A series of novel hybrids β-carboline-1,3,5-triazine were synthesized and evaluated for their in vitro antileishmanial activity against promastigote and amastigote forms of Leishmania amazonensis. ...Among the compounds tested, the hybrids 9d, 9e, 16a and 16b showed potent activity against the promastigote forms with IC50 values less than 8 μM. Compounds 9e and 16b were also active against amastigote forms, displaying IC50 values of 1.0 ± 0.1 μM and 1.2 ± 0.5 μM, respectively. Besides that, the hybrid 16b bearing the 4-methoxyphenyl group at C-1 of β-carboline and isopropylamino group at 1,3,5-triazine, showed low toxicity, being 23.5 and 121.4 times more toxic for promastigotes and axenic amastigotes, respectively, than for macrophage J774-A1 cell lines. Investigation of action mechanism in promastigotes showed that compound 16b caused alterations in cell division cycle and an increase of lipid-storage bodies, leading the cells to death through various factors. The accumulation of lipid bodies may be associated with apoptotic cell death.
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•Novel hybrids β-carboline-1,3,5-triazine were assayed for antileishmanial activity.•Hybrids 9d, 9e, 16a and 16b were strongly active against Leishmania amazonensis.•Hybrid 16b showed low toxicity, and potent activity to amastigotes and promastigotes.•Compound 16b caused alterations in cell division cycle, and led to protozoan cell death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Atopic dermatitis is the most common inflammatory skin disease in childhood and has an important impact on quality of life, especially severe cases or those that are recalcitrant to treatments. ...Sensitization to allergens with the potential for allergic contact dermatitis is a factor associated with cases of recalcitrant atopic dermatitis. Understanding the relationship between atopic dermatitis, allergens, and allergic contact dermatitis is essential. In Brazil, there are no studies on sensitization to allergens found in patch tests with pediatric batteries in patients with atopic dermatitis.
To verify the main sensitizing agents, the prevalence of allergic contact dermatitis and the epidemiological and clinical profile of children and adolescents with atopic dermatitis.
Cross-sectional, prospective study in patients between 4 and 18 years of age, with recalcitrant atopic dermatitis, treated at the Sanitary Dermatology Outpatient Clinic (RS). All patients underwent patch tests with a battery of pediatric allergens.
The prevalence of sensitization and allergic contact dermatitis in the evaluated patients was 37.07% (20/54) and 27.7% (15/54), respectively. The most frequent allergens were: nickel sulfate (16.7%), disperse blue (5.6%), and fragrance mix I (5.6%). Nickel was associated with the female sex (p = 0.019).
Sample size and selection, absence of a control group.
A proportion of patients with recalcitrant atopic dermatitis may be sensitized to different allergens and may even have developed allergic contact dermatitis. Recognizing this context is important in the prevention strategy and management of the disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Two β-carboline compounds, 8i and 6d, demonstrated in vitro antileishmanial activity against Leishmania (L.) amazonensis promastigotes similar to that of miltefosine (MIL). Estimates of the ...membrane-water partition coefficient (KM/W) and the compound concentrations in the membrane (cm50) and aqueous phase (cw50) for half maximal inhibitory concentration were made. Whereas these biophysical parameters for 6d were not significantly different from those reported for MIL, 8i showed lower affinity for the parasite membrane (lower KM/W) and a lower concentration of the compound in the membrane required to inhibit the growth of the parasite (lower cm50). A 2-hour treatment of Leishmania promastigotes with the compounds 8i and 6d caused membrane rigidity in a concentration-dependent manner, as demonstrated by the electron paramagnetic resonance (EPR) technique and spin label method. This increased rigidity of the membrane was interpreted to be associated with the occurrence of cross-linking of oxidized cytoplasmic proteins to the parasite membrane skeleton. Importantly, the two β-carboline-oxazoline derivatives showed low hemolytic action, both in experiments with isolated red blood cells or with whole blood, denoting their great Leishmania/erythrocyte selectivity index. Using electron microscopy, changes in the membrane of both the amastigote and promastigote form of the parasite were confirmed, and it was demonstrated that compounds 8i and 6d decreased the number of amastigotes in infected murine macrophages. Furthermore, 8i and 6d were more toxic to the protozoa than to J774A.1 macrophages, with treated promastigotes exhibiting a decrease in cell volume, mitochondrial membrane potential depolarization, accumulation of lipid bodies, increased ROS production and changes in the cell cycle.
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•Two β-carboline derivatives caused membrane rigidity in Leishmania amazonensis.•Membrane rigidity was associated with antileishmanial activity.•It was suggested that β-carboline compounds cause peroxidation of membrane proteins.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•Design arylcarbamate-N-acylhydrazones derivatives were BuChE selective inhibitors.•The compounds were synthesized using low-cost and simple methodologies.•Compounds 10a-d are potent ...BuChE inhibitors, with IC50 values of 0.07–0.56 µM.•Best inhibitor 10c is non-competitive type of BuChE.•Docking studies confirmed important interactions of 10c with hBuChE active site.
