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Abstract: In general, a cancerous process starts from uncontrolled cell growth, apoptosis, and rapid proliferation of cellular clones, as well as, reactive oxygen species (ROS) and imbalance of ROS-antioxidant production also could be involved in the genesis of the disease. Cancer has accounted for millions of deaths worldwide every year, representing a relevant threat to human lives. In this context, malignant melanoma represents the most aggressive and deadliest type of cancer, leading to increased rates of patient deaths. Natural active compounds have demonstrated their pharmacological benefits in several different studies. Among these compounds, coumarin analogs have demonstrated promising biological profiles, considering their efficacy and low toxicity. In this context, this phytochemical oxygenated core has been broadly investigated since it presents several biological properties of interest in the medicinal field. Herein, we reported a complete compilation of studies focused on natural coumarins against melanoma, as well as, tyrosinase since it is a cooper-catalyzed oxidase that performs an essential role during melanogenesis (Eu-melanins and Pheo-melanins), which is associated with melanoma. Thus, three different subclasses of natural coumarin were described in detail, such as simple coumarin core, furanocoumarins, pyranocoumarins, and pyrone-substituents. Additionally, insights on tyrosinase have been provided, allowing an overview of some structural/functional aspects of its enzyme, such as the presence of a binuclear type 3 cooper coordination at the binding site of this target, acting as cofactors. Posteriorly, several coumarin-based analogs with anti-tyrosinase activity also were reported and discussed. Finally, we believe that unprecedented review can be a valuable source of information, which can be used to design and develop novel coumarin-based analogs targeting melanoma and also tyrosinase enzyme, contributing to the advances in the field of natural products.

Herein, nine phthalimide-based thiazoles (4a–4i) were synthesized and investigated as new human neutrophil elastase (HNE) inhibitors using spectrofluorimetric and computational methods. The most active compounds containing 4-trifluoromethyl (4c), 4-naphthyl (4e) and 2,4,6-trichloro (4h) substituents in the phenyl ring exhibited high HNE inhibitory activity with IC50 values of 12.98–16.62 µM. Additionally, compound 4c exhibited mixed mechanism of action. Computational investigation provided a consistent picture of the ligand-receptor pattern of inter-actions, common for the whole considered group of compounds. Moreover, compounds 4b, 4c, 4d and 4f showed high antiproliferative activity against human cancer cells lines MV4-11, and A549 with IC50 values of 8.21 to 25.57 µM. Additionally, compound 4g showed high activity against MDA-MB-231 and UMUC-3 with IC50 values of 9.66 and 19.81 µM, respectively. Spectrophotometric analysis showed that the most active compound 4c demonstrated high stability under physiological conditions.

The important role substituents play on proton chemical shifts in heterocyclic compounds was investigated in detail. For this purpose, a considerable number of model oxiranes, oxetanes, and oxathietanes with different substituents were studied in a systematic way. In addition, the oxygen and sulfur heteroatom influence on the chemical shift values was analyzed. The density functional theory (DFT) approximation was employed together with the M06 and the B3LYP functionals and the aug-pcS-1 and the 6-311++G** basis sets. We carried out a careful analysis of the shift values and the changes in the corresponding molecular electrostatic potential surfaces due to substitution. We observed that chemical shift values for the protons closest to the substituents are larger for the chloro and fluoro derivatives than those for the cyano and ethynyl ones. The presence of oxygen as well as sulfur in the ring causes an increase of the chemical shift values, most pronounced for the atom closest to the substituent. A large decrease of the proton shifts was observed when going from methylenecyclopropane to methyleneoxirane that can be attributed to π-electron resonance. Protons diagonal to the substituents behaved in a different way depending on their cis or trans disposition with respect to them. The conclusions of the present study will be useful in theoretical and experimental work on NMR spectra of heterocyclic compounds.

A series of 3,3-diethylazetidine-2,4-dione based thiazoles 3a–3j were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds 3c, 3e, and 3h exhibit high HNE inhibitory activity with IC50 values of 35.02–44.59 nM, with mixed mechanism of action. Additionally, the most active compounds 3c and 3e demonstrate high stability under physiological conditions. The molecular docking study showed good correlation of the binding energies with the IC50 values, suggesting that the inhibition properties are largely dependent on the stage of ligand alignment in the binding cavity. The inhibition properties are correlated with the energy level of substrates of the reaction of ligand with Ser195. Moreover, most compounds showed high and broad-spectrum antiproliferative activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast adenocarcinoma (MDA-MB-231), and urinary bladder carcinoma (UMUC-3), with IC50 values of 4.59–9.86 μM. Additionally, compounds 3c and 3e can induce cell cycle arrest at the G2/M phase and apoptosis via caspase-3 activation, leading to inhibition of A549 cell proliferation. These findings suggest that these new types of drugs could be used to treat cancer and other diseases in which immunoreactive HNE is produced.

