In vitro anti-Giardia lamblia activity of 2-aryl-3-hydroxymethyl imidazo[1,2-a]pyridines and -pyrimidines, individually and in combination with albendazole.

Giardiasis is a major diarrheal disease found throughout the world, the causative agent being the flagellate protozoan Giardia intestinalis. Infection is more common in children than in adults. The appearance of drug resistance has complicated the treatment of several parasitic diseases, including giardiasis. Thus, the aim of this investigation was to make an in vitro evaluation of the antigiardia response of synthetic derivatives 2-aryl-3-hydroxymethylimidazo[1,2-a]pyridines 1 and -pyrimidines 2 against trophozoites of Giardia lamblia WB, in comparison with the reference drug, albendazole. Additionally, the synergistic action of albendazole in combination with each of the most active 2-aryl-3-hydroxymethyl imidazo[1,2-a]pyridines and pyrimidines was also assessed. Based on the IC50 values obtained, the best anti-Giardia activity was provided by the 3-hydroxymethyl-4-fluorophenylimidazo[1,2-a]pyrimidine derivative 2c and the corresponding imidazo[1,2-a]pyrimidine with the p-tolyl substituent 2d, followed by 2a and 2b. These four compounds showed effectiveness at a concentration similar to that of albendazole. Regarding synergism, the IC50 of the combination of albendazole with 2a, 2b or 2c gave the best anti-Giardia action, showing greater efficacy than albendazole alone. Hence, G. lamblia WB showed high susceptibility to some 2-aryl-3-hydroxymethyl imidazo[1,2-a] pyrimidines, which acted synergistically when used in combination with albendazole.

Targeting quorum sensing by designing azoline derivatives to inhibit the N-hexanoyl homoserine lactone-receptor CviR: Synthesis as well as biological and theoretical evaluations.

To counteract bacterial resistance, we investigated the interruption of quorum sensing mediated by non-classical bioisosteres of the N-hexanoyl homoserine lactone with an azoline core. For this purpose, a set of selected 2-substituted azolines was synthesized, establishing the basis for a new protocol to synthesize 2-amino imidazolines. The synthesized compounds were evaluated as inhibitors of violacein production in Chromobacterium violaceum. Theoretical studies on bioisostere-protein interactions were performed using CviR. The results show that some azolines decreased violacein production, suggesting an antiquorum sensing profile against Gram-negative bacteria. Docking and molecular dynamic simulations together with binding free energy calculations revealed the exact binding and inhibitory profiles. These theoretical results show relationship with the in vitro activity of the azoline series.

Computational POM and DFT Evaluation of Experimental in-vitro Cancer Inhibition of Staurosporine-Ruthenium(II) Complexes: the Power Force of Organometallics in Drug Design.

A computational Petra/Osiris/Molinspiration/DFT(POM/DFT) based model has been developed for the identification of physico-chemical parameters governing the bioactivity of ruthenium-staurosporine complexes 2-4 containing an antitumoral-kinase (TK) pharmacophore sites. The four compounds 1-4 analyzed here were previously screened for their antitumor activity, compounds 2 and 4 are neutral, whereas analogue compound 3 is a monocation with ruthenium(II) centre. The highest anti- antitumor activity was obtained for compounds 3 and 4, which exhibited low IC(50) values (0.45 and 8 nM, respectively), superior to staurosporine derivative (pyridocarbazole ligand 1, 150 · 10(3) nM). The IC(50) of 3 (0.45 nM), represents 20,000 fold increased activity as compared to staurosporine derivative 1. The increase of bioactivity could be attributed to the existence of pi-charge transfer from metal-staurosporine to its (CO(δ)--NH(δ+)) antitumor pharmacophore site.

Intramolecular H-bonding interaction in angular 3-π-EWG substituted imidazo[1,2-a]pyridines contributes to conformational preference.

