Sabrina B. Ferreira

Synthesis, Biological Activity, and Molecular Modeling Studies of 1H-1,2,3-Triazole Derivatives of Carbohydrates as α-Glucosidases Inhibitors

A class of drugs in use for treating type II diabetes mellitus (T2D), typified by the pseudotetrasaccharide acarbose, act by inhibiting the alpha-glucosidase activity present in pancreatic secretions and in the brush border of the small intestine. Herein, we report the synthesis of a series of 4-substituted 1,2,3-triazoles conjugated with sugars, including D-xylose, D-galactose, D-allose, and D-ribose. Compounds were screened for alpha-glucosidase inhibitory activity using yeast maltase (MAL12) as a model enzyme. Methyl-2,3-O-isopropylidene-beta-D-ribofuranosides, such as the 4-(1-cyclohexenyl)-1,2,3-triazole derivative, were among the most active compounds, showing up to 25-fold higher inhibitory potency than the complex oligosaccharide acarbose. Docking studies on a MAL12 homology model disclosed a binding mode consistent with a transition-state-mimicking mechanism. Finally, the actual pharmacological potential of this triazole series was demonstrated by the reduction of postprandial blood glucose levels in normal rats. These compounds could represent new chemical scaffolds for developing novel drugs against T2D.

Synthesis and anti-Trypanosoma cruzi activity of β-lapachone analogues.

The available chemotherapy for Chagas disease, caused by Trypanosoma cruzi, is unsatisfactory; therefore, there is an intense effort to find new drugs for the treatment of this disease. In our laboratory, we have analyzed the effect on bloodstream trypomastigotes of 16 new naphthoquinone analogues of β-lapachone modified in the pyran ring, aiming to find a new prototype with high trypanocidal activity. The new compounds presented a broad spectrum of activity, and five of them presented IC(50)/24 h in the range of 22-63 μM, whereas β-lapachone had a higher value of 391.5 ± 16.5 μM.

Pyrazine derivatives: a patent review (2008 – present)

Introduction: Pyrazines derivatives are well-known and important two-nitrogen-containing six-membered ring aromatic heterocyclic compounds and can carry substituents at one or more of the four ring carbon atoms. Pyrazines are a class of compounds that occur in nature and various methods have been worked out for their synthesis. A large number of pyrazine derivatives have been found to possess diverse pharmacological properties, which has caused an increasing interest by researchers in this core. Area covered: This review provides a comprehensive review of the pyrazines derivatives patented between the years 2008 to 2012 as potential active compounds. The patent databases SciFinder and esp@cenet were used to locate patent applications that were published between 2008 to present. Information from articles published was also included. Expert opinion: The diversity of pyrazines derivatives found in organisms in nature with different applications began to arouse the interest of research in this nucleus. The pyrazines derivatives have numerous prominent pharmacological effects, such as antibacterial, antifungal, antimycobacterial, anti-inflammatory, analgesic, anticancer for different types, antidiabetic, treatment for arteriosclerosis, antiviral. Its the time to conduct further studies aimed at rationalizing the biological activities found in order to develop more effective and clinically interesting compounds.

Synthesis of α‐ and β‐Pyran Naphthoquinones as a New Class of Antitubercular Agents

A series of α‐ and β‐pyran naphthoquinones (lapachones) have been synthesized and evaluated for their in‐vitro antibacterial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294) using the Alamar‐Blue susceptibility test; the activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL. The synthetic methodology consisted of the formation of methylene and aryl o‐quinone methides (o‐QMs) generated by Knoevenagel condensation of 2‐hydroxy‐1,4‐naphthoquinone with formaldehyde and arylaldehydes. These o‐QMs then undergo facile hetero Diels–Alder reactions with dienophiles in aqueous ethanol media. Some naphthoquinones exhibited inhibition with MIC values of 1.25 μg/mL, similar to that of pharmaceutical concentrations currently used in tuberculosis treatment. These results justify further research into the value of these quinones as part of an original treatment for tuberculosis.