The paper presents synthesis and characterization of nine new thiazolyl-(phenyldiazenyl)-2H-chromen-2-one dyes. The impact of substituent structure in thiazole ring in the synthesized azocoumarin derivatives on electrochemical properties, photoisomerization process and photovoltaic response was examined. The dyes were electrochemically active and undergo reduction and oxidation processes. They showed low electrochemically estimated energy band gap in the range of 1.71–2.13 eV. Photoisomerization process of the synthesized molecules was studied in various solvents such as ethanol, chloroform and N,N-dimethylformamide (DMF) upon the UV illumination. It was found that novel azodyes showed reversible trans-cis-trans isomerization and exhibited long thermal back to the trans form, that was even 7 days in DMF. Selected azocoumarin were molecularly dispersed in polystyrene for preparation of guest-host azopolymer systems to study the cis-trans thermal isomerization of obtained dyes in solid state. The photovoltaic activity of the azochromophores was tested in bulk-heterojunction solar cells. They acting as weak donors in device with structure ITO/PEDOT:PSS/dye:PC70BM/Al. No photovoltaic response of cells with azocoumarin derivatives bearing 4-fluorobenzene, 3,4-dichlorobenzene, or 4-(1-adamantyl) unit was found. Additionally, dye which showed the best activity was examined in three-component solar cells ITO/PEDOT:PSS/PTB7:PC70BM:dye/PFN/Al.

Synthesis and investigation of antimicrobial activity of fifteen novel thiazoles containing cyclohexene moiety are presented. Among the derivatives, compounds 3a–3d, 3f, 3n, and 3o showed very strong activity against the reference Candida spp. strains with MIC = 0.015–3.91 µg/ml. The activity of these compounds is similar and even higher than the activity of nystatin used as positive control. Compounds 3d, 3f, 3n, 3o showed the highest activity with very strong effect towards most of yeasts isolated from clinical materials with MIC = 0.015–7.81 µg/ml. The cytotoxicity studies for the most active compounds showed that Candida spp. growth was inhibited at noncytotoxic concentrations for the mammalian L929 fibroblast. In addition, a good correlation was obtained between lipophilicity of compounds determined using reversed phase thin-layer chromatography and their antifungal activity.

There is a need to search for new antifungals, especially for the treatment of the invasive Candida infections, caused mainly by C. albicans. These infections are steadily increasing at an alarming rate, mostly among immunocompromised patients. The newly synthesized compounds (3a-3k) were characterized by physico-chemical parameters and investigated for antimicrobial activity using the microdilution broth method to estimate minimal inhibitory concentration (MIC). Additionally, their antibiofilm activity and mode of action together with the effect on the membrane permeability in C. albicans were investigated. Biofilm biomass and its metabolic activity were quantitatively measured using crystal violet (CV) staining and tetrazolium salt (XTT) reduction assay. The cytotoxic effect on normal human lung fibroblasts and hemolytic effect were also evaluated. The results showed differential activity of the compounds against yeasts (MIC = 0.24-500 µg/mL) and bacteria (MIC = 125-1000 µg/mL). Most compounds possessed strong antifungal activity (MIC = 0.24-7.81 µg/mL). The compounds 3b, 3c, and 3e, showed no inhibitory (at 1/2 MIC) and eradication (at 8 x MIC) effect on C. albicans biofilm. Only slight decrease in the biofilm metabolic activity was observed for compound 3b. Moreover, the studied compounds increased the permeability of the membrane/cell wall of C. albicans and their mode of action may be related to action within the fungal cell wall structure and/or within the cell membrane. It is worth noting that the compounds had no cytotoxicity effect on pulmonary fibroblasts and erythrocytes at concentrations showing anticandidal activity. The present studies in vitro confirm that these derivatives appear to be a very promising group of antifungals for further preclinical studies.

Carbazole derivatives are the structural key of many biologically active substances, including naturally occurring and synthetic ones. Three novel (E)-2-(2-(4-9H-carbazol-9-yl)benzylidene)hydrazinyl)triazole dyes were synthesized with different numbers of chlorine substituents attached at different locations. The presented research has shown the influence of the number and position of attachment of chlorine substituents on electrochemical, optical, nonlinear, and biological properties. The study also included the analysis of the use of the presented derivatives as potential fluorescent probes for in vivo and in vitro tests. Quantum-chemical calculations complement the conducted experiments.

Abstract Recently, the occurrence of candidiasis has increased dramatically, especially in immunocompromised patients. Additionally, their treatment is often ineffective due to the resistance of yeasts to antimycotics. Therefore, there is a need to search for new antifungals. A series of nine newly synthesized thiazole derivatives containing the cyclopropane system, showing promising activity against Candida spp., has been further investigated. We decided to verify their antifungal activity towards clinical Candida albicans isolated from the oral cavity of patients with hematological malignancies and investigate the mode of action on fungal cell, the effect of combination with the selected antimycotics, toxicity to erythrocytes, and lipophilicity. These studies were performed by the broth microdilution method, test with sorbitol and ergosterol, checkerboard technique, erythrocyte lysis assay, and reversed phase thin-layer chromatography, respectively. All derivatives showed very strong activity (similar and even higher than nystatin) against all C. albicans isolates with minimal inhibitory concentration (MIC) = 0.008–7.81 µg/mL Their mechanism of action may be related to action within the fungal cell wall structure and/or within the cell membrane. The interactions between the derivatives and the selected antimycotics (nystatin, chlorhexidine, and thymol) showed additive effect only in the case of combination some of them and thymol. The erythrocyte lysis assay confirmed the low cytotoxicity of these compounds as compared to nystatin. The high lipophilicity of the derivatives was related with their high antifungal activity. The present studies confirm that the studied thiazole derivatives containing the cyclopropane system appear to be a very promising group of compounds in treatment of infections caused by C. albicans. However, this requires further studies in vivo. Key points • The newly thiazoles showed high antifungal activity and some of them — additive effect in combination with thymol. • Their mode of action may be related with the influence on the structure of the fungal cell wall and/or the cell membrane. • The low cytotoxicity against erythrocytes and high lipophilicity of these derivatives are their additional good properties. Graphical abstract