BACKGROUND: The proton at position 5 of imidazo[1,2-a]pyridines substituted with an angular electron withdrawing group (EWG) at position 3, shows an unusual downfield chemical shift, which is usually explained in terms of a peri effect. However usage of this term is sometimes confusing. In this investigation, it is proposed that the aforementioned shift is in fact a combination of several factors: Anisotropy, long-distance mesomerism and an attractive intramolecular interaction of the electrostatic hydrogen bond type. RESULTS: Theoretical calculations were performed aimed to obtain evidence of the existence of an intramolecular non-bonding interaction between H-5 and the oxygen atom of the EWG. Results derived from conformational and vibrational analysis at the DFT B3LYP/6-311++G(d,p) level of theory, the determination of Bond Critical Points derived from AIM theory, and the measurement of some geometrical parameters, support the hypothesis that the higher stability of the prevailing conformation in these molecules (that in which the oxygen of the EWG is oriented towards H-5) has its origin in an intramolecular interaction. CONCLUSION: Computational calculations predicted correctly the conformational preferences in angular 3-π-EWG-substituted imidazo[1,2-a]pyridines. The existence of an electrostatic hydrogen bond between H-5 and the oxygen atom of the π-EWG was supported by several parameters, including X-ray crystallography. The existence of such structural array evidently impacts the H-5 chemical shift.

Fluorescent property of 3-hydroxymethyl imidazo[1,2-a]pyridine and pyrimidine derivatives.

BACKGROUND: Imidazo[1,2-a]pyridines and pyrimidines are important organic fluorophores which have been investigated as biomarkers and photochemical sensors. The effect on the luminescent property by substituents in the heterocycle and phenyl rings, have been studied as well. In this investigation, series of 3-hydroxymethyl imidazo[1,2-a]pyridines and pyrimidines were synthesized and evaluated in relation to fluorescence emission, based upon the hypothesis that the hydroxymethyl group may act as an enhancer of fluorescence intensity. RESULTS: Compounds of both series emitted light in organic solvents dilutions as well as in acidic and alkaline media. Quantitative fluorescence spectroscopy determined that both fused heterocycles fluoresced more intensely than the parent unsubstituted imidazo[1,2-a]azine fluorophore. In particular, 3-hydroxymethyl imidazo[1,2-a]pyridines fluoresced more intensely than 3-hydroxymethyl imidazo[1,2-a]pyrimidines, the latter emitting blue light at longer wavelengths, whereas the former emitted purple light. CONCLUSION: It was concluded that in most cases the hydroxymethyl moiety did act as an enhancer of the fluorescence intensity, however, a comparison made with the fluorescence emitted by 2-aryl imidazo[1,2-a]azines revealed that in some cases the hydroxymethyl substituent decreased the fluorescence intensity.

Imidazolines as non-classical bioisosteres of N-acyl homoserine lactones and quorum sensing inhibitors.

A series of selected 2-substituted imidazolines were synthesized in moderate to excellent yields by a modification of protocols reported in the literature. They were evaluated as potential non-classical bioisosteres of AHL with the aim of counteracting bacterial pathogenicity. Imidazolines 18a, 18e and 18f at various concentrations reduced the violacein production by Chromobacterium violaceum, suggesting an anti-quorum sensing profile against Gram-negative bacteria. Imidazoline 18b did not affect the production of violacein, but had a bacteriostatic effect at 100 µM and a bactericidal effect at 1 mM. Imidazoline 18a bearing a hexyl phenoxy moiety was the most active compound of the series, rendering a 72% inhibitory effect of quorum sensing at 100 µM. Imidazoline 18f bearing a phenyl nonamide substituent presented an inhibitory effect on quorum sensing at a very low concentration (1 nM), with a reduction percentage of 28%. This compound showed an irregular performance, decreasing inhibition at concentrations higher than 10 µM, until reaching 100 µM, at which concentration it increased the inhibitory effect with a 49% reduction percentage. When evaluated on Serratia marcescens, compound 18f inhibited the production of prodigiosin by 40% at 100 µM.

Synthesis of demethylated nidulol via an intramolecular Michael reaction.

An expeditious synthesis of 5,7-dihydroxy-6-methylphthalide from open-chain precursors is described. The key intermediates, synthons 3 and 4, were readily obtained from accessible materials and were further transformed to a common precursor, a five-membered lactone derivative, via an intramolecular Michael addition. Lactone 2 was aromatised to the phthalide system under basic conditions. The process thus constitutes a formal synthesis of the phthalide framework.

