Design, synthesis, and structure-activity relationship studies of l-amino alcohol derivatives as broad-spectrum antifungal agents.

To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of l-amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i, 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis, with MIC values in the range of 0.03-0.06 µg/mL, and against A. fumigatus and C. neoformans, with MIC values in the range of 1-2 µg/mL. Notably, Compounds 14i, 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S-configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent.

Synthesis and Antimalarial Activity of New Enantiopure Aminoalcoholpyrrolo[ 1,2-a]quinoxalines.

BACKGROUND: We prepared a novel series of enantiopure mefloquine analogues with pyrrolo[ 1,2-a]quinoxaline core in order to fight Plasmodium falciparum resistant strain. OBJECTIVES: To observe the influence of pyrrolo[1,2-a]quinoxaline core versus quinoline core on the antimalarial activity. METHOD: Four enantiopure aminoalcoholpyrrolo[1,2-a]quinoxalines 2 were synthetized via Sharpless asymmetric dihydroxylation reaction in eight steps. Their antimalarial activity was evaluated on two Plasmodium falciparum strains 3D7 and W2 with a SYBR Green I fluorescence-based method and their cytotoxicity was measured on four cell lines HepG2, THP-1, CHO and HFF. RESULTS: IC50 values of the four compounds 2 were close to the micromolar against the two P. falciparum strains. They were more active against P. falciparum strain W2 vs. P. falciparum strain 3D7. (R)- enantiomers were always more active than their (S)-counterpart whatever the strain. Selectivity indexes of compounds 2 were lower than 100. CONCLUSION: A novel series of enantiopure aminoalcohols with pyrrolo[1,2-a]quinoxaline core were synthesized in eight steps. They displayed IC50 values close to the micromolar against two P. falciparum strains 3D7 and W2. Although, In this series, 2,8-bistrifluoromethylquinoline was a best core than pyrrolo[1,2-a]quinoxaline for an optimal antimalarial activity, the pyrroloquinoxaline 2b showed an interesting antimalarial activity.

Cell density dependence of Microcystis aeruginosa responses to copper algaecide concentrations: Implications for microcystin-LR release.

Along with mechanistic models, predictions of exposure-response relationships for copper are often derived from laboratory toxicity experiments with standardized experimental exposures and conditions. For predictions of copper toxicity to algae, cell density is a critical factor often overlooked. For pulse exposures of copper-based algaecides in aquatic systems, cell density can significantly influence copper sorbed by the algal population, and consequent responses. A cyanobacterium, Microcystis aeruginosa, was exposed to a copper-based algaecide over a range of cell densities to model the density-dependence of exposures, and effects on microcystin-LR (MC-LR) release. Copper exposure concentrations were arrayed to result in a gradient of MC-LR release, and masses of copper sorbed to algal populations were measured following exposures. While copper exposure concentrations eliciting comparable MC-LR release ranged an order of magnitude (24-h EC50s 0.03-0.3mg Cu/L) among cell densities of 106 through 107 cells/mL, copper doses (mg Cu/mg algae) were similar (24-h EC50s 0.005-0.006mg Cu/mg algae). Comparisons of MC-LR release as a function of copper exposure concentrations and doses provided a metric of the density dependence of algal responses in the context of copper-based algaecide applications. Combined with estimates of other site-specific factors (e.g. water characteristics) and fate processes (e.g. dilution and dispersion, sorption to organic matter and sediments), measuring exposure-response relationships for specific cell densities can refine predictions for in situ exposures and algal responses. These measurements can in turn decrease the likelihood of amending unnecessary copper concentrations to aquatic systems, and minimize risks for non-target aquatic organisms.

Effects of Cutrine-Plus® algaecide and predators on wood frog (Lithobates sylvaticus) tadpole survival and growth.

