics and distribution in tissue of several novel triazole antifungal agents were studied in different animal species in order to select an appropriate lead compound. The purpose of the study was also to determine species differences in pharmacokinetics for SYN azoles to select the most appropriate species for secondary efficacy and toxicological evaluation of the selected compound. SYN-2836, SYN-2869, SYN-2903, and SYN-2921 were rapidly absorbed into the systemic circulation and reached maximum concentrations ( C max s) of 7.31 ± 2.53, 6.29 ± 0.85, 6.16 ± 0.39, and 3.41 ± 0.34 μg/ml, respectively, in BALB/c mice after administration of an oral dose of 50 mg/kg of body weight, with bioavailability being greater than 45% in all mice. The areas under the concentration-time curve from time zero to infinity (AUC 0–∞ s) after administration of a single intravenous dose of 20 mg/kg to mice varied between 25.0 and 63.6 μg · h/ml. The half-life was in the range of 4.5 to 6 h. In Sprague-Dawley rats there was no significant difference in AUC 0–∞ after administration of a single intravenous dose of 20 mg/kg, but on oral administration, the bioavailability of SYN-2836 was extremely low, while that of SYN-2869 was only 14.7%. In New Zealand White rabbits the C max and the time to reach C max for SYN-2836 and SYN-2869 after administration of a single oral dose of 50 mg/kg were similar. There were significant differences in AUC 0–∞ and half-life between SYN-2836 and SYN-2869. On the other hand, in beagle dogs the C max and AUC 0–∞ of SYN-2836 after administration of a single oral dose of 30 mg/kg were 4.82 ± 1.54 μg/ml and 41.8 ± 15.7 μg · h/ml, respectively, which were threefold higher than those of SYN-2869. The concentrations of the SYN compounds in tissue indicated that the AUC 0–∞ s of SYN-2836, SYN-2869, SYN-2903, and SYN-2921 in mouse lungs were significantly different from each other. The ratios of the concentrations of the SYN azoles in lungs to those in plasma were also significantly different from those for itraconazole. Among the SYN azoles the highest concentration in the lungs was found for SYN-2869. The higher level of distribution of SYN-2869 into lung tissue was considered to contribute to the potent efficacy in respiratory tract infection models compared with the potency of itraconazole. Significant differences in the pharmacokinetics of these compounds were observed in different animal species, and selection of an animal model for further evaluation was based on results obtained from these studies.

A simple and rugged reversed-phase high-performance liquid chromatographic method with ultraviolet absorbance detection at 263 nm was developed and validated for the analysis of novel triazole antifungal agents SYN-2869 and its derivatives in tissues. The method involved homogenization with 0.01 M phosphate buffer (pH 7.8) for lung, brain and spleen tissues. The liver and kidneys were homogenized with acetonitrile:acetone (1:1). The plasma proteins were precipitated with ice-cold acetonitrile and supernatent was evaporated to dryness. The reconstituted samples were injected onto an HPLC system. SYN-2869 was separated from the matrix components on a symmetry C(18) column using a aqueous mobile phase of acetonitrile and water with a flow rate of 1 mL/min. A step gradient of 40-80% acetonitrile eluted SYN-2869 and the internal standard (SYN-2506). The linear range was 0.5-10 microgram/g (r(2) > 0.99). The limit of quantitation was 0.5 microgram/g. The inter-day precision and accuracy for SYN 2869 standard concentration were from 2.6 to 7.4% and from -1.56 to +3.29%, respectively. The method was applied to tissue samples collected from single intravenous administration to mice to evaluate the distribution of these novel antifungal agents to different tissues.

Novel catalytic synthesis of 6,7-dimethoxyisatin with the use of heteropolyacids (HPAs) as acid solid catalyst An efficient method for the preparation of 6,7-dimethoxyisatin and its derivatives was developed with good yield by using Preyssler-type heteropolyacid (HPA) as acid catalyst under green conditions. The comparison between Keggin type heteropolyacids, H3[PW12O40], H4[SiW12O40] and H4[SiMo12O40], H3[PMo12O40] and mineral acids with Preyssler's anion shows that the latter possess better catalytical activity than the other heteropolyacids and no degradation of the structure was observed.