Many organophosphorus compounds (OPs), especially various α-aminophosphonates, exhibit anti-cancer activities. They act, among others, as inhibitors of the proteases implicated in cancerogenesis. Thesetypes of inhibitors weredescribed, e.g., for neutral endopeptidase (NEP) expressed in different cancer cells, including osteosarcoma (OS). The aim of the present study isto evaluate new borane-protected derivatives of phosphonous acid (compounds 1–7) in terms of their drug-likeness properties, anti-osteosarcoma activities in vitro (against HOS and Saos-2 cells), and use as potential NEP inhibitors. The results revealed that all tested compounds exhibited the physicochemical and ADME properties typical for small-molecule drugs. However, compound 4 did not show capability of blood–brain barrier penetration (Lipiński and Veber rules;SwissAdme tool). Moreover, the α-aminophosphonite-boranes (compounds 4–7) exhibited stronger anti-proliferative activity against OS cells than the other phosphonous acid-borane derivatives (compounds 1–3),especially regarding HOS cells (MTT assay). The most promising compounds 4 and 6 induced apoptosis through the activation of caspase 3 and/or cell cycle arrest at the G2 phase (flow cytometry). Compound 4 inhibited the migration and invasiveness of highly aggressive HOS cells (wound/transwell and BME-coated transwell assays, respectively). Additionally, compound 4 and, to a lesser extent, compound 6 inhibited NEP activity (fluorometric assay). This activity of compound 4 was involved in its anti-proliferative potential (BrdU assay). The present study shows that compound 4 can be considered a potential anti-osteosarcoma agent and a scaffold for the development of new NEP inhibitors.

Interaction of (S)-thalidomide molecule with four nucleobases: adenine, guanine, cytosine and thymine, is investigated in details employing density functional theory methods. Different mutual positions of the molecules are considered, with the starting geometries enabling hydrogen bond interactions between the monomers. Optimization of geometrical parameters is carried out within the B3LYP/6-311G** approximation and followed by evaluation of vibrational frequencies. Binding and interaction energies are calculated employing exchange-correlation functionals including long-range corrections and properly diffuse basis sets. The strongest interaction exists within the (S)-thalidomide-guanine complex. Interestingly, in one of the investigated (S)-thalidomide-guanine complexes two bifurcated hydrogen bonds are observed. The two hydrogens involved in one of them are bonded to a carbon atom in the α position relative to carbonyl group. The present study can be useful in the design of new anticancer and antiviral drugs interacting selectively with DNA or RNA.

Carbazole skeleton is the key structural motif of many biologically active compounds including synthetic and natural products. Based on the (E)-2-(2-(4-9H-carbazol-9-yl)benzylidene) hydrazinyl)thiazole as skeleton, three novel carbazole dyes were synthesized. The scientific analysis includes the effect of changing the strength of the activating substituents and their exchange for the deactivating substituent on the chemical and biological properties. The presented research showed a significant influence of the CH3, OCH3 and CH2 COOC2H5 groups on the spectral properties of the tested derivatives. Their significant influence is also visible in electrochemical, nonlinear-optic and biological properties. The study also included the analysis of the use of the presented derivatives as potential fluorescent probes for in vivo and in vitro tests. Quantum-chemical calculations complement the conducted experiments.

Synthesis and investigation of antifungal activity of ten novel thiazoles derived from tetrahydrothiophen-3-one are presented. Among the derivatives, (E/Z)-2-(2-(dihydrothiophen-3(2H)-ylidene)hydrazinyl)thiazoles 3a-3d and 3h had very strong activity against reference strains of Candida albicans and Candida krusei with MIC = 0.24–3.91 μg/ml. Their lipophilicity was determined using reversed-phase high performance liquid chromatography and correlated with antifungal activity. Additionally, their DPPH radical scavenging activities was evaluated by spectrophotometric method. According to our results, compounds 3b, 3h and 3j have very strong antioxidant activities with IC50 values from 3.0 to 9.5 μg/ml. The antioxidant activity of these compounds is 5–17 times higher than butylated hydroxytoluene. The RP HPLC analysis revealed that the products are obtained as E/Z mixture in approximately 60:40 ratio, in good agreement with DFT predictions.

