Jackson A. L. C. Resende

New oxirane derivatives of 1,4-naphthoquinones and their evaluation against T. cruzi epimastigote forms

New oxirane derivatives were synthesized using six naphthoquinones as the starting materials. Our biological results showed that these oxiranes acted as trypanocidal agents against Trypanosoma cruzi with minimal cytotoxicity in the VERO cell line compared to naphthoquinones. In particular, oxirane derivative 14 showed low cytotoxicity in a mammalian cell line and exhibited better activity against epimastigote forms of T.cruzi than the current drug used to treat Chagas disease, benznidazole.

Dolabelladienols A-C, new diterpenes isolated from Brazilian brown alga Dictyota pfaffii.

The marine brown alga Dictyota pfaffii from Atol das Rocas, in Northeast Brazil is a rich source of dolabellane diterpene, which has the potential to be used in future antiviral drugs by inhibiting reverse transcriptase (RT) of HIV-1. Reexamination of the minor diterpene constituents yielded three new dolabellane diterpenes, (1R*,2E,4R*,7S,10S*,11S*,12R*)10,18-diacetoxy-7-hydroxy-2,8(17)-dolabelladiene (1), (1R*,2E,4R*,7R*,10S*,11S*,12R*)10,18-diacetoxy-7-hydroxy-2,8(17)-dolabelladiene (2), (1R*,2E,4R*,8E,10S*,11S,12R*)10,18-diacetoxy-7-hydroxy-2,8-dolabelladiene (3), termed dolabelladienols A–C (1–3) respectively, in addition to the known dolabellane diterpenes (4–6). The elucidation of the compounds 1–3 was assigned by 1D and 2D NMR, MS, optical rotation and molecular modeling, along with the relative configuration of compound 4 and the absolute configuration of 5 by X-ray diffraction. The potent anti-HIV-1 activities displayed by compounds 1 and 2 (IC50 = 2.9 and 4.1 μM), which were more active than even the known dolabelladienetriol 4, and the low cytotoxic activity against MT-2 lymphocyte tumor cells indicated that these compounds are promising anti-HIV-1 agents.

An insight into carvedilol solid forms: effect of supramolecular interactions on the dissolution profiles

Carvedilol, a β-blocker drug used to treat hypertension, is known to exhibit polymorphism. Thus far, the crystal structure of two polymorphs (I and II) and one hydrate have been reported. In this study, three crystal modifications of carvedilol were obtained from crystallization experiments. The structure of another polymorph (III) was elucidated for the first time and the crystal structure of the hydrate was also determined from single-crystal diffraction data. Carvedilol structures are characterized by variations in their molecular conformations, with different orientations of the carbazole moiety. Further conformational details also differentiate them. Carvedilol structures II, III and hydrate were characterized by thermal and microscopic methods. A higher melting temperature polymorph (III), compared to form II, was identified when carvedilol was crystallized from methanol. This polymorph showed a higher intrinsic dissolution rate than polymorph II in hydrochloric acid at pH 1.4 containing sodium lauryl sulfate (0.1% w/v). Although it was not expected due to its greater stability, the higher dissolution rate of polymorph III could be explained by its structural features. The dissolution of carvedilol in acid medium is related to its ability to form protonated molecules. DFT calculations with the WB97XD functional were carried out for evaluation of the classical and non-classical hydrogen bonds between the molecules in carvedilol structures. The energies involved in the intermolecular interactions explain some experimental observations. This result showed that intermolecular interactions influence the solid-state properties of carvedilol. Moreover, polymorph III exhibits a higher dissolution rate than II, showing great potential for formulation strategies of this poorly water soluble drug.

Synthesis, characterization and catalytic activity of two novel cis-dioxovanadium(v) complexes: [VO2(L)] and [VO2(Hlox)]

respectively, in a distorted octahedral environment. The catalytic activity of these compounds towards cyclohexane oxidation was evaluated using H2O2 and t-BuOOH as oxidants. Both complexes presented > 70% selectivity for cyclohexylhydroperoxide formation. B3LYP/6-31G(d) calculations were used to confirm the geometry and to help assign the electronic spectra.