Two new phenylpropanoid glycosides, [4-(3- β - d -glucopyranosyloxy-1- E -propenyl)-2,6-dimethoxyphenyl]-6- O - β - d -gluco pyranosyl- β - d -glucopyranoside and [4-(3-hydroxy-1- Z -propenyl)-2,6-dimethoxyphenyl]-6- O - β - d -glucopyranosyl- β - d -gluco pyranoside were isolated from the root of Stellera chamaejasme along with four known phenylpropanoid glycosides, coniferinoside, syringin, syringinoside, sinapyl alcohol 1,3-diglucopyranoside. Their structures were established on the basis of spectral and chemical evidence.

A new flavonoid, 3-[1-[[3-di(4-hydroxyphenyl)methyl]2,4,6-trihydroxyphenyl]3-di(4-hydroxyphenyl)1-propanone-2-yl]5,7-dihydroxy-4H-1-benzopyran-4-one, named mohsenone was isolated from the root of Stellera chamaejasme together with chamaechromone and (−)-epiafzelechin 7-O-β- d -glucopyranoside and their structures were elucidated by spectral analyses.

The synthesis of a series of azole antifungal compounds which incorporate the aminimide functional moiety is described. The procedure involves the reaction of an epoxide intermediate with 1,1-disubstituted hydrazines to form aminimines which are subsequently treated with acyl chlorides resulting in the desired zwitterionic aminimides. The aminimides were tested for in vitro antifungal activity and found to be moderately active against Candida and Cryptococcus species, but inactive versus Aspergillus.

Crude extracts from 40 Iranian and Canadian plants were tested for their antifungal activity against several species of Aspergillus, Candida, and Cryptococcus. Of the 40 plant extracts, 26 (65%) showed activity against at least one fungal strain. The extracts with the most wide spectrum of activity were related to Diplotaenia damavandica, Heracleum persicum, Sanguisorba minor, and Zataria multiflora. The high percentage of activity among the studied plants might be attributed to the non-random nature of the selection. A total number of eight factors was used to select the plants in this study. Cytotoxicity test in KB cells was performed on some of the most promising plant extracts. Diplotaenia damavandica and Bunium persicum were found to exhibit the lowest cytotoxicity among the plants studied.

The(1)H-NMR signals of 2-cephems and 3-cephems have been assigned and the Nuclear Overhauser Effect (NOE) study of these compounds was undertaken.

The syntheses of various azolylalkylquinoline derivatives in which the nature of the linkage between the quinoline and azolylalkyl moieties of the molecule were altered are described. The compounds were tested for cytotoxic activity towards cancer cells and compound 27 was found to exhibit moderate in vivo activity in a murine sarcoma model.

Novel polycyclic quinoline-based heterocycles, structurally modeled on a promising antineoplastic agent, are synthesized.

Sticking point in the formation of the 1,3-thiazeto[3,2-a]quinoline skeleton is a cyclization step using the system vicinal dihaloalkane / potassium iodide as a controlled source of iodine monobromide which halogenates the carbon α to the thiol.

Taxane group of diterpenoids 2 and 3 which possess cinnamoyl moiety at C-5 position underwent selective cleavage to C-5 hydroxy compounds 4 and 5 on treatment with hydroxylamine. The resulting compounds were characterised based on their spectral data.

A facile synthesis of justicidin B is described, as well as related podophyllum lignans by employing Michael Initiated Ring Closure strategy followed by desulfurization mediated by nickel-containing complex reducing agent.

1. A commercially-available human cytochrome P450 isozyme (CYP2D6) preparation was used in imipramine metabolism studies. This isozyme catalysed both aromatic C-oxidation and N-demethylation. 2-Hydroxyimipramine was the major metabolite; desipramine was isolated in a significant amount and 2-hydroxydesipramine was a trace metabolite. 2. To prevent decomposition of metabolites during the analytical procedure, the metabolism mixture was derivatized with acetic anhydride prior to extraction, and the derivatized metabolites were separated and quantified by g.l.c. with N/P detection. The analytical procedure had excellent sensitivity and was capable of routinely quantifying imipramine and its metabolites down to the 0.36 nmol level. 3. In excess of 90% of drug and metabolites was consistently recovered when metabolism was conducted over a 5-60-min duration. 4. The formation of the secondary metabolite, 2-hydroxydesimipramine, from imipramine proceeds by two pathways, via desipramine and via 2-hydroxyimipramine; the former is the preferred pathway. 5. CYP2D6 catalyses C-hydroxylation of imipramine to 2-hydroxyimipramine more efficiently than its N-demethylation to desipramine. Also, the C-hydroxylation of imipramine to 2-hydroxyimipramine proceeds more efficiently than the conversion of desipramine to 2-hydroxydesipramine.