Synthesis, characterization, and investigation of antiproliferative activities against human cancer cell lines (MV4-11, MCF-7, and A549) and Toxoplasma gondii parasite of twelve novel 2,4-diaminotriazine-thiazoles are presented. The toxicity of the compounds was studied at three different cell types, normal mouse fibroblast (Balb/3T3), mouse fibroblast (L929), and human VERO cells. The structures of novel compounds were determined using 1H and 13C NMR, FAB(+)-MS, and elemental analyses. Among the derivatives, 4a–k showed very high activity against MV4-11 cell line with IC50 values between 1.13 and 3.21 µg/ml. Additionally, the cytotoxic activity of compounds 4a–k against normal mouse fibroblast Balb/3T3 cells is about 20–100 times lower than against cancer cell lines. According to our results, compounds 4a, 4b, 4d, and 4i have very strong activity against human breast carcinoma MCF-7, with IC50 values from 3.18 to 4.28 µg/ml. Moreover, diaminotriazines 4a–l showed significant anti-Toxoplasma gondii activity, with IC50 values 9–68 times lower than those observed for sulfadiazine. Molecular docking studies indicated DNA-binding site of hTopoI and hTopoII as possible anticancer targets and purine nucleoside phosphorylase as possible anti-toxoplasmosis target. Our UV–Vis spectroscopic results indicate also that diaminotriazine-thiazoles tends to interact with DNA by intercalation. Additionally, the structure and the interaction and binding energies of a model complex formed by compound 4a and two thymine molecules are investigated using quantum mechanical methods.

Synthesis and investigation of anti-Toxoplasma gondii activity of novel thiazoles containing benzo [b]thiophene moiety are presented. Among the derivatives, compound 3k with adamantyl group shows exceptionally high potency against Me49 strain with IC50 (8.74 μM) value which is significantly lower than the activity of trimethoprim (IC50 39.23 μM). In addition, compounds 3a, 3b and 3k showed significant activity against RH strain (IC50 51.88–83.49 μM). The results of the cytotoxicity evaluation showed that Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mammalian L929 fibroblast (CC30 ∼ 880 μM). The most active compound 3k showed tyrosinase inhibition effect, with IC50 value of 328.5 μM. The binding energies calculated for compounds 3a-3e, 3k are strongly correlated with the experimentally determined values of tyrosinase inhibition activity. Moreover, the binding energies corresponding to the same ligands and calculated for both tyrosinase and tyrosine hydroxylase are also correlated with each other, suggesting that tyrosinase inhibitors may also have an inhibitory effect on tyrosine hydroxylase. Compounds 3j and 3k have also very strong antioxidant activity (IC50 15.9 and 15.5 μM), respectively, which is ten times higher than well-known antioxidant BHT.

We have designed novel tropinone-thiazole derivatives that showed high antiproliferative activity against a variety of cancer cell lines via caspase 3/7 activation mechanism. Among the derivatives, compounds 3b-3h were found to exhibit high activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast carcinoma (MCF-7), and skin melanoma (B16–F10) cancer cell lines, with IC50 values of 5.43–11.06 μM. The lead compound 3g increases caspase 3/7 activity in A549 cells 25 times more than the control, and 2 times more than reference drug camptothecin. We have also found that tropinone-thiazole derivatives exhibit high tyrosinase inhibitory activity. The lead compounds 3g and 3h showed tyrosinase inhibition effect, with IC50 values 3.22 and 3.51 μM, respectively. These inhibitory activities are 22 times higher than the activity of kojic acid (IC50 72.27 μM) and 120 times higher than activity of ascorbic acid (IC50 386.5 μM). For compounds 3g and 3h, the experimentally determined lipophilicity correlates very well with their enzymatic activities. These data suggest that presented compounds could constitute lead anticancer drug candidates.

Taking as examples a series of oxiranes, oxetanes, and oxathietanes with different substituents, we study in a systematic way the role that the latter play on the optical rotation of the molecules. For this, we use time-dependent density functional theory together with a hierarchy of Dunning's basis sets. The B3LYP and CAM-B3LYP exchange-correlation functionals are employed. We select results obtained with the CAM-B3LYP functional and the daug-cc-pVTZ basis set as our reference values. Additionally, specific rotation in all systems is calculated with the ORP basis set, specifically designed to carry out optical rotation calculations. The present study shows its good performance in CAM-B3LYP estimations of this property, providing results close to the reference values. The proper choice of the exchange-correlation functional proves to be much more important than that of the basis set. Considering the effect of the substituents, some of the presently investigated molecules show a behavior in line with earlier findings; however we have also found systems that do not match the conclusions previously available in the literature.

There is a need to search for new antifungals, especially for the treatment of the invasive Candida infections, caused mainly by C. albicans. These infections are steadily increasing at an alarming rate, mostly among immunocompromised patients. The newly synthesized compounds (3a–3k) were characterized by physicochemical parameters and investigated for antimicrobial activity using the microdilution broth method to estimate minimal inhibitory concentration (MIC). Additionally, their antibiofilm activity and mode of action together with the effect on the membrane permeability in C. albicans were investigated. Biofilm biomass and its metabolic activity were quantitatively measured using crystal violet (CV) staining and tetrazolium salt (XTT) reduction assay. The cytotoxic effect on normal human lung fibroblasts and haemolytic effect were also evaluated. The results showed differential activity of the compounds against yeasts (MIC = 0.24–500 µg/mL) and bacteria (MIC = 125–1000 µg/mL). Most compounds possessed strong antifungal activity (MIC = 0.24–7.81 µg/mL). The compounds 3b, 3c and 3e, showed no inhibitory (at 1/2 × MIC) and eradication (at 8 × MIC) effect on C. albicans biofilm. Only slight decrease in the biofilm metabolic activity was observed for compound 3b. Moreover, the studied compounds increased the permeability of the membrane/cell wall of C. albicans and their mode of action may be related to action within the fungal cell wall structure and/or within the cell membrane. It is worth noting that the compounds had no cytotoxicity effect on pulmonary fibroblasts and erythrocytes at concentrations showing anticandidal activity. The present studies in vitro confirm that these derivatives appear to be a very promising group of antifungals for further preclinical studies.