Copper contamination is increasing in many aquatic ecosystems. One mode by which copper can be introduced into aquatic ecosystems is as an algaecide, such as Cutrine-Plus®. Using a mesocosm experiment, we examined the effects of Cutrine-Plus® on wood frog (Lithobates sylvaticus) tadpoles. In addition, we examined how the presence of a nonnative predator the Western mosquitofish (Gambusia affinis) may interact with exposure to Cutrine-Plus®. Exposure to our low and high Cutrine-Plus® treatments had a strong negative effect on the wood frog tadpoles, and survivorship was greatly decreased in the low treatment, and no tadpoles survived in the high treatment. Additionally, the tadpoles that survived the low treatment were significantly smaller than those in the control treatment. Mosquitofish had no effect on the survivorship or growth of wood frog tadpoles, and mosquitofish presence did not have a significant interaction with the Cutrine-Plus® treatments. Cutrine-Plus® clearly had a negative effect on wood frog tadpoles at the concentrations used in our experiment, which were at and below the label-recommended dosages, suggesting that the use of Cutrine-Plus® in natural ponds may have negative consequences for wood frog populations and possibly other amphibians.

Design, synthesis and cytotoxic activities of novel ß-amino alcohol derivatives.

Three series of novel ß-amino alcohols possessing an N-anthranyl group have been obtained using tryptophan as the major starting material. These compounds were screened for cytotoxic activity against five human cancer cell lines in vitro by MTT assay, and some of them exhibited potential ability to be anticancer agents. Structure-activity relationship was carefully investigated. Only the compounds possessing small substituents (H or CH(3)) at C-6 position showed the same activity as cisplatin (DDP) did.

Preparation of amino alcohols condensed with carbohydrates: Evaluation of cytotoxicity and inhibitory effect on NO production.

This work reports the preparation of several amino alcohols condensed with d-arabinose, d-glucose, and d-galactose derivatives. These compounds were evaluated in vitro for their cytotoxicity and ability to decrease nitric oxide production in J774A.1 cells. Arabinofuranoside derivatives 5a, 5b and 5c showed a significant inhibition of nitric oxide production (>80% at 5 µg/mL), while the galactopyranoside derivative 8d showed a notable nitric oxide inhibitory activity (126% at 0.5 µg/mL).

Synthesis and immunosuppressive activity of lipophilic amino alcohols and diamines.

In this work, we report the preparation and evaluation of the in vitro and in vivo of the immunosuppressive activity of a series of lipophilic amino alcohols and diamines. All compounds were evaluated for inhibition of cell proliferation, cytotoxicity and NO production. Compounds 9, 12, 13, 17, and 18 did not display inhibition of cell proliferation while decreased NO production. The two most potent compounds, 13 and 17, submitted to delayed-type hypersensitivity assays showed immunosuppressive activity.

Synthesis of limonene β-amino alcohol derivatives in support of new antileishmanial therapies

A series of seven limonene β-amino alcohol derivatives has been regioselectively synthesised in moderate to good yields. Two of these compounds were found to be significantly effective against in vitro cultures of the Leishmania (Viannia) braziliensis promastigote form in the micromolar range. The activities found for 3b and 3f were about 100-fold more potent than the standard drug, Pentamidine, in the same test, while limonene did not display any activity. This is the first report of antileishmanial activity by limonene β-amino alcohol derivatives.

Effects of common antitussive drugs on the hERG potassium channel current.

A common over-the-counter (OTC) non-opioid antitussive drug, clobutinol, was recently withdrawn from the market due to its potential to induce cardiac arrhythmias by a blockade of the potassium channel coded by the human ether-à-go-go-related gene (hERG). In this study, we investigated the effects of a number of antitussive compounds on the hERG ion channel current using patch-clamp electrophysiology, and compared the effects to that of clobutinol. The compounds clobutinol, pentoxyverine, dextromethorphan, and codeine inhibited the outward current in hERG transfected cells with half-maximal inhibition concentrations (IC50) of 1.9 microM, 3.0 microM, 5.1 microM, and 97 microM, respectively. For theobromine, no significant effect on the hERG current at a concentration up to 100 microM was detected. Safety margins between the effects of the drugs on the hERG ion channel current and their calculated maximal free therapeutic plasma concentration were calculated. These results were compared to assess potential risks of the compounds to induce torsade de pointes-type arrhythmias.

Acaricidal activity of limonene, limonene oxide and beta-amino alcohol derivatives on Rhipicephalus (Boophilus) microplus.

Limonene, limonene oxide and eight beta-amino alcohol derivatives obtained by synthesis were investigated for the effect on egg hatchability and mortality rates of newly hatched larvae of the cattle tick Rhipicephalus (Boophilus) microplus. At the doses between 10 microg/ml and 2.5 microg/ml all the compounds were highly lethal to the larvae and some of them showed activity at lower concentrations. The effect on the eggs hatchability was observed in all the treatments.

