Zorica M. Bugarčić

Mechanistic investigation of the base-promoted cycloselenoetherification of pent-4-en-1-ol

The mechanism of phenylselenoetherification of pent-4-en-1-ol using some bases (pyridine, triethylamine, quinoline, 2,2′-bipyridine) as catalyst was examined through studies of kinetics of the cyclization, by UV-VIS spectrophotometry. It was demonstrated that the intramolecular cyclization is facilitated in the presence of bases caused by the hydrogen bond between base and alkenol’s OH-group. The obtained values for rate constants have shown that the reaction with triethylamine is the fastest one. Quantum chemical calculations (MP2(fc)/6-311+G**//B3LYP/6-311+G**) show, that the transition state of the cyclisation is SN2 like.

An enolate ion as a synthon in biocatalytic synthesis of 3,4-dihydro-2(1H)-quinoxalinones and 3,4-dihydro-1,4-benzoxazin-2-ones: lemon juice as an alternative to hazardous solvents and catalysts

Innovative, efficient, clean, experimentally simple and environmentally friendly one-pot biocatalytic synthesis of two small libraries of 3,4-dihydro-2(1H)-quinoxalinones (4a–m) and 3,4-dihydro-1,4-benzoxazin-2-ones (5a, 5b, 5f and 5k–o) by heterocyclization of ethyl 2-hydroxy-4-alkyl(aryl)-4-oxo-2-butenoates (1a–o) or their corresponding salts (1a′–o′) with o-phenylenediamine (2) or o-aminophenol (3) in lemon juice as a solvent and a catalyst is presented. In all reactions where esters 1a–o are used for 24 h, very good-to-excellent yields were achieved, but the best yield was realized in the synthesis of 5a (97%) from 3 and 1a. The use of enolate salts (1a′–o′) instead of the corresponding esters 1a–o significantly reduced the reaction time (up to 6 h) and good-to-excellent yields were achieved. Groups with electron-donating or -withdrawing effects at the aromatic ring of the ester did not have significant influences on the yield of targeted products. In addition, several selected 3,4-dihydro-2(1H)-quinoxalinones and 3,4-dihydro-1,4-benzoxazin-2-ones on a gram-scale in the yields up to 92% were synthesized. The presented synthetic strategy has produced smaller amount of waste without by-products and with excellent values of green chemistry metrics (atom efficiency, reaction mass efficiency, E-factor and EcoScale).

Effects of cisplatin and other Pt(II) complexes on spontaneous motility of isolated human oviduct

The toxicity of platinum(II) ion could be significantly modified by coordination with some organic compounds. In our study, the cytotoxicity and the influence of platinum(II) complexes, such as cisplatin, cis-[PtCl(2)(NH(3))(2)], [PtCl(2)(SMC)] and [PtCl(2)(DMSO)(2)] (where SMC is S-methyl-l-cysteine and DMSO is dimethyl sulphoxide) on spontaneous motility of isolated human fallopian tubes were investigated. Cisplatin showed potent pro-apoptotic effects on peripheral blood mononuclear cells (PBMC). However, peripheral blood mononuclear cells were substantially less sensitive to [PtCl(2)(SMC)] and [PtCl(2)(DMSO)], and these compounds showed no toxic effect on PBMC in all concentrations examined. Cisplatin showed concentration-dependent inhibition of spontaneous contractions of the isolated ampulla. (EC(50)=1.14+/-0.03 x 10(-6)M/l, r=0.714, p<0.05) while [PtCl(2)(SMC)] and [PtCl(2)(DMSO)(2)] did not affect spontaneous contractions of isolated fallopian tube ampulla.

Vitamin B12-catalyzed conversion of some γ- and δ-bromoalkanols to polyhydroxy alkanols

Abstract Vitamin B 12 -catalyzed allylic dimerization of some γ- and δ-bromoalkanols with activated Zn-dust in mixture ethanol/water (1:1) has been studied. Investigated bromoalkanols were prepared from corresponding tertiary Δ 4 - and Δ 5 -alkenols by means of benzeneselenyl bromide and subjected to chemical reduction with vitamin B 12 . All investigated bromoalkanols, after dehydrobromination, underwent to oxidative allylic coupling and hydratation in the presence of protic solvents to give predominantly polyhydroxy alkanols.

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

Kinetic investigation in the formation of 2,2,5-trisubstituted tetrahydrofurans by catalyzed phenylselenoetherification of some terpenic alcohols

The mechanism of the phenylselenoetherification of some naturally occurring alcohols linalool and nerolidol in the presence of some bases (piperidine, pyridine, triethylamine, quinoline) as catalysts was examined through the kinetic study of the cyclization under pseudo-first order conditions by UV–Vis spectrophotometry. It was demonstrated that the intramolecular cyclization is facilitated in the presence of some bases caused by the hydrogen bond between base and OH-group of the alkenol. The obtained values for the rate constants show that there is a good agreement between those constants and the basicity of the catalyst. The fastest reaction is the one using the strongest base (piperidine) and the smallest rate constant corresponded to the use of the weakest base (quinoline).

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.