Phthalimide derivatives are a promising group of anticancer drugs, while aminothiazoles have great potential as elastase inhibitors. In these context fourteen phthalimido-thiazoles containing a dichloro-substituted phenyl ring with high antiproliferative activity against various cancer cell lines were designed and synthesized. Among the screened derivatives, compounds 5a-5e and 6a-6f showed high activity against human leukemia (MV4-11) cells with IC50 values in the range of 5.56–16.10 µM. The phthalimide-thiazoles 5a, 5b and 5d showed the highest selectivity index (SI) relative to MV4-11 with 11.92, 10.80 and 8.21 values, respectively. The antiproliferative activity of compounds 5e, 5f and 6e, 6f against human lung carcinoma (A549) cells is also very high, with IC50 values in the range of 6.69–10.41 µM. Lead compounds 6e and 6f showed elastase inhibition effect, with IC50 values about 32 μM with mixed mechanism of action. The molecular modeling studies showed that the binding energies calculated for all set of compounds are strongly correlated with the experimentally determined values of IC50. The lead compound 6e also increases almost 16 times caspase 3/7 activity in A549 cells compared to control. We have also demonstrated that compound 6f reduced EGFR tyrosine kinase levels in A549 cells by approximately 31%. These results clearly suggest that 3,4-dichloro-derivative 6e and 3,5-dichloro-derivative 6f could constitute lead dual-targeted anticancer drug candidates.

Synthesis and investigation of antimicrobial activities of novel thiazoles and selenazoles is presented. Their structures were determined using NMR, FAB(+)-MS, HRMS and elemental analyses. To support the experiment, theoretical calculations of the 1H NMR shifts were carried out for representative systems within the DFT B3LYP/6-311++G** approximation which additionally confirmed the structure of investigated compounds. Among the derivatives, compounds 4b, 4h, 4j and 4l had very strong activity against reference strains of Candida albicans ATCC and Candida parapsilosis ATCC 22019 with MIC = 0.49–7.81 μg/ml. In the case of compounds 4b, 4c, 4h – 4j and 4l, the activity was very strong against of Candida spp. isolated from clinical materials, i.e. C. albicans, Candida krusei, Candida inconspicua, Candida famata, Candida lusitaniae, Candida sake, C. parapsilosis and Candida dubliniensis with MIC = 0.24–15.62 μg/ml. The activity of several of these was similar to the activity of commonly used antifungal agent fluconazole. Additionally, compounds 4m – 4s were found to be active against Gram-positive bacteria, both pathogenic staphylococci Staphylococcus aureus ATCC with MIC = 31.25–125 μg/ml and opportunistic bacteria, such as Staphylococcus epidermidis ATCC 12228 and Micrococcus luteus ATCC 10240 with MIC = 7.81–31.25 μg/ml.

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a&ndash, 3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC50 values of 1.51&ndash, 3.03 &micro, M. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8&ndash, 70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC50 distinct correlation with experiment.

A detailed theoretical investigation of specific rotation is carried out in solution for nine flexible molecules of biological importance. Systematic search for the main conformers is followed by time-dependent density functional theory (TD-DFT) calculations of specific rotation employing a wide range of basis sets. Due to conformational flexibility of the compounds under study, the possibility of basis set size reduction without deterioration of the results is investigated. The increasing size (d-)aug-cc-pVXZ (X=D, T, Q) bases of Dunning et al., and the ORP basis set, recently developed to efficiently provide molecular specific rotation, are used for this purpose. The polarizable continuum model is employed at all steps of the investigation. Comparison of the present results with the available data obtained in vacuum reveals considerable differences, being the values in solvent much closer to the experimental specific rotation data available. The ORP basis set proves to be competitive with the d-aug-cc-pVDZ set of Dunning in specific rotation calculations carried out in solvent. While having the same number of functions, the former yields in general results considerably closer to the reference triple-zeta values. We can thus recommend the ORP basis set to study the optical rotation in conformationally flexible molecules in solvent.

We evaluated the proton chemical shieldings and the corresponding chemical shifts of ten newly developed antibacterial 4-formylbenzoic acid-based thiazoles, using computational chemistry methodology. Due to the large size of the studied molecules, we resorted to density functional theory. After a systematic method and basis set selection study carried out on methane, benzene, and thiazole, we selected the M06 DFT functional together with the aug-pcS-1 basis set to carry out the calculations on the larger systems. This combination of functional and basis set seems to be very efficient in providing shifts close to the experimental data available at a relatively low computational cost. The theoretical results for the molecules under investigation were compared to the experimental chemical shifts available, and reasonable agreement was reached in all cases, allowing the theoretical calculations a more detailed analysis of the one-dimensional experimental spectra, i.e. the assignment of individual experimental aromatic signals to specific protons of the phenyl rings, that was not possible based solely on the experimental results. Considering this, we can recommend the M06 functional and the aug-pcS-1 basis set for the evaluation of proton shifts in larger 4-formylbenzoic acid-based thiazoles.