Kinetics Studies on the Inhibition Mechanism of Pancreatic α-Amylase by Glycoconjugated 1H-1,2,3-Triazoles: A New Class of Inhibitors with Hypoglycemiant Activity

Glycoconjugated 1H‐1,2,3‐triazoles (GCTs) comprise a new class of glycosidase inhibitors that are under investigation as promising therapeutic agents for a variety of diseases, including type 2 diabetes mellitus. However, few kinetics studies have been performed to clarify the mode of inhibition of GCTs with their target glycosidases. Our group has previously shown that some methyl‐β‐D‐ribofuranosyl‐1H‐1,2,3‐triazoles that inhibit bakers yeast maltase were also able to reduce post‐prandial glucose levels in normal rats. We hypothesized that this hypoglycemiant activity was attributable to inhibition of mammalian α‐glucosidases involved in sugar metabolism, such as pancreatic α‐amylase. Hence, the aim of this work was to test a series of 26 GCTs on porcine pancreatic α‐amylase (PPA) and to characterize their inhibition mechanisms. Six GCTs, all ribofuranosyl‐derived GCTs, significantly inhibited PPA, with IC50 values in the middle to high micromolar range. Our results also demonstrated that ribofuranosyl‐derived GCTs are reversible, noncompetitive inhibitors when using 2‐chloro‐4‐nitrophenyl‐α‐D‐maltotrioside as a substrate. E/ES affinity ratios (α) ranged from 0.3 to 1.1, with the majority of ribofuranosyl‐derived GCTs preferentially forming stable ternary ESI complexes. Competition assays with acarbose showed that ribofuranosyl‐derived GCTs bind to PPA in a mutually exclusive fashion. The data presented here show that pancreatic α‐amylase is one of the possible molecular targets in the pharmacological activity of ribofuranosyl‐derived GCTs. Our results also provide important mechanistic insight that can be of major help to develop this new class of synthetic small molecules into more potent compounds with anti‐diabetic activity through rational drug design.

Synthesis of α- and β-lapachone derivatives from hetero diels-alder trapping of alkyl and aryl o-quinone methides

Foram sintetizados, em um unico pote reacional, alguns derivados da α- e β-lapachonas a partir de reacao de hetero Diels-Alder, em etanol aquoso, entre estirenos substituidos (como dienofilos) e o-quinonas metideos (o-QMs) metilenicas e arilicas geradas por condensacao de Knoevenagel da 2-hidroxi-1,4-naftoquinona com formaldeido e aldeidos aromaticos. Methylene and aryl o-quinone methides (o-QMs) generated by Knoevenagel condensation of 2-hydroxy-1,4-naphthoquinone with formaldehyde and arylaldehydes, undergo facile hetero Diels-Alder reaction with some substituted styrenes (as dienophiles) in aqueous ethanol media providing derivatives of α- and β-lapachone.

An Improved One-pot Procedure for the Preparation of β-Lapachone and nor-β-Lapachone, Two Potent Drug Prototypes

Since the finding that lapachol (1), a natural 1,4-naphthoquinone isolated from the Lapacho trees, displays antitumor activity against carcinoma Walker 256, many other natural and synthetic 1,2and 1,4-naphthoquinones have been reported as potent antitumor compounds.1 Among the natural cytotoxic 1,2-naphthoquinones, β-lapachone (2) or ARQ501 is one of the most studied quinones in recent years. It is a natural pyran-ortho-naphthoquinone originally obtained from heartwood of several Lapacho trees that belong to the genus Tabebuia (Bigoniaceae) and grow throughout South America. This important compound has been shown to have many different pharmacological effects2–6 including promising anti-cancer activity.7 Currently, it is undergoing multiple Phase II clinical trials. Similar to β-lapachone (2), nor-β-lapachone (3) showed expressive cytotoxicity activity for different human carcinoma cell lines such as KB (human epidermal carcinoma), HeLa (human cervical carcinoma), and HepG2 (human hepatocellular carcinoma)8 reported by Kongkathip and co-workers. In 2007, Ferreira and co-workers reported cytotoxic activities against six neoplastic cancer cells: SF-295 (central nervous system), HCT-8 (colon), MDAMB-435 (breast), HL-60 (leukemia), PC-3 (prostate), and B-16 (murine melanoma) for new arylamino derivatives of nor-β-lapachone.9 To date there are no efficient methods for preparing these substances. The best method for the preparation of 2 and 3 is the acid-catalyzed cyclization of lapachol (1), and of nor-lapachol (5), respectively.10 The latter compound is also obtained from lapachol (1) via a two-step Hooker oxidation.11,12 It should be noted that lapachol (1) can be synthetically obtained from 2-hydroxy-1,4-naphthoquinone (lawsone, 4)13 by

