Gustavo Seoane

Synthesis and antitrypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives. Structure-activity relationships.

Several novel semicarbazone derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde and semicarbazides bearing a spermidine-mimetic moiety. All derivatives presented the E-configuration, as determined by NMR-NOE experiments. These compounds were tested in vitro as potential antitrypanosomal agents, and some of them, together with the parent compounds, 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives, were also evaluated in vivo using infected mice. Structure-activity relationship studies were carried out using voltammetric response and lipophilic-hydrophilic balance as parameters. Two of the compounds (1 and 3) displayed the highest in vivo activity. A correlation was found between lipophilic-hydrophilic properties and trypanocidal activity, high R(M) values being associated with low in vivo effects.

Synthesis and anti-trypanosomal activity of novel 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives

Several novel semicarbazones derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde, and tested in vitro as potential anti-trypanosomal agents. The compounds were prepared in good to excellent yields in 2-3 steps from readily available starting materials. Some derivatives were found to be active against Trypanosoma cruzi with an activity similar to that of Nifurtimox.

CYCLIC VOLTAMMETRY AND ELECTRON PARAMAGNETIC RESONANCE STUDIES OF SOME ANALOGUES OF NIFURTIMOX

Abstract The EPR of radicals obtained by electrolytic reduction of some new analogues of the antiprotozoal drug nifurtimox were measured in DMSO and DMF. The electrochemistry of these compounds was studied using cyclic voltammetry AM1 and INDO semiempirical molecular orbital calculations were performed to obtain the optimized geometries and spin distribution, respectively. Density functional theory was used to rationalize the reduction potentials of these compounds.

Electron Spin Resonance and Cyclic Voltammetry Studies of Nitrofurane and Nitrothiophene Analogues of Nifurtimox

Abstract The electron spin resonance (ESR) of radicals obtained by electrolytic reduction of 4-[2-(3,4-Dimethoxiphenyl)ethyl]-1-(5-nitrofurfurylidine)semicarbazide and 4-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(5-nitrothienilydene)semicarbazide were measured in DMSO. The electrochemistry of these compounds was studied in DMSO, DMF and ACN using cyclic voltammetry.

Chemoenzymatic Synthesis and Biological Evaluation of (−)‐Conduramine C‐4

Abstract Previously unreported (−)‐conduramine C‐4 was synthesized in six steps from a bacterial bromobenzene metabolite in 23% overall yield. The chemoenzymatic route involved toluene dioxygenase dihydroxylation, β‐epoxidation, epoxide ring‐opening, Staudinger reduction, radical debromination, and Amberlite‐ catalyzed hydrolysis. (−)‐Conduramine C‐4 and other related compounds synthesised were assayed for galactosidase‐activity inhibition against β‐D‐galactoside galactohidrolase isolated from Aspergillus oryzae.

Computer assisted design of potentially active anti-trypanosomal compounds

Abstract A computer assisted molecular modeling was used to design molecules having a shape complementary to the active site of glutathione reductase (GR) and trypanothione reductase (TR). The designed 5-nitro compound derivatives, were obtained from structural knowledge gleaned on glutathione (GSSG), trypanothione (T[S]2) and GSP disulfide (glutathionylspermidine disulfide). These molecules form complexes with the enzymes GR and TR. The theoretical lead compound was: N1-[1-(5-nitro-2-furyl)methylidene]-N4-{4-[3-(2,2,2-trifluoroacetyl)hexahydro-1-1-pyrimidynil]butyl} semicarbazide (NPIPCO). A multi-disciplinary team developed around the efforts to synthesize this lead. In this work we report on eight compounds that were synthesized in the pathway to NPIPCO: 4-(2-methoxyethyl)-1-, 4-butyl-1-, 4-hexyl-1- and 2-methoxphenyl-1-(5-nitrofurfurilidene) semicarbazides and the corresponding 5-nitrothiophenes. These substances are expected to act as pro-transition state analogues. Enzymologic studies proved that many of these compounds are inhibitors of TR. Furthermore, they showed inhibitory activity on Tripanosoma cruzi growth in vitro.

Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile

Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed. The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep. For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software. Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT2A receptor activation by hallucinogens, was not modified. We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression. In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects.

Early detection of chloroform hot spots in the Montevideo drinking water network

Abstract The use of chlorine to disinfect water produces a series of by-products, particularly trihalomethanes. This is important given that there is a recognized association with different types of cancer after prolonged exposure, as well as with probable adverse effects on reproduction, especially in relation to offspring. The concentrations of these organic compounds vary greatly depending on the season and the conditions involved in providing water for consumption. This study was aimed at determining the geographic distribution pattern of chloroform in the city of Montevideo, and correlating that with the characteristics of the water distribution network. A total of 400 samples were taken from a sampling network between 2009 and 2015. Chloroform was identified by analyzing these samples using the headspace gas chromatography/mass spectrometry method. Data regarding piping length, diameter, and type of material were obtained. A geographic information system was constructed and hot spots were analyzed using the Getis–Ord Gi* statistic. A neighborhood piping density index was also proposed. The analysis found two zones in the city: hot and cold spots. The proposed index showed an increase in the Gi* statistic as the neighborhoods’ piping density increased, with a strong correlation. In addition, the highest Gi* statistic values corresponded to larger amounts of iron piping in neighborhoods. This work was able to determine that the hot spots were associated with the piping density in the neighborhoods as well as with the type of piping material, particularly iron.

Nuclear Magnetic Resonance for the Structural Study of Bioactive Semicarbazones

Laboratorio de RMN, Facultad de Ciencias, Igua S/N, Universidad de la Republica, Montevideo,UruguayE-mail: megonzal@bilbo.edu.uyAbstract: NMR studies of bioactive semicarbazones are described.IntroductionWithin our work on the development of bioactive compounds, we have employed the semicarba-zone moiety as a joining function between different pharmacophores.

Reactivity Studies of 5,6-Dimethyl- and 3,5,6-Trimethyl -1,2,4-Triazine–N4-Oxide Against Different Electrophiles

It describes the regioselectivity studies of 5,6-Dimethyl-1,2,4-triazine-N4-oxide using different electrophiles.