A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC50 values of 0.07–2.07 µM, highlighting the compound 10c (IC50 = 0.07 µM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC50 = 3.54 µM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CH⋯O interactions with His438, Gly121 and Glu197. Based on these data, compound10cwas identified as low-cost promising candidate for a drug prototype for AD treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract The β-carboline-1,3,5-triazine hydrochlorides 8-13 were evaluated in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The analysed compounds were selective to ...BuChE, with IC50 values in the range from 1.0-18.8 µM being obtained. The N-{2-(4,6-dihydrazinyl-1,3,5-triazin-2-yl)aminoethyl}-1-phenyl-β-carboline-3-carboxamide (12) was the most potent compound and kinetic studies indicate that it acts as a competitive inhibitor of BuChE. Molecular docking studies show that 12 strongly interacts with the residues of His438 (residue of the catalytic triad) and Trp82 (residue of catalytic anionic site), confirming that this compound competes with the same binding site of the butyrylthiocholine.
A series of novel hybrids β-carboline-4-thiazolidinones were synthesized and evaluated for their in vitro antitumor activity against human cancer cell lines and for antiviral activity towards Herpes ...simplex virus type-1 (HSV-1). From the N′-(2-ylidene-4-thiazolidinone)-β-carboline-3-carbohydrazide series (9–11), compounds 9c and 11d were the most active, showing growth inhibition 50% (GI50) values less than 5 μM for all cell lines tested. Compound 9c, bearing the 4-dimethylaminophenyl group at C-1 of β-carboline was selected for further investigation concerning cell death and cell cycle profile, focusing on the human renal adenocarcinoma cell line 786-0. Treatments with 25 μM of compound 9c induced cell death after 15 h of treatment, characterized by phosphatidylserine exposure and loss of membrane integrity. Moreover, treatment with 12.5 μM promoted a sub-G1 arrest, which indicates cell death. Derivatives of the N-(2-substituted-aryl-4-thiazolidinone)-β-carboline-3-carboxamide series (18–23) showed a potent activity and high selectivity for glioma (U251) and ovarian (OVCAR-3) cancer cell lines. Also, some β-carboline-4-thiazolidinone hybrids showed potent antiviral activity against Herpes simplex virus type-1. The N-(2-substituted-aryl-4-thiazolidinone)-carboxamide moiety in 18, 19 and 22 confer a potent anti-HSV-1 activity for these derivatives, which presented EC50 values of 0.80, 2.15 and 2.02 μM, respectively. The assay results showed that the nature of 4-thiazolidinone moiety and of the substituent attached at the 3- and 1- position of β-carboline nucleus influenced the antitumor and antiviral activities.
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•Novel hybrids β-carboline-4-thiazolidinones were synthetized.•Compounds were evaluated for their in vitro antitumor and antiviral activities.•Compounds 9c and 11d displayed potent antitumor activity in vitro.•Compound 9c induced cell death in the renal human tumor cell line 786-0.•Potent anti-HSV-1 activity was observed for derivatives 18, 19 and 22.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A series of novel 1-(substituted-phenyl)-3-(4,5-dihydro-1,3-oxazol-2-yl)-9H-β-carboline (8a-8i) and 1-(substituted-phenyl)-3-(5,6-dihydro-4H-1,3-oxazin-2-yl)-9H-β-carboline (9a-9h) derivatives, as ...well as their respective N-(chloroalkyl)-1-(substituted-phenyl)-9H-β-carboline-3-carboxamide precursors (6a-6i and 7a-7h), were synthesized and evaluated for their in vitro antileishmanial activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. Compounds 8d, 8i, 9e and 9h exhibited significant activity for both promastigote and amastigote forms, with IC50 (50% inhibitory concentration) values ranging from 2.9 to 23.0 µM. In addition, spin label electron paramagnetic resonance (EPR) spectroscopy studies were carried out for the most active compounds against L. amazonensis promastigotes. The studies indicated that the tested compounds cause strong stiffness in the parasite plasma membrane and are capable of inducing internal metalloproteins oxidation of the parasite, resulting in their cross-linking to skeletal proteins. Compounds 8d and 8i produced the largest effect, showing that the presence of oxazoline group at C-3 of β-carboline nucleus is important for antileishmanial activity.
Cutaneous leishmaniasis is caused by
spp., and its treatment is limited. The β-carbolines have shown activity against kinetoplastids.
To evaluate the activity and effects of the β-carbolines, ...N-{2-(4,6-bis(isopropylamino)-1,3,5-triazin-2-yl)aminoethyl}-1-(4-methoxyphenyl)-β-carboline-3-carboxamide (
and N-benzyl-1-(4-methoxy)phenyl-9H-beta-carboline-3-carboxamide
, against
intracellular amastigotes and to suggest their mechanism of action.
We analyzed the activity and cytotoxicity of β-carbolines and the morphological alterations by electron microscopy. Mitochondrial membrane potential, production nitric oxide, reactive oxygen species, lipidic bodies, autophagic vacuoles and ATP were also evaluated.
The results showed that
and
are active against intracellular amastigotes and were able to induce oxidative stress and ultrastructural alterations such as accumulation of lipid bodies and autophagic vacuoles, leading to parasite death.
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