Novel o-naphthoquinones induce apoptosis of EL-4 T lymphoma cells through the increase of reactive oxygen species.

Novel β-lapachone analogs 2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ1), 2-p-tolyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ3) and 2-methyl-2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ7), which have trypanocidal activity, were assayed for cytotoxic effects on murine EL-4 T lymphoma cells. The NQs inhibited the proliferation of EL-4 cells at concentrations above 1μM. Nuclear staining of the EL-4 cells revealed chromatin condensation and a nuclear morphology compatible with the induction of apoptosis. Flow cytometry assays with annexin V-FITC and propidium iodide confirmed the cell death by apoptosis. Using electron paramagnetic resonance (EPR), a semiquinone radical was detected in EL-4 cells treated with NQs. In addition, a decrease in the GSH level in parallel with reactive oxygen species (ROS) production was observed. Preincubation with n-acetyl-l-cysteine (NAC) was able to reverse the inhibitory effects of the NQs on cell proliferation, indicating that ROS generation is involved in NQ-induced apoptosis. In addition, the NQs induced a decrease in the mitochondrial membrane potential and increased the proteolytic activation of caspases 9 and 3 and the cleavage of Poly (ADP-Ribose) Polymerase (PARP). In conclusion, these results indicate that redox cycling is induced by the NQs in the EL-4 cell line, with the generation of ROS and other free radicals that could inhibit cellular proliferation as a result of the induction of the intrinsic apoptosis pathway.

Synthesis of 1H-1,2,3-triazoles and Study of their Antifungal and Cytotoxicity Activities

We report herein the results of antifungal activity of fifteen 1,2,3-triazoles against Candida albicans, Candida krusei, Candida parapsilosis, Candida kefyr, Candida tropicalis, Candida dubliniensis, Tricophyton rubrum, Microporum canis and Aspergillus niger. All of the 1,2,3-triazoles were prepared from 1,3-dipolar cyclizations between aryl azides and alkynes catalyzed by Cu(I), and several of the compounds exhibited antifungal activity with low cytotoxicity. The results demonstrated the potential and importance of developing new 1,2,3-triazoles compounds with antifungal activity.

Synthetic 1,4-pyran naphthoquinones are potent inhibitors of dengue virus replication.

Dengue virus infection is a serious public health problem in endemic areas of the world where 2.5 billion people live. Clinical manifestations of the Dengue infection range from a mild fever to fatal cases of hemorrhagic fever. Although being the most rapidly spreading mosquito-borne viral infection in the world, until now no strategies are available for effective prevention or control of Dengue infection. In this scenario, the development of compounds that specifically inhibit viral replication with minimal effects to the human hosts will have a substantial effect in minimizing the symptoms of the disease and help to prevent viral transmission in the affected population. The aim of this study was to screen compounds with potential activity against dengue virus from a library of synthetic naphthoquinones. Several 1,2- and 1,4-pyran naphthoquinones were synthesized by a three-component reaction of lawsone, aldehyde (formaldehyde or arylaldehydes) and different dienophiles adequately substituted. These compounds were tested for the ability to inhibit the ATPase activity of the viral NS3 enzyme in in vitro assays and the replication of dengue virus in cultured cells. We have identified two 1,4-pyran naphthoquinones, which inhibited dengue virus replication in mammal cells by 99.0% and three others that reduced the dengue virus ATPase activity of NS3 by two-fold in in vitro assays.