Héctor Salgado-Zamora

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

BackgroundImidazo[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.ResultsCompounds 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.ConclusionIt 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.

POM analyses of antimicrobial activity of some 2,3-armed 4,5,6,7-tetrahydro-1-benzothiophenes: favourable and unfavourable physico-chemical parameters in design of antibacterial and mycolytic agents

In the present contribution, we have used petra, osiris and molinspiration (POM) analyses to identify pharmacophores and anti-pharmacophores for antibacterial/antifungal activity of some benzothiophene derivatives (THBT). Lipophilicity and presence of tautomerism processes were the major factors that governed the orientation to antibacterial and/or antiviral activity. It was also observed that these compounds POM analyzed have a closed pharmacophore site which might be bioactivity low. Further, we have carried out receptor-based electrostatic analysis to confirm the electronic, steric and hydrophobic requirements for future modifications. The POM analyses provide substantial idea about the structural features responsible for their combined antibacterial/antifungal activity and provide guidelines for further modifications, with the aim of improving the activity and selectivity of designed drugs targeting potentially the drug-resistant microorganisms.Graphical AbstractThe impact of intramolecular OH/N and NH/N interactions on bioactivity of pharmacophores sites of THBT series 5–15 is established. The POM analyses of 2,3-armed 4,5,6,7-tetrahydro-1-benzothiophenes (THBT) 5–15 provide substantial idea about the structural features responsible for their failure as dual antibacterial/antifungal agents and provide guidelines for further modifications, with the aim of improving the activity and selectivity of designed drugs targeting potentially the bacterial and fungal enzymes responsible of diseases.

Anti‐anxiety and sedative profile evaluation of imidazo[1,2‐a]pyridine derivatives

Three imidazo[1,2‐a]pyridine‐3‐nitrosated (L‐1, L‐2, L‐3) and a 3‐formyl imidazo[1,2‐a]pyridine thiosemicarbazone (L‐4) were synthesized and evaluated for their effects in the elevated plus maze, burying behavior test, rotarod performance, the horizontal wire test, and locomotor activity. L‐2 and L‐3 increased the percent time spent in the open arms of the plus maze at doses of 1 and 2 mg/kg without modifying the number of total entries. In addition, L‐2 and L‐3 (1 mg/kg) increased the number of open arm entries indicating anxiolytic‐like activity at this dose. In the burying behavioral test, L‐1 (2–8 mg/kg), L‐2 (8 mg/kg), and L‐3 (4 and 8 mg/kg), induced a clear reduction in cumulative burying behavior, without modifying burying behavior latency, thus reducing experimental anxiety. In the rotarod test, L‐1 and L‐2 impaired rotarod performance only at the highest evaluated dose (64 mg/kg) at which reduction of motor activity was observed and thereby no conclusions about myorelaxant effects can be proposed. All compounds showed a clear sedative effect and corresponding ED50 values were obtained. Results indicate that compounds L‐1, L‐2, and L‐3 show a sedative and an anxiolytic profile. Drug Dev Res 71:371–381, 2010.

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.

Impact of Geometric Parameters, Charge, and Lipophilicity on Bioactivity of Armed Quinoxaline, Benzothiaole, and Benzothiazine: Pom Analyses of Antibacterial and Antifungal Activity

Abstract A series of four different armed heterocyclic candidates; 1-(2-methyl-2,3-dihydro-1,3-benzothiazol-2-yl)acetone (2), 1-(3-methyl-4H-1,4-benzothiazin-2-yl)ethanone (3), 2-[(2-aminophenyl)dithio]aniline (4), and 3-hydroxy-3-methyl-4-(3-methyl-2-quinoxalinyl)-2-butanone (5) have been prepared and their microbial activities were evaluated. A correlation of the structure and activities relationships of these compounds with respect to molecular modeling, Lipinski Rule of Five, drug likeness, toxicity profiles, and other physico-chemical properties of drugs are described and verified experimentally. GRAPHICAL ABSTRACT

SYNTHESIS OF ENAMINONITRILE IMIDAZO[l. 2-a]PYRIDINE BY AN EHRLICHSACHS TYPE REACTION ON 2-NITROSOPYRIDINE

An Erlich-Sachs type reaction on 2-nitrosopyridines with malononitrile and a few drops of triethylamine produced 3-amino-2-cyanoimidazo[l,2-a]pyridines directly. The structure of the enaminonitrile was confirmed by an independent synthesis and chemical behavior. The Imidazopyridine nitroester derivative used in the synthesis was employed as a synthon in an alternative route to pyridoimidazopyrimidones.

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.

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.

POM analyses for antimicrobial evaluation of thienopyrimidinones derivatives: a rapid method for drug design

AbstractIn this work, a new and efficient strategy to identify pharmacophores and anti-pharmacophores sites in thienopyrimidinone derivatives for antibacterial/antifungal activity using Petra, Osiris and Molinspiration (POM) analyses is described. We carried out receptor based electrostatic analysis to confirm the electronic, steric and hydrophobic requirements for further modifications. Results showed that the major factors that govern the orientation to antibacterial/antiviral activity were of lipophilicity and presence of tautomerism. In addition, POM analyzed compounds constitute different supplementary attractive active sites that possess significant bioactivity and qualify them as promising candidates that might be responsible to inhibit kinase enzymes. Furthermore, the POM analyses provide substantial idea about the structural features of thienopyrimidinone derivatives in relation to biological activities against disease causing agents. Our results suggest future work on these POM assessed derivatives to evaluate their toxicity in human cells and selectivity which improve activity against cancer causing kinase enzymes by developing target oriented new drugs to save humanity.Graphical AbstractThe identification of potential combined antibacterial/ antifungal and antitumor pharmacophores sites of 4-12, using POM analyses, is the crucial step in optimization of hits. The POM analyses of thienopyrimidinones 4-12 provide substantial idea about the structural features responsible for their combined antibacterial/antifungal activity and provide guidelines for further modifications, with the aim of improving the activity and selectivity of designed drugs targeting potentially the kinase enzyme responsible of cancer.