Using a novel method based on increasingly accurate calculations, we obtain the main conformers of a set of flexible molecules. We then employ the recently developed ORP basis set for calculating the specific rotation of the found set carried out at the TD-DFT level of theory. The results are compared to those obtained with the (d-)aug-cc-pVXZ (X = D, T and Q) basis sets of Dunning et al. The ORP values are in good overall agreement with the aug-cc-pVTZ results making the ORP a good basis set for routine TD-DFT optical rotation calculations of conformationally flexible molecules. The results presented for the investigated chiral azido alcohols are to our knowledge the first estimations of their specific rotations.

Synthesis, characterization and investigation of antimicrobial activity of 11 novel adamantanyl-thiazoles are presented. Their structures were determined using 1H and 13C NMR, EI(+)-MS, HRMS, and elemental analyses. Among the derivatives, compound 3c showed very strong activity, especially against Candida albicans ATCC 10231 and Candida parapsilosis ATCC 22019 with minimal inhibitory concentration (MIC) values ranging from 1.95 to 7.81 µg/ml. Compounds 3a and 3b showed good antifungal activity. Among the examined compounds, the widest spectrum of antibacterial activity possessed 3f that showed good activity, especially against Staphylococcus epidermidis ATCC 12228, Micrococcus luteus ATCC 10240, Bacillus subtilis ATCC 6633 with MIC values ranging from 31.25 to 62.5 µg/ml. Molecular docking studies of all compounds on the active sites of microbial enzymes indicated possible targets sterol 14α-demethylase, secreted aspartic proteinase (SAP), N-myristoyltransferase (NMT), and topoisomerase II. Thiazoles 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k showed more favorable affinity to SAP and NMT than the native ligand.

Synthesis, characterization, and investigation of antimicrobial activities of nine novel imidazolylthiazoles are presented. Their structures were determined using 1H NMR, 13C NMR, and elemental analysis. Compounds 3e and 3i show very strong or strong bacteriostatic or bactericidal activity [minimal bactericidal concentration/minimal inhibitory concentration (MIC)=2–64] against Staphylococcus spp. (MIC=7.81–15.62 μg/mL), Micrococcus luteus ATCC 10240 (MIC=1.95–3.91 μg/mL), and Bacillus spp. (MIC=3.91–15.62 μg/mL). Compounds 3e and 3i also show the highest fungicidal effect (minimal fungicidal concentration/MIC=2–4) against reference strains of fungi belonging to Candida spp. with MIC ranging from 3.91 to 31.25 μg/mL.

Synthesis and investigation of antifungal, anticonvulsant and anti-Toxoplasma gondii activities of ten novel (2-(cyclopropylmethylidene)hydrazinyl)thiazole 3a–3j are presented. Among the derivatives, compounds 3a–3d and 3f–3j possess very high activity against Candida spp. ATCC with MIC = 0.015–7.81 µg/ml. Compounds 3a–3d and 3f–3j possess also very high activity towards most of strains of Candida spp. isolated from clinical materials with MIC = 0.015–7.81 µg/ml. The activity of these compounds is similar and even higher than the activity of nystatin used as positive control. Additionally, compounds 3c and 3e showed interesting anticonvulsant activities in the MES test, whereas compounds 3f and 3i demonstrated the anticonvulsant activity in PTZ-induced seizures. Noteworthy, none of these compounds impaired animals’ motor skills in the rotarod test. Moreover, thiazoles 3a, 3h, and 3j showed significant anti-Toxoplasma gondii activity, with IC50 values 31–52 times lower than those observed for sulfadiazine. The results of the cytotoxicity evaluation, anti-Candida spp. and anti-Toxoplasma gondii activity studies showed that Candida spp. and Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mouse L929 fibroblast and the African green monkey kidney (VERO) cells. Molecular docking studies indicated secreted aspartic proteinase (SAP) as possible antifungal target.

Synthesis, characterization and investigation of antimicrobial activities of seven new 6-(1,3-thiazol-4-yl)-1,3-benzoxazol-2(3H)-ones are presented. Their structures were determined using 1H NMR, 13C NMR and elemental analyses. The compounds possess some biological activity against Gram-positive bacteria, especially against Micrococcus luteus belonging to opportunistic pathogens, with an MIC of 31.25 μg/mL.

Details of generation of the optical rotation prediction (ORP) basis set developed for accurate optical rotation (OR) calculations are presented. Specific rotation calculations carried out at the density functional theory (DFT) level for model chiral methane molecule, fluorooxirane, methyloxirane, and dimethylmethylenecyclopropane reveal that the ORP set outperforms larger basis sets, among them the aug-cc-pVTZ basis set of Dunning (J. Chem. Phys. 1989, 90, 1007) and the aug-pc-2 basis set of Jensen (J. Chem. Phys. 2002, 117, 9234; J. Chem. Theory Comput. 2008, 4, 719). It is shown to be an attractive choice also in the case of larger systems, namely norbornanone, β-pinene, trans-pinane, and nopinone. The ORP basis set is further used in OR calculations for 24 other systems, and the results are compared to the aug-cc-pVDZ values. Whenever large discrepancies of results are observed, the ORP values are in an excellent agreement with the aug-cc-pVTZ results. The ORP basis set enables accurate specific rotation calculations at a reduced cost and thus can be recommended for routine DFT OR calculations, also for large and conformationally flexible molecules. © 2013 Wiley Periodicals, Inc.

