Alessandra C. Pinheiro

Design, synthesis and biological evaluation of (E)-2-(2-arylhydrazinyl)quinoxalines, a promising and potent new class of anticancer agents

A series of forty-seven quinoxaline derivatives, 2-(XYZC6H2CHN-NH)-quinoxalines, 1, have been synthesized and evaluated for their activity against four cancer cell lines: potent cytotoxicities were found (IC50 ranging from 0.316 to 15.749 μM). The structure-activity relationship (SAR) analysis indicated that the number, the positions and the type of substituents attached to the aromatic ring are critical for biological activity. The activities do not depend on the electronic effects of the substituents nor on the lypophilicities of the molecules. A common feature of active compounds is an ortho-hydroxy group in the phenyl ring. A potential role of these ortho-hydroxy derivatives is as N,N,O-tridentate ligands complexing with a vital metal, such as iron, and thereby preventing proliferation of cells. The most active compound was (1: X,Y=2,3-(OH)2, Z=H), which displayed a potent cytotoxicity comparable to that of the reference drug doxorubicin.

Synthesis and Biological Aspects of Mycolic Acids: An Important Target Against Mycobacterium tuberculosis

Mycolic acids are an important class of compounds, basically found in the cell walls of a group of bacteria known as mycolata taxon, exemplified by the most famous bacteria of this group, the Mycobacterium tuberculosis (M. tb.), the agent responsible for the disease known as tuberculosis (TB). Mycolic acids are important for the survival of M. tb. For example, they are able to help fight against hydrophobic drugs and dehydration, and also allow this bacterium to be more effective in the hosts immune system by growing inside macrophages. Due to the importance of the mycolic acids for maintenance of the integrity of the mycobacterial cell wall, these compounds become attractive cellular targets for the development of novel drugs against TB. In this context, the aim of this article is to highlight the importance of mycolic acids in drug discovery.

(S)-1-[N-(Benzylidene)hydrazinylcarbonyl]-2-hydroxyethylcarbamate esters: layered structures created from X—H···O (X = N,O) hydrogen-bonds

Abstract The molecular structures of tert-butyl (S)-2-hydroxy-[N-(substituted-benzylidene)hydrazinyl-carbonyl]-ethylcarbamates, C15H20N3O4X (3: X = H, o-OH, o-NO2, m-NO2 and p-CN), derived from L-serine, are formally rather similar. Despite the variation in substituent, X, tricälinic (3: X = H), (3: X = o-OH), (3: X = m-NO2) and (3: X = p-CN) are isostructural and exhibit, with minor variations, the same fundamental intermolecular O—H···O and N—H···O hydrogen-bond connectivity in two-dimensions in layers of molecules. In monoclinic (3: X = o-NO2), however, the oxygen atoms of the nitro group function as additional O—H···O and N—H···O hydrogen-bond acceptors resulting in a more complex form of two-dimensional connectivity.

Synthesis, cytotoxicity, and in vitro antileishmanial activity of mono-t-butyloxycarbonyl-protected diamines☆

Leishmania amazonensis is the etiologic agent of the cutaneous and diffuse leishmaniasis. This species is often associated with drug resistance, and the conventional treatments exhibit high toxicity for patients. Therefore, the search for new antileishmanial compounds is urgently needed since there is no vaccine available. In this study, using the in vitro traditional drug screening test, we have analyzed the effects of a series of diaminoalkanes monoprotected with t-butyloxycarbonyl (BOC) against L. amazonensis. Among the 18 tested compounds, 6 exhibited antileishmanial activity (2, 7-9, 17, and 18). Best IC(50) values (10.39 ± 0.27 and 3.8 ± 0.42 μg/mL) were observed for compounds 17 and 18 (H(2)N(CH(2))nNHBoc, n = 10 and 12), respectively. Although those compounds had higher lipophilicity as indicated by their cLog P values, compound 17 was very toxic. Determination of the selective indexes indicated that 50% of the active compounds were very toxic for HepG2 cells. However, compounds 2, 8, and 18 had good lipophilicity and were less toxic among all polyamine derivatives tested. The chemical properties of antileishmanial diamine derivatives, such as lipophilicity and cytotoxicity, are relevant factors for the design of new drugs. A higher lipophilicity is likely to improve the chances of reaching this intracellular parasite.

