Alsinol, an arylamino alcohol derivative active against Plasmodium, Babesia, Trypanosoma, and Leishmania: past and new outcomes.

Malaria, babesiosis, trypanosomosis, and leishmaniasis are some of the most life-threatening parasites, but the range of drugs to treat them is limited. An effective, safe, and low-cost drug with a large activity spectrum is urgently needed. For this purpose, an aryl amino alcohol derivative called Alsinol was resynthesized, screened in silico, and tested against Plasmodium, Babesia, Trypanosoma, and Leishmania. In silico Alsinol follows the Lipinski and Ghose rules. In vitro it had schizontocidal activity against Plasmodium falciparum and was able to inhibit gametocytogenesis; it was particularly active against late gametocytes. In malaria-infected mice, it showed a dose-dependent activity similar to chloroquine. It demonstrated a similar level of activity to reference compounds against Babesia divergens, and against promastigotes, and amastigotes stages of Leishmania in vitro. It inhibited the in vitro growth of two African animal strains of Trypanosoma but was ineffective in vivo in our experimental conditions. It showed moderate toxicity in J774A1 and Vero cell models. The study demonstrated that Alsinol has a large spectrum of activity and is potentially affordable to produce. Nevertheless, challenges remain in the process of scaling up synthesis, creating a suitable clinical formulation, and determining the safety margin in preclinical models.

Inhibitory mechanism of 17ß-aminoestrogens in the formation of Aß aggregates.

Alzheimer's disease (AD) is a complex neurodegenerative disorder associated with the aggregation of the amyloid-beta peptide (Aß) into large oligomers and fibrils that damage healthy brain cells. The predominant peptide fragments in the plaques are mainly formed by the Aß1-40 and Aß1-42 peptides, albeit the eleven-residue Aß25-35 segment is largely used in biological studies because it retains the neurotoxic properties of the longer Aß peptides. Recent studies indicate that treatment with therapeutic steroid hormones reduces the progress of the disease in AD models. Particularly, treatment with 17ß-aminoestrogens (AEs) has shown a significant alleviation of the AD development by inhibiting oxidative stress and neuronal death. Yet, the mechanism by which the AE molecules exhibit their beneficial effects remains speculative. To shed light into the molecular mechanism of inhibition of the AD development by AEs, we investigated the possibility of direct interaction with the Aß25-35 peptide. First, we calculate various interacting electronic properties of three AE derivatives as follows: prolame, butolame, and pentolame by performing DFT calculations. To account for the polymorphic nature of the Aß aggregates, we considered four different Aß25-35 systems extracted from AD relevant fibril structures. From the calculation of different electron density properties, specific interacting loci were identified that guided the construction and optimization of various complexes. Interestingly, the results suggest a similar inhibitory mechanism based on the direct interaction between the AEs and the M35 residue that seems to be general and independent of the polymorphic properties of the Aß aggregates. Our analysis of the complex formation provides a structural framework for understanding the AE therapeutic properties in the molecular inhibitory mechanism of Aß aggregation.

ß-amino alcohols and their respective 2-phenyl-N-alkyl aziridines as potential DNA minor groove binders.

It is known that aziridines and nitrogen mustards exert their biological activities, especially in chemotherapy, via DNA alkylation. The studied scaffold, 2-phenyl-1-aziridine, provides a distinct conformation compared to commonly used aziridines, and therefore, leads to a change in high-strained ring reactivity towards biological nucleophiles, such as DNA. The above series of compounds was tested in three breast cell lines: MCF-10, a healthy cell; MCF-7, a hormone responsive cancer cell; and MDA-MB-231, a triple negative breast cancer cell. Both aziridines and their precursors, ß-amino alcohols, showed activity towards these cells, and some of the compounds showed higher selectivity index than cisplatin, the drug used as control. When the type of cell death was investigated, the synthesized compounds demonstrated higher apoptosis and lower necrosis rates than cisplatin, and when the mechanism of action was studied, the compounds were shown to interact with DNA via its minor groove instead of alkylation or intercalation.

