Nenad Janković

Ferrocenyl based pyrazoline derivatives with vanillic core: synthesis and investigation of their biological properties

Vanillin O-alkylated derivatives and acetylferrocene reacted under Claisen–Schmidt conditions yielding the corresponding ferrocene containing chalcones in good-to-high yields. Under similar conditions, O-alkylated derivatives of acetovanillone were reacted with ferrocenylcarbaldehyde. Two series of novel N-acetyl and N-formyl pyrazoline derivatives were prepared by cyclocondensation of previously described chalcones (containing ferrocene framework and vanillic fragment) with hydrazine hydrate in acidic solvent (formic acid or acetic acid). All synthesized compounds were fully characterized by spectral and physical data and were tested for their biological activity. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration using the broth microdilution method. The activity of the synthesized compounds was compared with standard antibiotics. The most active antibacterial compounds were 1-[5-(3,4-dimethoxyphenyl)-3-ferrocenyl-4,5-dihydro-1H-pyrazol-1-yl]ethanone (4a) and 1-[5-(4-benzyloxy-3-methoxyphenyl)-3-ferrocenyl-4,5-dihydro-1H-pyrazol-1-yl]ethanone (4f); the best antifungal activity was shown by compounds of type 4. The interaction of 4a, 4f, 5a and 5e with DNA and bovine serum albumin (BSA) were investigated by fluorescence spectroscopic method. The results achieved in competitive experiments with ethidium bromide (EB) indicated that 4a and 5e have larger affinity to displace EB from the EB–DNA complex than 4f and 5a, probably through intercalation. Fluorescence spectroscopy data show that the fluorescence quenching of BSA is a result of the formation of the 4a, 4f, 5a and 5e–BSA complex species. Measured values of Ka showed that compounds which contain the acetovanillone-formyl core (5a and 5e) formed more stable complexes with BSA than compounds with the vanillin-acetyl core (4a and 4f), suggesting that 4a– and 4f–BSA are less suitable for drug–cell interactions.

Solvent-free synthesis of novel vanillidene derivatives of Meldrum's acid: biological evaluation, DNA and BSA binding study

A series of novel O-alkyl vanillidene derivatives containing Meldrums acid scaffold under solvent-free conditions were synthesized. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration (MIC) using the broth microdilution. The most active compounds were 5-(4′-hydroxy-2′-iodo-3′-methoxybenzylidenyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3a), 5-(4′-acetoxy-3′-methoxybenzylidenyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3f), and 5-(4′-bromopropoxy-3′-methoxybenzylidenyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3h) with the MIC values ranging from 0.039 to 10 mg mL−1. Antioxidant activity was evaluated by DPPH free radical scavenging activity. 3h showed the largest scavenging activity with an IC50 value of 55.61 μg mL−1 (0.14 mmol L−1). The interaction of 3a and 3h with DNA and bovine serum albumin (BSA) were investigated by the fluorescence spectroscopic method. The results achieved in competitive experiments with ethidium bromide (EB) indicated that 3a and 3h have an affinity to displace EB from the EB–DNA complex through intercalation. Fluorescence spectroscopy data show that the fluorescence quenching of BSA is a result of the formation of the 3a- and 3h-BSA complex species, and indicate that 3a-BSA is more stable, suggesting that 3h-BSA is less suitable for drug–cell interactions.

DFT study of the mechanism of the phenylselenoetherification reaction of linalool

A systematic study of the mechanism of phenylselenoetherification of a naturally occurring alcohol linalool with PhSe+ was performed at the B3LYP/6-311+G(d,p) level of theory, in conjunction with the CPCM solvation model. The syn and anti reaction pathways were examined in the absence and presence of some Lewis bases (quinoline, piperidine, pyridine, and triethylamine) as catalysts. It was found that the reaction occurs via the phenylseleniranium intermediate, which further suffers a nucleophilic attack of the oxygen to two olefinic carbon atoms. This intramolecular cyclization yields 5-ethenyl-5-methyl-2-[2-(phenylseleno)-prop-2-yl]tetrahydrofuran as the major product and 6-ethenyl-2,2,6-trimethyl-3-phenylselenotetrahydropyran as the minor product. Lewis bases facilitate the reaction by strong hydrogen bonds between the alcoholic hydrogen and nitrogen of an additive moiety, and they stabilize the product complexes. Since the formation of the tetrahydrofuran derivative requires higher activation energy, but is thermodynamically more stable than the tetrahydropyran, it was concluded that the phenylselenoetherification reaction of linalool is thermodynamically controlled.Graphical Abstract

Influence of the counteranion on the phenylselenoetherification reaction of nerolidol