The synthesis of beta-lactamase inhibitory activity of a series of sodium 6-[(1-heteroarylthioethyl-1,2,3-triazol-4-yl)methylene]pe nicillanate, 1,1-dioxides are described. Their activity was compared with tazobactam and sulbactam. The Z-isomers were more active than the E-isomers. The in vitro activity of the Z-isomers of the phenylthiadiazole derivatives (13a and 15a) was better than sulbactam against the tested beta-lactamases and comparable to tazobactam especially against TEM-2 and cephalosporinase. But their synergistic activity with five antibiotics was inferior to tazobactam.

The synthesis of a series of azole antifungal compounds which incorporate the aminimide functional moiety is described. The procedure involves the reaction of an epoxide intermediate with 1,1-disubstituted hydrazines to form aminimines which are subsequently treated with acyl chlorides resulting in the desired zwitterionic aminimides. The aminimides were tested for in vitro antifungal activity and found to be moderately active against Candida and Cryptococcus species, but inactive versus Aspergillus.

In our continued research on chlorogenic acid analogues and derivatives with improved bioactivity, we have synthesized some caffeoyl 5,6-anhydroquinic acid derivatives. The 1,7 acetonides of chlorogenic acid (15), and of the mono-caffeoyl 5,6-anhydroquinic acids (7-8) showed appreciable anti-HIV activity. The 3,4-dicaffeoyl 5,6-anhydroquinic acid (12) exhibited an anti-HIV activity twice as that of 3,5-dicaffeoylquinic acid (22). The caffeoyl 5,6-anhydroquinic acid derivatives displayed potent anti-oxidant activities. The mono-caffeoyl 5,6-anhydroquinic acids (10-11) were more than twice stronger than chlorogenic acid (21) on SOD-like activity.

Life-threatening fungal infections have increased dramatically in recent decades in immunocompromised patients. An estimated 40% of all deaths from hospital-acquired infections are due to infections caused by opportunistic fungi. The current treatment options are either causing serious toxicity, or becoming inactive against the drug-resistant fungal strains. Thus, the discovery and development of new antifungal agents that are economically feasible, have excellent therapeutic value, and address the problems of toxicity and species resistance is very important. We have recently designed and synthesized a series of chlorogenic acid-based peptidimimetics using structure-based methodology starting with cyclic peptides of the candin class of antifungals. These novel and totally synthetic compounds exhibit promising antifungal activity against pathogenic fungi with very low toxicity against brine shrimps. The possible novelty in their mechanism of action and economically feasible synthetic approach are the attractive features of this class of compounds that make them different from the already utilized antifungal agents.

1. The in vivo metabolism of iprindole in rat is described. Each rat received a single dose of iprindole (10 mg/kg) and urine was collected for 48 h. 2. Fourteen metabolites of iprindole were isolated from rat urine after enzymic hydrolysis and their structures were determined by a computerized g.l.c.-mass spectrometric technique, before and after appropriate chemical derivatization. 3. Three concurrent metabolic pathways have been identified for iprindole in rat; aromatic ring hydroxylation is a minor pathway. 4. This is the first reported comprehensive study on the in vivo metabolism of iprindole in rat.

The in vitro antifungal activity of several N2-phenyl-3(2H)-isothiazolones substituted at C4 of the phenyl moiety with heterocyclic nucleus or groups of different physico-chemical properties against four human pathogenic fungi was determined by broth macrodilution method; results were compared with those obtained with itraconazole and ketoconazole. These isothiazolones showed moderate to high activity against some or all tested strains and in comparison with the reference drugs, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g), 5-chloro-2-phenylisothiazol-3-one (1c), 4-[4-(5-chloro-3-oxo-3H-isothiazol-2-yl)phenyl]-1,4-dihydrotriazol-5-one (1s) and 2-(4-nitrophenyl)isothiazol-3-one (2g) against Aspergillus niger, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g) and 4-[4-(5-chloro-3-oxo-3H-isothiazol-2-yl)phenyl]piperazine-1-carboxamide (1q) against Trichophyton mentagrophytes had comparable activity, compounds 1g and 2g showing higher activity against Microsporum canis. Antifungal activity was favored by the presence of chlorine at C5 of the isothiazolone and/or the presence of nitro group or heterocyclic nucleus at C4 of the phenyl ring and proper hydrophilicity of the molecule.