Differential effect of the 17ß-aminoestrogens prolame, butolame and pentolame in anxiety and depression models in rats.

Estrogens of clinical use produce consistent antidepressant- and anxiolytic-like effects in animal models of menopause. Regulation of the hypothalamic-pituitary-adrenal (HPA) or stress axis, has been proposed as a pathway through which estrogens improve affective-like behaviors. Anticoagulant 17ß-aminoestrogens (17ß-AEs) butolame and pentolame mimic some effects of estradiol (E2), i.e., on female rodent sexual behavior, with opposite actions on coagulation. However, their psychoactive actions have not been explored. On the basis of similitude with E2's effects, we hypothesized that these 17ß-AEs would induce anxiolytic- and antidepressant-like effects, which would be reflected in a reduction of activity in the HPA axis. In ovariectomized female rats, chronic treatment with prolame (60 µg/kg), butolame (65 µg/kg) and pentolame (70 µg/kg) reduced anxiety-like behavior in the elevated plus maze (evidenced by an increase in time in open arms, E2 (40 µg/kg) +176%; prolame +201%; butolame, +237%; and pentolame +295%, in comparison to the control vehicle group 100%). Pentolame also decreased significantly anxiety-like behavior in the burying behavior test. Prolame and E2 produced a significantly antidepressant-like action, which was not induced by butolame and pentolame. Behavioral effects of 17ß-AEs (and E2) on anxiety and depression did not follow the same pattern than corticosterone or E2 levels; they also were associated to changes in locomotor activity, evaluated by the open field test. These results constitute the first evidence of specific and selective actions of butolame and pentolame as anxiolytics for females with a hypoestrogenic condition. Results also confirm the potential of prolame as an antidepressant steroid with equivalent actions to E2. Psychoactive properties of 17ß-AEs in combinations with reduced adverse effects on coagulation, suggest that 17ß-AEs may be a good alternative replacement therapy for women with symptoms associated with menopause.

Synthesis and evaluation of antibacterial and antitumor activities of new galactopyranosylated amino alcohols.

Three series of d-galactose derivatives linked to a lipophilic aminoalcohol moiety were synthesized and their antibacterial activity was evaluated against Mycobacterium tuberculosis and representative species of Gram positive and Gram negative bacteria. Five out of the thirteen tested compounds displayed activity against M. tuberculosis, with a minimal inhibitory concentration (MIC) of 12.5 µg/mL and seven compounds were active against the four bacterial strains tested. The best results were obtained for amino alcohols 10 and 11 against Staphylococcus epidermidis (MIC = 2 µg/mL). The antitumor activity was evaluated against three tumor cell lines (MCF-7, HeLa and MO59J) and compared to the normal cell line GM07492A. The results showed that the lowest IC50 values were observed for the amino alcohol 16 against MCF-7 (11.9 µM) and MO59J (10.0 µM).

A novel one-pot and one-step microwave-assisted cyclization-methylation reaction of amino alcohols and acetylated derivatives with dimethyl carbonate and TBAC.

A simple and efficient microwave-assisted methodology for the synthesis of 4-substituted-3-methyl-1,3-oxazolidin-2-ones from amino alcohols catalyzed by a ionic liquid was developed. This novel one-pot and one-step cyclization-methylation reaction represents an easier and faster method than any other reported protocols that can be used to obtain the desired products in good yields and high purity. Applying microwave irradiation at 130°C in the presence of TBAC, dimethyl carbonate acts simultaneously as carbonylating and methylating agent and surprisingly promotes an in situ basic trans esterification when a N-acetylated amino alcohol is used as starting material. Furthermore, dimethyl carbonate worked better than diethyl carbonate in performing this reaction.

Anthelmintic effects of alkylated diamines and amino alcohols against Schistosoma mansoni.