Abstract The pyridine-mediated reactions of nerolidol with both PhSe+ and PhSeCl were investigated using two DFT methods. Comparison of the obtained results provides a description of the counterion influence for the first time. As a consequence of very low solvation free energy of the neutral reactants, addition of the phenylselenyl group to the double bond of nerolidol is an endergonic process, and occurs via a transition state to yield an intermediate that undergoes cyclisation. Due to the influence of the counteranion on the positively charged moiety of the reaction system, the activation free energies in the reaction with PhSeCl are significantly larger than those in the reaction with PhSe+. Thus, only the anti pathway is favoured. The lower activation energy required for the formation of less stable cis-5-ethenyl-5-methyl-2-[6-methyl-2-(phenylseleno)hept-5-en-2-yl]tetrahydrofuran confirms that the examined reaction is kinetically controlled.Graphical abstract

Synthesis, crystal and solution structures and antimicrobial screening of palladium(II) complexes with 2-(phenylselanylmethyl)oxolane and 2-(phenylselanylmethyl)oxane as ligands

Two novel Pd(II) complexes with 2-(phenylselanylmethyl)oxolane and 2-(phenylselanylmethyl)oxane as ligands were synthesized. The crystal and molecular structure of the complexes has been determined by single crystal X-ray diffraction. It turned out for both complexes that the two ligands are coordinated to Pd via Se atoms in a trans-fashion and the other two trans-positions are occupied by Cl ions. Detailed 1D- and 2D-NMR analyses revealed the existence of equilibrating trans-diastereomeric species differing in the configuration at four chiral centers (selenium and carbon) in the solution of the complexes. A computational study was also undertaken to assess the relative stabilities of the mentioned stereoisomeric species. The antimicrobial properties of the complexes were investigated against a series of human pathogenic bacterial and fungal strains. The complexes were shown to possess promising broad spectrum moderate antimicrobial activity that is more pronounced against fungal organisms. The noted activity could be completely attributed to the Pd(II) center, whereas the ligands probably mediate the transportation of a Pd(II) species across cell membranes.

Evaluation of antimicrobial activity and retention behavior of newly synthesized vanilidene derivatives of Meldrum’s acids using QSRR approach

HIGHLIGHTSLipophilicity and antimicrobial activity of 13 vanilidene derivatives of Meldrums acid has been evaluated.Clustering of the compounds according to their lipophilicity was performed with the help of PCA and HCA.ADME properties of newly synthetized derivatives were analyzed by applying sum of ranking differences (SRD) method.Statistically significant predictive models of antimicrobial activity were obtained using MLR analysis. ABSTRACT Increased antimicrobial resistance together with the lack of new antimicrobial drugs suggest on an urgent need for new therapeutics in this field. Vanilidene derivatives of Meldrums acid present one of the possible approaches. In this work lipophilicity of 13 vanilidene derivatives of Meldrums acid as well as their predicted antimicrobial activity towards several characteristic species has been evaluated. 10 vanilidene derivatives have been previously synthesized and 3 new compounds are synthetized afterwards following the same procedure. These selected 13 candidates were examined using thin layer chromatography in two different solvent systems. Gained retention parameters were a starting point for further Quantitative Structure Property Relationships (QSRR) studies in which minimum inhibitory concentration (MIC) for Candida albicans, Trichoderma viride, Penicillium italicum, Fuscarium oxysporum, Pseudomonas aeruginosa and Escherichia coli were determined. Statistically significant QSRR models were established and clustering of the compounds was performed with the help of principal component analysis (PCA) and hierarchical cluster analysis (HCA). Absorption, Distribution, Metabolism, and Excretion (ADME) properties of investigated molecules were subjected to sum of ranking differences (SRD) analysis in order to explore their pharmacokinetic properties. SRD analysis was also performed for the ranking of the established QSRR models. It was shown that compounds 6, 8 and 9 possess a significant antimicrobial activity, satisfied ADME properties and these candidates should be further optimized in order to utilize unexplored potential of Meldrums acid in synthesis of novel antifungal compounds.

Biological evaluation of selected 3,4-dihydro-2(1H)-quinoxalinones and 3,4-dihydro-1,4-benzoxazin-2-ones: Molecular docking study

In order to investigate new potential therapeutically active agents, we investigated the biological properties of two small libraries of quinoxalinones and 1,4‐benzoxazin‐2‐ones. The results obtained showed that compounds 5, 9–11 have good cytotoxic activity against HeLa cells where the lowest IC50 value (10.46 ± 0.82 μM/mL) was measured for compound 10. Additionally, the most active compounds (5, 9–11) showed much better selectivity for MRC‐5 cells (up to 17.4) compared to cisplatin. In vitro evaluation of the inhibition of the enzyme α‐glucosidase showed that compounds 10 and 11 exert significant inhibition of the enzyme at 52.54 ± 0.09 and 40.09 ± 0.49 μM, respectively. Competitive experiments with ethidium bromide (EB) indicated that all tested compounds have affinity to displace EB from the EB‐DNA complex through intercalation, suggesting good competition with EB (Ksv = (3.1 ± 0.2), (5.1 ± 0.1), (5.6 ± 0.2), and (6.3 ± 0.2) × 103 M−1). A molecular docking study was also performed to better understand the binding modes and to conclude the structure–activity relationships of the synthesized compounds.