Synthesis and in vitro activity towards Mycobacterium tuberculosis of L-serinyl ester and amino derivatives of pyrazinoic acid

Reactions between either L-serine methyl ester hydrochloride (1), or the cbz derivative, methyl (S)-(+)-2-(benzyloxycarbonylamino)-3-hydroxypropanoate (2), and pyrazinoyl chloride (3), have been studied. Methyl (S)-(+)-2-benzyloxycarbonylamino-3-[(pyrazinecarbonyl)oxy]propionate (4), methyl (S)-(+)-3-hydroxy-2-[(pyrazine-2-carbonyl) amino]propionoate (7), methyl 2-[(pyrazinecarbonyl)amino]acrylate (8) were obtained. Additional products, methyl (S)-(+)-2-benzyloxycarbonylamino-3-formyloxypropionoate (5) and methyl (R)-(+)-2-benzyloxycarbonylamino-3-chloropropionoate (6), were isolated from reaction of 2 with 3, in the presence of DMF remaining from the preparation of 3, from pyrazinecarboxylic acid. The coupling of pyrazinecarboxylic acid with 1, in the presence of DCC was prevented by the formation of the unreactive adduct between DCC and pyrazinoic acid. The compounds were tested against M. tuberculosis: compounds (8) and (6) exhibited a MIC (μg/ml) value of 50 and 100, respectively, compared to the MIC value of 100 for the first line TB drug, pyrazinamide. The confirmation of the structure of (8) was obtained via X-ray crystallography.

Synthesis and Antitubercular Activity of Novel Amino Acid Derivatives

In this work, 17 new N‐acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. The compounds 8b, 8e, 8f, 9a–d, and 10c exhibited an important minimum inhibitory concentration activity between 12.5 and 50 μg/mL, which can be compared with that of the tuberculostatic drug d‐cycloserine (20 μg/mL).

Simple Methodology for the Preparation of Amino Alcohols from Amino Acid Esters Using NaBH4–Methanol in THF

Abstract Amino alcohols constitute a very useful and versatile class of organic compounds, with important applications in synthetic and medicinal chemistry. However, in most of the procedures described in the literature for the obtainment of these compounds, considerable limitations can be found, such as drastic conditions, long time reactions, poor yields, and purification problems. The present article describes a methodology that gives amino alcohols and N-protected amino alcohols based on the reduction of amino acid esters under mild conditions, employing NaBH4 in the presence of methanol. The reactions occurred in a short time (15–20 min) and provide yields of 50–95%.

Synthesis and antitubercular activity of new L-serinyl hydrazone derivatives.

A series of 32 L-serinyl hydrazone derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv, being also evaluated their cell viabilities in non infected and infected macrophages with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). The compounds 8c, 8e, 8h and 8i, were non-cytotoxic and exhibited an important minimum inhibitory concentration (MIC) activity between 25 and 100 μg/mL, which can be compared with that of the tuberculostatic drug D-cicloserine (5-20 μg/mL).

Benzyl N-[(S)-2-hydroxy-1-({[(E)-2-hydroxy-4-methoxybenzylidene]hydrazinyl}carbonyl)ethyl]carbamate

The shape of the title compound, C19H21N3O6, is curved with the conformation about the imine bond [1.291 (3) Å] being E. While the hydroxy-substituted benzene ring is almost coplanar with the hydrazinyl residue [N—N—C—C = 177.31 (18)°], an observation correlated with an intramolecular O—H⋯N hydrogen bond leading to an S(6) ring, the remaining residues exhibit significant twists. The carbonyl residues are directed away from each other as are the amines. This allows for the formation of O—H⋯O and N—H⋯O hydrogen bonds in the crystal, which lead to two-dimensional supramolecular arrays in the ac plane. Additional stabilization to the layers is afforded by C—H⋯π interactions.

Benzyl N-((S)-2-hydr­oxy-1-{N′-[(E)-2-methoxy­benzyl­idene]hydrazinecarbon­yl}eth­yl)carbamate from synchrotron data

A U-shaped conformation is found in the title compound, C19H21N3O5, with the benzene rings lying to the same side of the molecule; the dihedral angle between them is 10.83 (16)°. The dihedral angle formed between the hydrazinecarbonyl and carbamate residues is 68.42 (13)°. The carbonyl groups lie approximately at right angles to each other [O—C⋯C—O pseudo torsion angle of 107.7 (3)°], and the conformation about the C12=N3 bond [1.279 (4) Å] is E. An intramolecular Ncb—H⋯Ohy (cb = carbmate and hy = hydroxy) hydrogen bond occurs, generating an S(6) loop. In the crystal, intermolecular Oh—H⋯Oca (ca = carbonyl) and Nhz—H⋯Oca (hz = hydrazine) hydrogen bonds lead to the formation of a supramolecular chain, two molecules thick, which propagates along the a axis; these are connected by C—H⋯Oca contacts.