Polyamines are substances involved in many aspects of cell growth, division, and differentiation. Because of the metabolic differences between host cells and parasite cells, polyamine metabolism has been considered as a potential target for the chemotherapy of parasitic diseases. The aim of this work was to evaluate the schistosomicidal activity of different N-alkylated diamines (3a-3h), amino alcohols (4a-4d), and glycosylated amino alcohols (10a-10d). Compounds were prepared by synthetic methods and submitted to in vitro evaluation against adult worms of Schistosoma mansoni. At 100 µM, 3b, 3e, and 3h as well as 4a, 4b, 4d, 10a, 10b, and 10d resulted in 100% mortality of adult schistosomes. Compound 3d (12.5 to 100 µM) caused the death of 100% of both male and female adult schistosomes, while 3f (12.5 to 100 µM) resulted in 100% mortality of only male adult worms, whereas no mortality in female worms was observed. Compounds 3d and 3f were also able to reduce viability and decrease production of developed eggs in comparison with the negative control group. Diamines 3d and 3f may represent useful lead compounds for further optimization in order to develop new schistosomicidal agents.

Synthesis and antimicrobial activity of novel amphiphilic aromatic amino alcohols.

We report in this work the preparation and in vitro antimicrobial evaluation of novel amphiphilic aromatic amino alcohols synthesized by reductive amination of 4-alkyloxybenzaldehyde with 2-amino-2-hydroxymethyl-propane-1,3-diol. The antibacterial activity was determined against four standard strains (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa) and 21 clinical isolates of methicillin-resistant Staphylococcus aureus. The antifungal activity was evaluated against four yeast (Candida albicans, Candida tropicalis, Candida glabrata and Candida parapsilosis). The results obtained showed a strong positive correlation between the lipophilicity and the antibiotic activity of the tested compounds. The best activities were obtained against the Gram-positive bacteria (MIC=2-16µgml(-1)) for the five compounds bearing longer alkyl chains (4c-g; 8-14 carbons), which were also the most active against Candida (MIC=2-64µgml(-1)). Compound 4e exhibited the highest levels of inhibitory activity (MIC=2-16µgml(-1)) against clinical isolates of MRSA. A concentration of twice the MIC resulted in bactericidal activity of 4d against 19 of the 21 clinical isolates.

Synthesis and antibacterial activity of aromatic and heteroaromatic amino alcohols.

Two series of aromatic and heteroaromatic amino alcohols were synthesized from alcohols and aldehydes and evaluated for their antibacterial activities. All the octylated compounds displayed a better activity against the four bacteria tested when evaluated by the agar diffusion method and were selected for the evaluation of minimal inhibitory concentration. The best results were obtained for p-octyloxybenzyl derivatives against Staphylococcus epidermidis (minimal inhibitory concentrations = 32 µm).

Synthesis and anti-mycobacterial activity of novel amino alcohol derivatives.

Thirteen new hydroxyethylamines have been synthesized from reactions of (2S,3S)Boc-phenylalanine epoxide, piperonylamine and arenesulfonyl chlorides in good yields. These compounds were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in µM. Two amino alcohols displayed significant activity when compared with first line drug ethambutol (EMB). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of tuberculosis.

Energetic features of copper and lead sorption by innovative aminoalcohol-functionalized cobalt phyllosilicates.

Inorganic-organic cobalt phyllosilicate hybrids were synthesized by the sol-gel procedure under mild non-hydrothermal conditions with a silicon precursor, formed through individual reactions between the silane 3-glycidoxypropyltriethoxysilane and the aminoalcohols ethanol- or diethanolamine. These procedures generated talc-like phyllosilicates containing pendant organic chains with nitrogen and oxygen basic centres located in the interlamellar region. For organofunctionalized phyllosilicates the lamellar structure obtained through the sol-gel method was confirmed by X-ray powder diffraction, while elemental analysis indicated that the densities of the organic groups attached to the new matrices were 3.31 ± 0.05 and 3.08 ± 0.07 mmol g(-1) for hybrids functionalized with ethanol- and diethanolamines, respectively. Infrared spectroscopy and nuclear magnetic resonance in the solid state for (13)C and (29)Si showed that the organic groups are indeed covalently bonded to the inorganic structures and the process of functionalization did not affect the original structures of the silylating agents employed. The thermally stable hybrids presented well-formed particles with a homogeneous distribution of cobalt and nitrogen atoms. Their abilities for copper removal from aqueous solutions gave maximum capacities of sorption of 2.01 ± 0.11 and 2.55 ± 0.15 mmol g(-1) for phyllosilicates containing ethanol- and diethanolamine groups, respectively. For lead sorption the values of 2.59 ± 0.11 and 2.43 ± 0.12 mmol g(-1) were found for this same sequence. These sorption data were adjusted to the non-linear regression of the Langmuir equation. Energetic features related to the interactions between the cations and the pendant basic centres were determined through calorimetric titrations. The acid-basic interactions reflect the spontaneity of the reactions, which are also enthalpically and entropically favourable for these chelating processes at the solid-liquid interface.