Efecto anabólico y androgénico del esteroide acetato de trembolona en el guppy (Poecilia reticulata) / Anabolic and androgenic effect of steroid trenbolone acetate on guppy (Poecilia reticulata)

The effect of semi-synthetic steroid trenbolone acetate (TBA) on the ornamental fish Poecilia reticulata (guppy) was studied. The steroid at a dose of 300 mg/kg feed was administered to 30 days old juvenile specimens during 60 days. Forty days after treatment was ended, an evaluation aimed to determine the steroid residual effect was undertaken. Survival, masculinization ratio and the drug anabolic effect were analyzed. Results showed TBA to be effective to induce masculinization, differing (P < 0.001) with the control group, which registered 32% males and 68% females. TBA turned out to be an excellent anabolic as well, since treated fish showed weight increase, a larger body and an increased size of caudal fin. The steroid did not cause any damage on the treated population. The survival factor was 93.3% for the treated fish as compared to 83% for the control group.

Se investigó el efecto del esteroide semisintético acetato de trembolona (ATB) en el pez de ornato Poecilia reticulata (guppy). Especímenes juveniles de 30 días de edad fueron tratados con el esteroide a dosis de 300 mg/kg de alimento durante 60 días. Al término del tratamiento, 40 días después, se estimó el efecto residual del esteroide. Se analizó la sobrevivencia, la proporción de peces masculinizados, así como el efecto anabólico. Los resultados indicaron que el ATB es eficaz para inducir la masculinización, a diferencia del grupo testigo, donde se registraron 32% de machos. Asimismo, el ATB tuvo un efecto anabólico, ya que los peces tratados mostraron mayor peso y talla e incremento de la aleta caudal. El esteroide no causó daño en la población tratada, al sobrevivir 93.3% de los peces, comparado con 83% del grupo testigo.

Synthesis and anti-inflammatory activity evaluation of unsymmetrical selenides.

The alkylation reaction of 2,2'-diseleno and 4,4'-diseleno-bis(benzoic acid) derivatives in the presence of sodium borohydride and alkyl halides allowed the synthesis of various new o- and p-alkylselenenylated benzoic acid derivatives in good yields. The anti-inflammatory activity of selected selenide derivatives on granuloma induced by subcutaneous implantation of cotton pellets in Wistar rats was examined. Selenium derivatives 2a, 2c and 2e showed anti-inflammatory activity although to a lesser extent as compared to indomethacin, however they were found less toxic than the latter.

A high-throughput colorimetric and fluorometric microassay for the evaluation of nitroimidazole derivatives anti-trichomonas activity.

Several nitroimidazole derivatives were synthesized and tested as possible trichomonicidal agents. A fast, simple, practical and reliable in vitro colorimetric method was applied to the screening of the nitroimidazole derivatives anti-trichomonas activity. The colorimetric technique was based on the use of Alamar blue as a redox-indicator. The test was carried out both qualitatively (minimal inhibitory concentration determined by naked eye observation) and quantitatively (fluorometric determination of 50% and 90% inhibitory concentrations), the latter took advantage of the dye fluorometric properties. The performance of the method was excellent affording an exactitude 97.86% and a reproducibility of 95% and no interference of the trichomonas-culture medium was observed during the test. Some of the nitroimidazole compounds tested showed a fair trichomonicidal activity, however none of them was as active as the model compound, metronidazole.

Cytogenetic study of metronidazole and three metronidazole analogues in cultured human lymphocytes with and without metabolic activation.

Metronidazole (MTZ) and other nitroimidazole derivatives have been extensively used to treat infections caused by protozoa and anaerobic bacteria. However, the need for new derivatives with similar therapeutic activity but lower toxicity to human beings prevails. On this purpose, three metronidazole analogues were synthesized, namely: 1-(p-methylphenacyl)-2-methyl-4-nitro imidazole (CPMe), 1-(p-methoxyphenacyl)-2-methyl-4-nitroimidazole (CPMeO), and 1-(p-fluorphenacyl)-2-methyl-4-nitroimidazole (CPF), which at low concentrations (0.5-2 microg/ml) showed a higher activity against Entamoeba histolytica than MTZ (3-6 microg/ml). The aim of this work was to investigate the cytogenetic effect of the three MTZ analogues on human lymphocyte cultures with and without metabolic activation in vitro, using the sister chromatid exchange test (SCE), comparatively with MTZ. The effect of the compounds on the cell proliferation kinetics (CPK) measured by the replication index (RI) and the cytotoxic effect in the mitotic index (MI) was evaluated as well. The SCE frequencies with and without S9 metabolic activation in treated and control lymphocytes showed no significant statistical differences. However when metabolic activation was involved a significant increase in the amount of third division metaphases provoked the CPK increased significantly with all the tested compounds. The RI showed similar behaviour, except for compound CPF.