Using computational chemistry methodology, we evaluate the proton magnetic shieldings and the corresponding chemical shifts of 12 polycyclic aromatic hydrocarbons that derive from chrysene, perylene and picene. Due to the large size of the studied compounds, we resort to density functional theory (DFT) and use it together with the B3LYP and the KT1 functionals. After a systematic method and basis set selection study carried out on methane, benzene and anthracene, the DFT(B3LYP) method and the 6-31G*, 6-31G** and 6-311++G** bases are selected to carry out the calculations, because of the efficiency in providing shifts close to the experimental data available. Additionally, we select the DFT(KT1) method together with the aug-pcS-1 basis set, and HF/6-31G* shifts are also calculated. In order to estimate the error in the theoretical results, we take as reference accurate experimental chemical shifts obtained for the molecules under investigation. Extra measurements are needed for this purpose and are included in the present work. The best combination of method and basis set is DFT(B3LYP)/6-31G**, proving to be very efficient in getting shifts close to experiment at a relatively low computational cost, and therefore we recommend it for the evaluation of proton shifts in larger polycyclic aromatic hydrocarbons.

Synthesis and investigation of antimicrobial and anticonvulsant activity of eleven novel quinuclidinone-thiazole derivatives are presented. Among the derivatives, compounds 3a–3f showed a broad-spectrum antibiotic activity against all reference Gram-positive or Gram-negative bacteria and fungi. These compounds exhibited very strong or good bactericidal activity towards Gram-positive bacteria (Staphylococcus spp., Micrococcus spp. and Bacillus spp.) with MIC = 0.48–15.62 µg/ml. The tested substances 3a–e and 3f were found also to be active against reference Gram-negative bacteria (Bordetella spp. and rod-shaped bacteria of the family Enterobacteriaceae) with MIC = 31.25–500 µg/ml. The fungicidal effect of compounds 3a–e was very strong or strong against Candida spp. with MIC = 1.95–31.25 µg/ml. The results of anticonvulsant screening revealed that the compound 3f demonstrated high anticonvulsant activity in electrically-induced seizure models, i.e., MES and 6-Hz tests. It was also effective in pilocarpine-induced model of seizures. Noteworthy, 3f did not impair animals’ motor skills in the rotarod test. Molecular docking studies of all compounds into the active sites of microbial enzymes indicated secreted aspartic proteinase as possible antifungal target and DNA gyrase subunit A as possible antibacterial target.

Four carene β-amino alcohols are subject of conformational analysis and optical rotation calculations carried out by using density functional theory with the hybrid B3LYP functional and aug-cc-pVDZ basis set. Despite relatively small values of the experimental optical rotations and conformational flexibility of these systems, the correct sign for the specific rotation was predicted for three of studied cases.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The regio- and stereoselective osmium-catalysed aminohydroxylation of (+)-2-carene (99% ee), and (+)-3-carene (99% ee), (−)-β-pinene (99% ee) and (−)-camphene (75% ee) with chloramine-T is described. The products β-hydroxy-p-toluenesulfonamides were reduced with sodium in liquid ammonia to give the corresponding β-amino alcohols with 48–83% yields. The methylation-reduction of β-hydroxy-p-toluenesulfonamides gave β-methylamino alcohols with 33–55% yields.

Purpose of the research was to determine the activity of chiral imine ligands prepared from (1S,2R)-norephedrine for the enantioselective addition of diethylzinc to aldehydes. Imine ligands reveal medium enantioselectivity, with the ee exceeding 30%. The highest ee (97%) was obtained for imine with 9-anthryl substituent, when p-methoxybenzaldehyde was used as substrate. The yields of the reaction obtained after 24–72 h reached 76–96%. The absolute configuration of the addition product depends on the geometry of presented transition states and π–π stacking interactions between the investigated ligands and the benzaldehyde substrate. Imine ligands derived 2-hydroxyacetophenone and with 9-anthryl substituent reveal strong absorbance in UV–vis spectra. Intermediates for the imines – diethylzinc – based catalysis and probable mechanisms were proposed.

Asymmetric synthesis of ( S )- N -(1-arylethyl)- N -hydroxyureas, ( S )- N -(6-methoxy)- and ( S )- N -(6-benzyloxy-2,3-dihydrobenzofuran-3-yl)- N -hydroxyurea— lipoxygenase inhibitor, is described. Three approaches to the formation of the N -hydroxyurea moiety at the stereogenic center have been used. The first one, via the reaction of ( R )-6-benzyloxy-2,3-dihydrobenzofuran-3-ol with N , O -bis(phenoxycarbonyl)hydroxylamine under Mitsunobu conditions, leads to a partially racemized product. Alternatively, the enantioselective reduction of oximes O -benzyl ethers of acetophenone, 4-methoxy- and 4-benzyloxyacetophenone, 6-methoxy- and 6-benzyloxy-2,3-dihydrobenzofuran-3-one with borane/oxazaborolidines can be controlled to produce either the corresponding hydroxylamine O -benzyl ethers or primary amines which have been transformed into N-substituted N -hydroxyureas in 57% to 99% ee.