Sesquiterpenes from the Brazilian Red Alga Laurencia dendroidea J. Agardh

Two new chamigrane sesquiterpenes 1–2 and three known compounds 3–5 were isolated from a lipophilic extract of the red alga Laurencia dendroidea collected from the Southeastern Brazilian coast. Dendroidone (1) and dendroidiol (2) were isolated from samples collected at Biscaia Inlet, Angra dos Reis, Rio de Janeiro and at Manguinhos Beach, Serra, Espírito Santo, respectively. Debromoelatol (3), obtusane (4) and (1S*,2S*,3S*,5S*,8S*,9S*)-2,3,5,9-tetramethyltricyclo[6.3.0.01.5]undecan-2-ol (5) were obtained from specimens collected at Vermelha Beach, Parati, Rio de Janeiro. The structures of new compounds were elucidated by extensive NMR (1H-, 13C-, COSY, HSQC, HMBC and NOESY) and high resolution mass spectrometry analysis. Additionally, the absolute configuration of compound 2 was assigned by X-ray analysis. Full spectroscopic data is described for the first time for compound 3. Anti-inflammatory and antimycobacterial activities of compounds 2–5 were evaluated. Compounds 3–5 inhibited the release of inflammatory mediator NO while TNF-α levels were only affected by 3. All compounds tested displayed moderate antimycobacterial action.

Synthesis of carbohydrate-based naphthoquinones and their substituted phenylhydrazono derivatives as anticancer agents

A novel series of carbohydrate-based 1,2-naphthoquinones 13a–c and their substituted phenylhydrazono derivatives 14a–l were synthesized and evaluated for cytotoxicity against HL-60, MDA-MB435, HCT-116 and SF-295 cancer cell lines. The compounds 9a–c showed the best cytotoxicity profile (IC50 below 2 μM) against HL-60 and MDA-MB 435 human cells, while the hydrazone derivative 14i (IC50 HL-60 1.65 μM) was selective for leukemia when compared to the reference drug doxorubicin. None of the compounds exhibited lytic effects against mouse erythrocytes. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques (1H, 13C-APT, COSY-1H × 1H and HETCOR 1JCH) and by elemental analysis.

A series of mononuclear Co(III) complexes using tridentate N,O-donor ligands: Chemical properties and cytotoxicity activity

Continuing our interest in tridentate ligands to develop new prototypes of cobalt-based metallodrugs for combating cancer, modifications in the backbone of HL1, [(2-hydroxybenzyl)(2-(pyridil-2-yl)ethyl]amine) were proposed in order to modulate the redox potential of new Co(III) complexes. Three ligands with electron withdrawing groups were synthesized: HL2: [(2-hydroxy-5-nitrobenzyl)(2-(pyridil-2-yl)ethyl]amine); HL3: [(2-hydroxybenzyl)(2-(pyridil-2-yl)ethyl]imine) and HL4: [(2-hydroxy-5-nitrobenzyl)(2-(pyridil-2-yl)ethyl]imine). They were used to obtain the respective mononuclear complexes 2, 3 and 4, which are discussed compared to the previous reported complex 1 (obtained from HL1). The new complexes were characterized and studied by several techniques including X-ray crystallography, elemental and conductimetric analysis, IR, UV-vis and (1)H NMR spectroscopies, and electrochemistry. The substitutions of the group in the para position of the phenol (HL1 and HL2) and the imine instead of the amine (HL3 and HL4), promote anodic shifts in the complexes reduction potentials. The influence of these substitutions in the biological activities of the Co(III) complexes against the murine melanoma cell line (B16F10) was also evaluated. Little effect was observed on cellular viability decrease for all free ligands, however the coordination to Co(III) enhances their activities in the following range: 1>4≈2>3. The data suggest that no straight correlation can be addressed between the reduction potential of the Co(III) center and the cell viability.

Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors

The synthesis, physico-chemical characterization and cytotoxicity of four new ligands and their respective copper(II) complexes toward two human leukemia cell lines (THP-1 and U937) are reported (i.e. [(HL1)Cu(μ-Cl)2Cu(HL1)]Cl2·H2O (1), [(H2L2)Cu(μ-Cl)2Cu(H2L2)]Cl2·5H2O (2), [(HL3)Cu(μ-Cl)2Cu(HL3)]Cl2·4H2O (3), [(H2L4)Cu(μ-Cl)2Cu(H2L4)]Cl2·6H2O (4)). Ligands HL1 and HL3 contain two pyridines, amine and alcohol moieties with a naphthyl pendant unit yielding a N3O coordination metal environment. Ligands H2L2 and H2L4 have pyridine, phenol, amine and alcohol groups with a naphthyl pendant unit providing a N2O2 coordination metal environment. These compounds are likely to be dinuclear in the solid state but form mononuclear species in solution. The complexes have an antiproliferative effect against both leukemia cell lines; complex (2) exhibits higher activity than cisplatin against U937 (8.20 vs 16.25μmoldm(-3)) and a comparable one against THP-1. These human neoplastic cells are also more susceptible than peripheral blood mononuclear cells (PBMCs) toward the tested compounds. Using C57BL/6 mice an LD50 of 55mgkg(-1) was determined for complex (2), suggesting that this compound is almost four times less toxic than cisplatin (LD50=14.5mgkg(-1)). The mechanism of cell death promoted by ligand H2L2 and by complexes (2) and (4) was investigated by a range of techniques demonstrating that the apoptosis signal triggered at least by complex (2) starts from an extrinsic pathway involving the activation of caspases 4 and 8. This signal is amplified by mitochondria with the concomitant release of cytochrome c and the activation of caspase 9.

Synthesis of new 2-aminocarbohydrate-1,4-naphthoquinone derivatives promoted by ultrasonic irradiation

Neste trabalho nos descrevemos o uso do ultrassom na sintese de novas naftoquinonas, 6a-f e 7a-c, contendo na posicao 2 do anel quinonoidico substituintes do tipo aminocarboidratos. Estas substâncias foram preparadas, em condicoes brandas, atraves da reacao da 1,4-naftoquinona (8a) ou do metoxi-lapachol (8b) com diferentes aminocarboidratos 9a-d. As estruturas das substâncias foram confirmadas atraves das tecnicas de RMN de 1H e de 13C-APT, uni- e bi-dimensionais (COSY-1H vs. 1H e HETCOR 1JCH), e por espectrometria de massas de alta resolucao com ionizacao por electrospray (ESI MS).

Synthesis and antimicrobial evaluation of promising 7-arylamino-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylates and their halogenated amino compounds for treating Gram-negative bacterial infections

Pathogenic bacteria may cause serious infections, such as pneumonia, which can be fatal especially to immunosuppressed individuals. Hospitalized patients are particularly susceptible to antibiotic-resistant infections, which are worsened when caused by resistant Gram-negative pathogens due to there being few therapeutic options available. Thus, this work describes the synthesis and in vitro antimicrobial profile of 7-arylamino-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylates and their halogenated aminoquinones against Gram-positive and Gram-negative bacteria. Interestingly, these bioactive substances have shown promising activity against Gram-negative pathogenic strains. Among these derivatives, two non-halogenated amino compounds exhibited promising MIC and MBC values (MIC = MBC = 1–2 μg mL−1) against Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853, two Gram-negative strains of clinical importance. In addition, mono- and di-brominated aminoquinones were also effective in preventing the growth of E. coli (MIC = MBC = 2–4 μg mL−1). The in vitro hemocompatibility evaluation showed a low toxicity profile for the active aminoquinones in hemolysis assays. These results suggest that these substances have potential for exploring the design of new antimicrobial prototypes against Gram-negative bacteria.