Synthesis of limonene beta-amino alcohol derivatives in support of new antileishmanial therapies.

A series of seven limonene beta-amino alcohol derivatives has been regioselectively synthesised in moderate to good yields. Two of these compounds were found to be significantly effective against in vitro cultures of the Leishmania (Viannia) braziliensis promastigote form in the micromolar range. The activities found for 3b and 3f were about 100-fold more potent than the standard drug, Pentamidine, in the same test, while limonene did not display any activity. This is the first report of antileishmanial activity by limonene beta-amino alcohol derivatives.

Synthesis and evaluation of some lipidic aminoalcohols and diamines as immunomodulators.

Lymphoproliferation inhibition and cytotoxicity of a number of lipidic aminoacids, aminoalcohols and diamines were evaluated as a preliminary screening to select potential immunomodulators. The four most potent/less toxic compounds were submitted to delayed hypersensibility (DTH) assays to define the best to be evaluated further Graft-vs-Host, NO production and other immunoevaluation (CD4(+), CD45, CD8, CD11b, I-Ek, and NK cells) assays, to establish their immunomodulation potential for being further considered as auxiliary agents for vaccination against some parasitic infections. Compounds 5d, 6d, 6f, 7a, and 9a, fairly inhibited the lymphoproliferation (71.6-79.5%, at 3.2-2.4 nM), while the aminoalcohol derivative 6f and the diamine 7a gave the most promising results in the DTH assays. Diamine derivative 8b induced nitrite production on normal macrophages, whereas compounds 6f and 7a induced nitrite production on LPS pre-stimulated macrophages. These two last compounds have been selected to follow in vivo vaccination assays.

Cytotoxicity of amino alcohols to rat hepatoma-derived Fa32 cells.

Amino alcohols are used as emulsifying agents in dry-cleaning soaps, wax removers, cosmetics, paints and insecticides. The cytotoxicities of 12 amino alcohols, which differed in chain length, position of the amino and alcohol groups, and the presence of an additional phenyl group, were determined by the neutral red uptake inhibition assay with normally cultured, glutathione-depleted or antioxidant-enriched Fa32 rat hepatoma-derived cells. Glutathione depletion and antioxidant enrichment were achieved by including 50(M L-buthionine-S,R-sulphoximine (BSO) or 100(M (-tocopherol acetate (vitamin E) in the culture medium for 24 hours before and during the assay. The cytotoxicity of the amino alcohols observed after treatment for 24 hours was expressed as the concentration of compound needed to induce a 50% reduction in neutral red uptake (NI50). The observed NI50 values ranged from 3mM to 30mM. The individual stereoisomers and a racemic mixture of 1-amino-2-propanol exhibited similar cytotoxicities (with normally cultured Fa32 cells, and vitamin E- and BSO-treated cultures). Similar NI50 values for D-(+)-2-amino-1-propanol, 3-amino-1-propanol and the L-, D- or DL- forms of 1-amino-2-propanol, indicated that the position of the amino group had little influence on the cytotoxicities of the amino alcohols. In contrast, the position of the hydroxyl group appeared to play an important role for the toxicity of the compound, as indicated by the significantly different NI50 values for 4-amino-1-butanol and 4-amino-2-butanol. An additional phenyl group greatly increased the cytotoxicity of 2-amino-1,3-propanediol. For most of the compounds, cytotoxicity increased when GSH was depleted, and decreased when the cells were enriched with vitamin E. This indicated that most of the tested chemicals interact with GSH, either directly or indirectly, by processes which generate oxygen free-radicals. Decreased toxicity was found for most of the chemicals administered to vitamin E-enriched cells, indicating that reactive oxygen species could be involved in the toxicity of the amino alcohols.

Algicidal effectiveness of Clearigate, Cutrine-Plus, and copper sulfate and margins of safety associated with their use.