Trypanocidal activity of lipophilic diamines and amino alcohols.

Trypanocidal activity of a number of lipophilic diamines and amino alcohols was evaluated in vitro against Trypanosoma cruzi blood stream forms. Several of the studied compounds showed inhibition of T. cruzi growth. The most active ones were compounds 3, 4 and 5 with a IC50 of 31.2 µg/mL, activity similar to the reference drug crystal violet.

Synthesis and antileishmanial activity of lipidic amino alcohols.

In this work, a number of lipidic amino alcohols wereas synthesized and evaluated in vitro on cultures of Leishmania amazonensis and Leishmania chagasi. Nine amino alcohols showed inhibition of L. chagasi growth, and seven of them showed inhibition of L. amazonensis with IC(50) below 10 microm. Compound 11f was more active than the reference drug amphotericin B against L. chagasi promastigote forms.

Preparation and antitubercular activities of alkylated amino alcohols and their glycosylated derivatives.

A series of N- and C-alkylated amino alcohols and of their protected galactopyranosyl derivatives was synthesized and evaluated for antitubercular activity. Five of these compounds displayed good activity, with a MIC below 12.5mug/mL. The presence of the carbohydrate slightly affected the antibacterial activity.

Changes on hemostatic parameters induced by 17beta-estradiol, ethinylestradiol, and the 17beta-aminoestrogen pentolame in the male Wistar rat.

Oral contraceptives containing estrogens increases the incidence of thromboembolic events. In contrast, administration of 17beta-aminoestrogens prolonged blood clotting time (BCT) in rodents. We studied the effect of estradiol (E(2)), ethinylestradiol (EE) and pentolame on some screening hemostatic tests. BCT was evaluated 24, 48, 72 and 96 h post-treatment. Rats received subcutaneously (s.c.) for five consecutive days E(2) (0.1-1000 microg), EE (1-1000 microg), pentolame (0.1-1000 microg), or vehicle (propyleneglycol 0.3 ml). At 48 h post-treatment E(2) (1000 microg) diminished BCT (32%, P<0.01), in contrast pentolame (1000 microg) augmented BCT by 41% (P<0.01). After 72 h, E(2) showed procoagulant effects with 10, 100 and 1000 microg doses (-45, -30, and -21%, respectively). Significant effects on BCT of EE were observed 72 h after with 1000 microg (-12%, P<0.05). Animals were treated s.c. for two consecutive days with E(2) (3mg/100g), pentolame (4 mg), or vehicle (0.1 ml). BCT, bleeding time (BT), platelet aggregation (PA), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen concentration were determined. E(2) produced a significant diminution on BCT (-20%) after 72 h whereas pentolame increased BCT from 24 to 96 h (62%, maximal response at 48 h). APTT and PT coagulation times of the groups treated with E(2) and pentolame were lengthened (33 and 29%; 16 and 24%, respectively; P<0.05). Fibrinogen concentration increased (115%, P<0.01) only in the pentolame-treated group. Pentolame and E(2) produced any effects on BT and PA compared with control groups, indicating that platelet function was not modified. Our results indicate that E(2), EE and pentolame affects the plasmatic phase of the hemostatic mechanism.