Cytotoxic Activity of Triterpenoids from Cheiloclinium cognatum Branches against Chronic and Acute Leukemia Cell Lines.

Cheiloclinium cognatum (Miers) A.C.Sm. is an endemic species of Brazilian Cerrado that belongs to Celastraceae family. The phytochemical study of C. cognatum branches led to the identification of ten triterpenoids (TPs), 3ß-acyloxyurs-12-ene (1), friedelin (2), ß-friedelinol (3), glut-5-en-3ß-ol (4), α-amyrin (5), ß-amyrin (6), ß-sitosterol (7), canophyllol (8), 29-hydroxyfriedelan-3-one (9) and friedelane-3ß,29-diol (10). TPs 4, 5 and 6 are described for the first Cheiloclinium genus and TPs 8 and 9 were isolated in expressive amounts. Their cytotoxic activities were evaluated against THP-1 and K562 leukemia cell lines. TPs 3 and 5 were the most active, exhibiting lower or similar IC50 against both cell lines when compared to the controls. Their mechanisms of action were investigated suggesting an intrinsic mitochondrial pathway of apoptosis evidenced by up-regulation of BAK mRNA expression. Chemometric studies indicated that their activities may be related to their molecular size and shape as well as electronic interactions of C-3 hydroxy group with molecular targets.

Synthesis of Novel 1,2,3-Triazole Derivatives of Isocoumarins and 3,4-Dihydroisocoumarin with Potential Antiplasmodial Activity In Vitro.

BACKGROUND: Malaria greatly affects the world health, having caused more than 228 million cases only in 2018. The emergence of drug resistance is one of the main problems in its treatment, demonstrating the need for the development of new antimalarial drugs. OBJECTIVE: Synthesis and in vitro antiplasmodial evaluation of triazole compounds derived from isocoumarins and a 3,4-dihydroisocoumarin. METHODS: The compounds were synthesized in 4 to 6-step reactions with the formation of the triazole ring via the Copper(I)-catalyzed 1,3-dipolar cycloaddition between isocoumarin or 3,4- dihydroisocoumarin azides and terminal alkynes. This key reaction provided compounds with an unprecedented connection of isocoumarin or 3,4-dihydroisocoumarin and the 1,2,3-triazole ring. The products were tested for their antiplasmodial activity against a Plasmodium falciparum chloroquine resistant and sensitive strains (W2 and 3D7, respectively). RESULTS: Thirty-one substances were efficiently obtained by the proposed routes with an overall yield of 25-53%. The active substances in the antiplasmodial test displayed IC50 values ranging from 0.68-2.89 µM and 0.85-2.07 µM against W2 and 3D7 strains, respectively. CONCLUSION: This study demonstrated the great potential of isocoumarin or 3,4-dihydroisocoumarin derivatives because practically all the tested substances were active against Plasmodium falciparum.

A positive allosteric modulator of mGluR5 promotes neuroprotective effects in mouse models of Alzheimer's disease.

Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder. Despite advances in the understanding of its pathophysiology, none of the available therapies prevents disease progression. Excess glutamate plays an important role in excitotoxicity by activating ionotropic receptors. However, the mechanisms modulating neuronal cell survival/death via metabotropic glutamate receptors (mGluRs) are not completely understood. Recent data indicates that CDPPB, a positive allosteric modulator of mGluR5, has neuroprotective effects. Thus, this work aimed to investigate CDPPB treatment effects on amyloid-ß (Aß) induced pathological alterations in vitro and in vivo and in a transgenic mouse model of AD (T41 mice). Aß induced cell death in primary cultures of hippocampal neurons, which was prevented by CDPPB. Male C57BL/6 mice underwent stereotaxic surgery for unilateral intra-hippocampal Aß injection, which induced memory deficits, neurodegeneration, neuronal viability reduction and decrease of doublecortin-positive cells, a marker of immature neurons and neuronal proliferation. Treatment with CDPPB for 8 days reversed neurodegeneration and doublecortin-positive cells loss and recovered memory function. Fourteen months old T41 mice presented cognitive deficits, neuronal viability reduction, gliosis and Aß accumulation. Treatment with CDPPB for 28 days increased neuronal viability (32.2% increase in NeuN+ cells) and reduced gliosis in CA1 region (Iba-1+ area by 31.3% and GFAP+ area by 37.5%) in transgenic animals, without inducing hepatotoxicity. However, it did not reverse cognitive deficit. Despite a four-week treatment did not prevent memory loss in aged transgenic mice, CDPPB is protective against Aß stimulus. Therefore, this drug represents a potential candidate for further investigations as AD treatment.

Butenafine and analogues: An expeditious synthesis and cytotoxicity and antifungal activities.

The incidence of fungal infections is considered a serious public health problem worldwide. The limited number of antimycotic drugs available to treat human and animal mycosis, the undesirable side effects and toxicities of the currently available drugs, and the emergence of fungal resistance emphasizes the urgent need for more effective antimycotic medicines. In this paper, we describe a rapid, simple, and efficient synthetic route for preparation of the antifungal agent butenafine on a multigram scale. This novel synthetic route also facilitated the preparation of 17 butenafine analogues using Schiff bases as precursors in three steps or less. All the synthesized compounds were evaluated against the yeast, Cryptococcus neoformans/C. gattii species complexes and the filamentous fungi Trichophyton rubrum and Microsporum gypseum. Amine 4bd, a demethylated analogue of butenafine, and its corresponding hydrochloride salt showed low toxicity in vitro and in vivo while maintaining inhibitory activity against filamentous fungi.

Application of a new bifunctionalized chitosan derivative with zwitterionic characteristics for the adsorption of Cu(2+), Co(2+), Ni(2+), and oxyanions of Cr(6+) from aqueous solutions: Kinetic and equilibrium aspects.

This study describes the synthesis of a new chitosan derivative (C2) with zwitterionic characteristics and its use for the removal of cationic species Cu(2+), Co(2+), and Ni(2+) and anionic species of Cr(6+) in a single aqueous solution. The new adsorbent was synthesized by quaternization of the amine group of chitosan and esterification of hydroxyl groups with EDTA dianhydride. These combined reactions gave both cationic and anionic characteristics to C2 with the release of quaternary ammonium groups and carboxylic groups. The capacity of C2 to adsorb Cu(2+), Co(2+), Ni(2+), and oxyanions of Cr(6+) was evaluated in a batch process with different contact times, pH values, and initial concentrations. Adsorption isotherms were best fitted to the Langmuir and Sips models. The maximum adsorption capacities (Q(max)) of C2 for adsorption of Cu(2+), Co(2+), Ni(2+), and Cr(6+) were 0.698, 1.125, 0.725, and 1.910 mmol/g, respectively. The Δ(ads)G° values were in the range from -20 to -28 kJ/mol. These values suggest a mixed mechanism controlling adsorption. Desorption studies using an aqueous solution consisting of 0.1 mol/L HNO3 were carried out. The reusability of the recovered C2 adsorbent after desorption was also evaluated.