An HPLC-PAD-MS(n) method was employed to profile the phenolic compounds of the aerial part of Artemisia pectinata (Neopallasia pectinata), a plant with no previous reports concerning its phenolic constituents. Three isomers of trans-caffeoylquinic acid accompanied by cis-5-caffeoylquinic acid, six isomers of trans-dicaffeoylquinic acid, two isomers of methyl trans-dicaffeoylquinate (including one new isomer), a trans-caffeoylferuloylquinic acid and three flavanoids were identified unambiguously by analysis of their UV and MS(n) spectra in comparison with standard compounds that were isolated from natural sources, or synthesised, or were surrogate standards (green coffee extract). Other compounds were identified by analysis of their UV and MSn data in comparison with those reported in the literature. MS(n) experiments also suggested the presence of groups of dicaffeoylquinic acid glycosides, caffeoylquinic acid diglycosides, caffeoylquinic acid glycosides and quinic acid diglycosides.

A simple HPLC-PAD-MS method was established to quantitatively analyse two spiroether isomers (cis-en-yn-dicycloether and trans-en-yn-dicycloether) and the main coumarin, herniarin, in chamomile herbs, simultaneously. By using this method, the contents of these three compounds in the flowers of two chamomile species, Roman chamomile (Chamaemelum nobile) and pineapple weed (Matricaria matricarioides), as well as in different parts of pineapple weed, were investigated. It was found that the flowers of both herbs contained large amounts of cis-en-yn-dicycloether and trans-en-yn-dicycloether, with the trans-form being more abundant than the cis-form. The leaves of pineapple weed were found to have the highest concentration of cis-en-yn-dicycloether and herniarin than the other parts. HPLC-PAD-MS-guided isolation and identification of other constituents are also discussed. Copyright © 2006 John Wiley & Sons, Ltd.

Several new and known 2-(4-substituted phenyl)-3(2H)-isothiazolone derivatives with or without chloro substituent at C-5 position were synthesized and their in vitro antibacterial activity against selected Gram-negative and Gram-positive bacteria were evaluated using agar dilution method. Most of compounds exhibited moderate to high activities against tested microorganisms, and in comparison with the reference drugs some compounds showed comparable or higher activities. In contrast to results of the previous studies, some 5-chloro derivatives showed lower or comparable activities against some tested microorganism, in comparison with analogues without C-5 substitution. In general, most of the compounds bearing electron withdrawing group at 4-position of the phenyl ring were more active against Gram-positive and most of those having piperazine derivatives were more active against Gram-negative bacteria.

The in vitro and in vivo activities of four azole compounds belonging to a new series of 2(2,4-difluorophenyl)-3-(4-substituted piperazin-1-yl)-1-(1,2,4-triazol-1-yl) butanol antifungal agents is described. The compounds were selected from a library of azole compounds synthesized by our group. The in vitro activities of Syn2869, Syn2836, Syn2903, and Syn2921 against a panel of over 240 recently collected clinical isolates of yeast and molds were determined, and the results were compared with those obtained with fluconazole (FLC), itraconazole (ITC), and amphotericin B (AMB). The MICs at which 90% of the isolates were inhibited (MIC 90 s) for the four test compounds for strains of Candida spp. ranged from Candida albicans and other Candida sp. strains. Moreover, MIC 90 s for strains of Cryptococcus neoformans , Aspergillus spp., Trichophyton spp., and Microsporum spp. were also low and ranged from C. albicans in a murine systemic infection model and significantly improved the survival rates of the infected mice. The results for Syn2903 were similar to those for FLC, while the other compounds were slightly less effective but had ranges of activities similar to the range of activity of ITC. The compounds were also evaluated against an Aspergillus fumigatus systemic infection. Syn2903 was also superior to ITC, whereas the efficacy data for the other compounds were similar to those for ITC. It was concluded from the data generated for this new series of azole compounds in the studies described above that further pharmacokinetic and toxicologic evaluations are warranted prior to selection of a candidate compound for preclinical testing.