Synthesis, characterization and investigation of in vivo anticonvulsant activities of 13 novel cyclopentanecarbaldehyde-based 2,4-disubstituted 1,3-thiazoles are presented. Their structures were determined using (1)H and (13)C NMR, FAB(+)-MS, HRMS and elemental analyses. The results of anticonvulsant screening reveal that seven intraperitoneally administered compounds: 3a, 3b, 3d, 3e, 3f, 3k and 3m containing F-, Cl-, Br-, CF3-, CH3- and adamantyl substituents demonstrated significant anticonvulsant activity in the pentylenetetrazole model with median effective doses (ED50) ≤ 20 mg/kg, respectively, which was approximately seven-fold lower than that reported for the reference drug, ethosuximide. Noteworthy, none of these compounds impaired animals' motor skills in the rotarod test.

Synthesis and investigation of antimicrobial activity of 22 novel thiazoles and selenazoles derived from dihydro-2H-thiopyran-4(3H)-one are presented. Additionally, anticonvulsant activity of six derivatives is examinated. Among the derivatives, compounds 4a-f, 4i, 4k, 4 l, 4n, 4o-s and 4v have very strong activity against Candida spp. with MIC = 1.95-15.62 μg/ml. In the case of compounds 4a-f, 4i, 4k, 4 l, 4n, 4o, 4r and 4s, the activity is very strong against some strains of Candida spp. isolated from clinical materials, with MIC = 0.98 to 15.62 μg/ml. Additionally, compounds 4n-v are found to be active against Gram-positive bacteria with MIC = 7.81-62.5 μg/ml. The results of anticonvulsant screening reveal that compounds 4a, 4b, 4m and 4n demonstrate a statistically significant anticonvulsant activity in the pentylenetetrazole model, whereas compounds 4a and 4n showed protection in 6-Hz psychomotor seizure model. Noteworthy, none of these compounds impaired animals' motor skills in the rotarod test. We also performed quantum chemical calculation of interaction and binding energies in complex of 4a with cyclodextrin.

Using the single and double excitation coupled cluster level of theory (CCSD) and the density functional theory/Becke 3-parameter Lee-Yang and Parr (DFT/B3LYP) methods, we test the performance of the Pol, ZPol, and LPol-n (n = ds, dl, fs, fl) basis sets in the accurate description of the intensity dependence of the refractive index in the Ne atom, and the N(2) and the CO molecules. Additionally, we test the aug-pc-n (n = 1, 2) basis sets of Jensen, and the SVPD, TZVPD, and QZVPD bases by Rappoport and Furche. Tests involve calculations of dynamic polarizabilities and frequency dependent second hyperpolarizabilities. The results are interpreted in terms of the medium constants entering the expressions for optically induced birefringences. In all achiral systems, the performance of the LPol-n sets is very good. Also the aug-pc-2 set yields promising results. Accurate CCSD results available in the literature allow us to select the best basis sets in order to carry out DFT/B3LYP calculations of medium constants in larger molecules. As applications, we show results for (R)-fluoro-oxirane and (R)-methyloxirane.

Ten oxazaborolidine–borane complexes, nine among them boron-substituted (B–R, R=CH3, CF3, and OCH3), are carefully analysed using quantum-chemistry methods to determine their equilibrium geometries and the corresponding oxazaborolidine–borane interaction energies. It is observed that in all B-trifluoromethyl substituted oxazaborolidine–borane complexes and in one B-methyl substituted complex the B–H–B bond is formed and the interaction energies are 1.5–2.5 times as large as in other investigated complexes. We believe that the presented results may be helpful in experimental recognition of oxazaborolidine–borane complexes which may appear, inter alia, as reaction intermediates.

Synthesis, characterization and investigation of antiproliferative activity of eight thiazole-based nitrogen mustard against human cancer cells lines (MV4-11, A549, HCT116 and MCF-7) and normal mouse fibroblast (BALB/3T3) are presented. Their structures were determined using NMR, FAB MS, HRMS and elemental analyses. Among the derivatives, 3a, 3b, 3e and 3h were found to exhibit high activity against human leukemia MV4-11 cells with IC50 values of 0.634-3.61 µg/ml. The cytotoxic activity of compound 3a against BALB/3T3 cells is up to 40 times lower than against cancer cell lines. Our data indicated also that compound 3e had very strong activity against MCF-7 and HCT116 with IC50 equal to 2.32 µg/ml and 2.81 µg/ml, respectively. Their activity was similar to the activity of cis-platin, which is clinically used as anticancer drug in the treatment of human solid tumours. We also perform quantum chemical calculation of interaction and binding energies in complexes of model systems and 3e with DNA bases. Interaction of real drug 3e with guanine is much stronger than with the remaining nucleobases, and the strongest among all investigated complexes. Computer simulations were performed with ATP-binding domain and DNA-binding site of hTopoII. Compounds 3a-h were recognized as potential inhibitors of hTopoII.