Laboratory studies of algicide toxicity to algal species provide information to improve the efficacy and efficiency of copper-containing algicides in actual field situations. The objectives of this study were (1) to measure the influence of copper form, initial concentration, and duration of exposure on the response of Raphidocelis subcapitata, a planktonic freshwater green alga; (2) to determine the contact time required for these copper-containing algicides (Clearigate, Cutrine-Plus, and copper sulfate) and the target species to obtain control; (3) to measure the critical burden of the three algicides required to obtain control of R. subcapitata; (4) to measure the residence time of the copper applied as the algicides in the water column of three waters having different water characteristics ( i.e., alkalinity, hardness, pH, and conductivity); and (5) to contrast exposures of copper (as algicides) required to control algae and the lower thresholds causing adverse effects on sensitive nontarget animal species. Algal control (EC(100)) was accomplished at 55.8, 117.5, and 187.5 microg Cu/L for CuSO(4), Cutrine-Plus and Clearigate with a contact time of 3 days in all cases. The critical burdens of copper (concentration sorbed by the algae) were 4.2, 7.3, and 7.9 microg Cu/mg algae (dry weight) for CuSO(4), Cutrine-Plus, and Clearigate, respectively. Because algicide toxicity generally decreases as cell density increases, the density of cells in algal blooms may hamper algicide effectiveness even at maximum label application rates. Determinations of critical burdens for algicides and target algal species provide necessary information to forecast the performance of algicide applications in field situations. The margin of safety ( i.e., the difference between the concentration where control of algae was obtained and the lower threshold concentration causing adverse effects on nontarget species) was greatest for Cutrine-Plus. However, the margins of safety are minimal (< 0, 12.5, and 82.5 microg Cu/L for Ceriodaphnia dubia exposed to CuSO(4), Clearigate, and Cutrine-Plus, respectively) when they are applied according to their labels.

Synthesis and in vitro cytotoxicity of long chain 2-amino alcohols and 1,2-diamines.

The synthesis of enantiomerically pure unsaturated long chain 1,2-diamines and amino alcohols was carried out starting from the corresponding non-natural alpha-amino acids. The in vitro cytotoxicity of the compounds prepared was evaluated against six solid tumor cell lines (A2780, H322, LL, WiDr, C26-10 and UMSCC-22B). Free 1, 2-diamines proved to be the most active compounds exhibiting IC50 values between 2.0 mM and 3.3 mM.

Toxicity and bioavailability of copper herbicides (Clearigate, Cutrine-Plus, and copper sulfate) to freshwater animals.

In designing aquatic herbicides containing copper, an important goal is to maximize efficacy for target species while minimizing risks for nontarget species. To have a margin of safety for nontarget species, the concentration, duration of exposure (i.e., uptake), and form (i.e., species) of copper used for herbicidal properties should not elicit adverse effects on populations of nontarget species. To determine the potential for risk or adverse effects (conversely the margin of safety), data regarding the comparative toxicity of copper-containing herbicides are crucial. A series of comparative toxicity experiments was conducted, including baseline estimates of toxicity (LC50s, LOECs), sensitive species relationships (thresholds and exposure-response slopes), and bioavailability of toxic concentrations and forms of copper 7 days after initial herbicide application. Aqueous 48-h toxicity experiments were performed to contrast responses of Daphnia magna Strauss, Hyalella azteca Saussure, Chironomus tentans Fabricius, and Pimephales promelas Rafinesque to copper herbicides: Clearigate(R), Cutrine(R)-Plus, and copper sulfate. D. magna was the most sensitive aquatic animal tested for all three herbicides; 48-h LC50s for organisms exposed to Clearigate, Cutrine-Plus, and copper sulfate were 29.4, 11.3, and 18. 9 microg Cu/L, respectively. In terms of potency (calculated from the linearized portion of the exposure-response curves, which included 50% mortality), D. magna was the most sensitive animal tested. Organisms exposed to Clearigate, Cutrine-Plus, and copper sulfate had exposure-response slopes of 2.55, 8.61, and 5.07% mortality/microg Cu/L, respectively. Bioavailability of Clearigate and Cutrine-Plus was determined by comparing survival data (LC50s) of test organisms exposed to herbicide concentrations during the first and last 48-h of a 7-day exposure period. Even in these relatively simplified water-only exposures, a transformation of copper to less bioavailable species over time was observed with a 100-200% decrease in toxicity (i.e., an increase in 48-h LC50s) for all four test animals. This series of laboratory experiments provides a worst-case scenario for determining the risk associated with the manufacturer's recommended application rates of Clearigate (100-1,000 microg Cu/L), Cutrine-Plus (200-1,000 microg Cu/L), and copper sulfate (100-500 microg Cu/L) in natural waters for four nontarget freshwater animals.