The increasing clinical importance of drug-resistant fungal pathogens has lent additional urgency to microbiological and antifungal research. Various thiazolo(or 1,2,3-thiadiazolo)thiosemicarbazides (2a-2e), 3-thiono-1,4-dihydrotriazolothiazoles-(or 1,2,3-thiadiazoles) (3a-3e), their related substituted thio-4H-1,2,4-triazoles (4a-4p) and sulfones (5a-5o) were synthesized. Most of the compounds tested for antifungal activity exhibited significant effects against Cryptococcus neoofrmans and Sacchromyces cerevisiae at MIC ranges of 0.53 to 12.5 micrograms/mL, whereas their activities were moderate against Candida albicans and weak against Aspergillus fumigatus. At 10 ppm concentration, all compounds showed low toxicity on brine shrimps (higher than 80% survival), except compounds 4c and 2c. At 100 ppm concentration most of the compounds showed toxicity except compounds 2b, 2e, 3c, 3d, 3e, and 4e. Compounds 4b, 4c, and 4h showed in vitro cytotoxicity against Kbalb cell lines and compounds 4c and 4g against 143B cell lines at 0.1 mM concentration.

A simple reversed-phase high-performance liquid chromatography (HPLC) method with UV detection was developed and validated for the quantitation of SYN-2869, a novel triazole antifungal agent and its analogs in rat plasma. The method involved a simple precipitation of plasma protein with acetonitrile (1:10 ratio). The reconstituted sample after evaporation to dryness was injected onto a HPLC column. SYN-2869 and its analogs were separated from the matrix components on a symmetry C18 column using an aqueous mobile phase of acetonitrile and water with a flow rate of 1 ml min(-1). A step gradient of 40-80% acetonitrile eluted all four compounds. The run time was 30 min. The linear range was 0.5 10 microg ml(-1)(r2 > 0.999). The limit of quantitation was 0.5 microg ml(-1). The inter-day precision and accuracy for SYN-2869 standard concentration were from 1.9 to 8.5% and from 1.4 to +/- 4.40%, respectively. The precision and accuracy of intra-day quality control samples were from 4.6 to 5.2% and from 4.6 to 12%, respectively.

The emergence of fungal infections due to the increase in the number of immunocompromised patients has become a matter of concern. Among the available sources for treating fungal infections, natural products can play a significant role. In this article, we have tried to categorize the different sources and chemical classes of fungitoxic agents as following: (1) animal sources such as defensins and other peptides, (2) plant sources such as terpenoids, flavonoids, and coumarins, (3) fungal metabolites like fatty acids, sugar derivatives and polyenes and (4) bacterial sources such as amino acids. The potentials of coumarins, which are mainly distributed in four plant families, Umbelliferae, Rutaceae, Leguminosae and Compositae, have been uncovered in this respect. In addition to antifungal property, the other bioactivities of coumarins include: anticoagulant, antibacterial, antiparasitie, anticancer, photodynamic, edema relieving, anti-inflammatory, radical scavenging, lipolytic, antiplatelet, and anti-allergic properties. Studies in structure-antifungal activity relationships of coumarins, which is presented here, reveal the essential strucutral features for their activity. In order to have a better understanding of the mode of action of coumarins, the cellular sites and the interactions of coumarins with biological systems have been explained. Effects on the enzymes gyrase and topoisomerase, and photodynamic reaction with lipids, proteins and DNA are among the main issues discussed. In this respect, morphological changes of Candida albicans cells due to coumarins, which are studied by scanning electron microscopy (SEM), support their biochemical effects.

Myristic acid analogs that are putative inhibitors of N-myristoyl-transferase were tested in vitro for activity against yeasts (Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans) and filamentous fungi (Aspergillus niger). Several (+/-)-2-halotetradecanoic acids including (+/-)-2-bromotetradecanoic acid (14c) exhibited potent activity against C. albicans (MIC = 39 microM), C. neoformans (MIC = 20 microM), S. cerevisiae (MIC = 10 microM), and A. niger (MIC < 42 microM) in RPMI 1640 media. Improved synthetic methods have been developed for the synthesis of 12-fluorododecanoic acid (12a) and 12-chlorododecanoic acid (12c). Three novel fatty acids, 12-chloro-4-oxadodecanoic acid (8a), 12-phenoxydodecanoic acid (12i), and 11-(4-iodophenoxy)-undecanoic acid (13d) were also synthesized and tested.