Synthesis, in vitro cytotoxicity and in vivo anti-inflammatory activity of long chain 3-amino-1,2-diols.

The synthesis of long chain 3-amino-1,2-diols was carried out based on Sharpless asymmetric epoxidation of long chain allylic alcohols and regioselective nucleophilic ring opening by azido group. The in vitro cytotoxicity of the compounds prepared was evaluated against six solid tumor cell lines (A2780, H322, LL, WiDr, C26-10, UMSCC-22B). Free 3-amino-1,2-diols exhibited IC50 values between 1.45 microM and 32 microM. These compounds also presented interesting inhibition of carrageenin-induced paw edema in rats (85.3% - 79.6% at a concentration of 0.15 mmol/kg).

Environmental assessment of the alkanolamines.

This review provides a summary of current information available on the environmental fate and aquatic toxicology of the alkanolamines. Because these materials are widely used, there is a need to understand their fate and effects in the environment. This assessment was confined to information regarding selected physical properties of the alkanolamines as well as their potential for degradation in the atmosphere, soil, surface water, and groundwater. In addition, their relevant aquatic toxicological information and bioconcentration potential were evaluated. In general, the alkanolamines have high water solubilities and low to moderate vapor pressures. Some are solids whereas others are liquids at room temperature. Aqueous solutions of the alkanolamines are basic, with the pKas decreasing with increased alkyl substitution. Predictions of the environmental distribution of these compounds, based on a unit world model of Mackay and Paterson, suggested that alkanolamines would partition primarily into the aqueous compartment at equilibrium, with the remainder distributed to the atmosphere. Only a very small fraction of these materials is expected to sorb to soil or sediments. However, adsorption mechanisms other than partitioning into the soil organic layer were not considered in this model. Since polar compounds may sorb to soil by alternate mechanisms, this model may underestimate the true adsorption potential and subsequent environmental distribution of the alkanolamines. Future work with these compounds should focus on other types of adsorption mechanisms that could impact the environmental distribution of the alkanolamines. Although only small amount of the alkanolamines are expected to partition to the atmosphere, they are expected to be removed by reactions with photochemically generated hydroxyl radicals. They may also be removed from the atmosphere by precipitation, due to their high water solubility. Because of the relatively low levels expected to be present in the atmosphere and the relatively short half-lives, the alkanolamines are not expected to adversely impact air quality. Alkanolamines have also been shown to be highly susceptible to biodegradation and are not expected to persist in the environment. Results from numerous studies have shown that these materials undergo rapid biodegradation in soil, surface waters, and wastewater treatment plants. Degradation rates for these compounds may vary, with half-lives routinely in the range of 1 d to 2 wk, depending on the length of acclimation period and other environmental factors. The relatively low bioconcentration factor (BCF) values reported for the alkanolamines indicate that they would not be expected to bioconcentrate in aquatic organisms. Available data on the toxicity of the alkanolamines to aquatic organisms suggest low toxicity to the majority of the species studied. Based on the facts that alkanolamines exhibit low aquatic toxicity, are shown to biodegrade in a wide range of environments, and exhibit no tendency to bioaccumulate, the routine manufacturing, use, and disposal of these materials are not expected to adversely impact the environment. With increased emphasis by consumers and regulatory agencies for industry to develop products that are "environmentally friendly," these properties of the alkanolamines make them an attractive choice for a wide range of applications.

(RS), (R)(-) and (S)(+) derivatives of 2-N-arylalkylamino-1-butanol having antiarrhythmic properties.

A series of theophyllinyl-7'-ethyl derivatives of (RS), (R)(-) and (S)(+) 2-aminobutanol were synthesized and tested in various models of experimental arrhythmia for their preventive and curative properties; (R)(-) 2-N-theophyllinyl-7'-ethyl amino-1-butanol (1a) and (R)(-) theophyllinyl-7'-ethyl-2-N-methylamino-1-butanol (3a) hydrochlorides showed interesting antiarrhythmic properties. The levorotatory compounds of R configuration showed stronger protective and also therapeutic effect in different experimental arrhythmias.