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The purpose of our research was to obtain and characterize Cu(II), Co(II) and Ni(II) complexes with herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA). The structural characterization of compounds in their powder form was based on various laboratory as well as synchrotron X-ray spectroscopic methods, magnetic measurements and atomistic calculations. The anhydrous [Cu(MCPA)2]n complex exhibits a distorted square-planar geometry. [Co(MCPA)2(H2O)4]·H2O and [Ni(MCPA)2(H2O)4]·H2O complexes have octahedral molecular geometry with two MCPA anions acting as monodentate ligands. The X-ray crystal structure analysis performed for Cu(II) complex after its recrystallization from N,N-dimethylformamide solution showed the formation of dinuclear complex with solvent molecules included in the coordination sphere of Cu(II). MCPA herbicide and its Cu(II), Co(II) and Ni(II) complexes showed the low cytotoxicity potential against HaCaT and V79 cells with IC50 in the range from 65 to >100 µM.

Upon analyzing the structure-activity relationship, it was found that coumarin-based derivatives exerted cytotoxic and antitumor activity. In the present study a new ester of α-lipoic acid and derivative of alloxanthoxyletin (LAA) was synthesized and evaluated for its anticancer activity. The structure of this new compound was confirmed by 1H NMR, 13C NMR, and HRMS spectroscopic analyses. Both, the cytotoxicity and the migration tests showed that human melanoma cells (HTB-140) and human lung cancer cells (A549) were more sensitive to LAA exposure than human normal keratinocytes (HaCaT). Moreover, LAA induced significant HTB-140 and A549 apoptosis, as evidenced by V-FITC/7-AAD flow cytometry analysis. Preincubation of the HTB-140 and A549 cells with LAA increased a sensitivity of tumor cells to a drug-induced cell death. Significantly lower expression of IL-6 mRNA was observed in A549 and HTB-140 cells which were pre-incubated with LAA and then treated with doxorubicin as compared to the cells pre-incubated with LAA and then treated with cisplatin. The results suggest that the newly synthetized LAA is compound with anticancer activity promising for potential applications, but further studies are needed to gain more insight into the mechanism of action of tested derivative.

Cancer represents one of the most serious health problems and the second leading cause of death around the world. Heterocycles, due to their prevalence in nature as well as their structural and chemical diversity, play an immensely important role in anti-cancer drug discovery. In this paper, a series of hydantoin and purine derivatives containing a 4-acetylphenylpiperazinylalkyl moiety were designed, synthesized, and biologically evaluated for their anticancer activity on selected cancer cell lines (PC3, SW480, SW620). Compound 4, a derivative of 3′,4′-dihydro-2′H-spiro[imidazolidine-4,1′-naphthalene]-2,5-dione, was the most effective against SW480, SW620, and PC3 cancer cell lines. Moreover, 4 has high tumor-targeting selectivity. Based on docking studies, it was concluded that R isomers of 3′,4′-dihydro-2′H-spiro[imidazolidine-4,1′-naphthalene]-2,5-dione could be further studied as promising scaffolds for the development of thymidine phosphorylase inhibitors.

In the current studies we carried out an optimized multistep asymmetric synthesis of R-enantiomers (eutomers) for a previously identified series of racemic hybrid anticonvulsants. The spatial structure of selected enantiomers was solved by the use of crystallographic methods. The compound (R)-16 was identified as a lead, which revealed broad-spectrum protective activity in a range of epilepsy models with the following ED50 values: the maximal electroshock (MES) test (36.0 mg/kg), the 6 Hz (32 mA) seizure model (39.2 mg/kg), and the pentylenetetrazole-induced seizure model (scPTZ) (54.8 mg/kg). Furthermore, (R)-16 displayed a low potency for the induction of motor impairment in the rotarod test (TD50 = 468.5 mg/kg), resulting in potentially very beneficial therapeutic window. Finally, (R)-16 showed satisfying ADME-Tox properties in the in vitro assays. Therefore, the data obtained in the current studies justify the further preclinical development of (R)-16 as candidate for potentially broad-spectrum and safe anticonvulsant.

Seven novel derivatives of bis(2-aminoethyl)amine were synthesized. For compounds 1 and 7 single crystals were isolated and X-ray diffraction experiments were done. Lipophilicity and drug likeness were calculated in the initial stage of research. All compounds were screened for their in vitro cytotoxic activity against a panel of human cancer cell lines, which is contrary to normal (HaCaT) cell lines, by using the MTT method. Studies were followed by lactate dehydrogenase assay, apoptotic activity, and interleukin-6 assay. Within the studied group, compound 6 showed the most promising results in all biological studies. The strongest influence in A549 cells was denoted for derivative 4, which inhibited interleukin release almost tenfold, as compared to the control.

A total of 14 of 1,5-disubstituted tetrazole derivatives were prepared by reacting appropriate thiourea and sodium azide in the presence of mercury (II) chloride and triethylamine. All compounds were evaluated in vitro for their antimicrobial activity. Derivatives 10 and 11 showed the highest inhibition against Gram-positive and Gram-negative strains (standard and hospital strains). The observed minimal inhibitory concentrations values were in the range of 1–208 μM (0.25–64 μg/ml). Inhibitory activity of 1,5-tetrazole derivatives 10 and 11 against gyrase and topoisomerase IV isolated from S. aureus was studied. Evaluation was supported by molecular docking studies for all synthesized derivatives and reference ciprofloxacin. Moreover, selected tetrazoles (2, 3, 5, 6, 8, 9, 10 and 11) were evaluated for their cytotoxicity. All tested compounds are non-cytotoxic against HaCaT and A549 cells (CC50 ≤ 60 μM).

The molecular structure of Cu(II) complexes, obtained using direct and electrochemical synthesis, with 4-oxo-4H-chromene-2-carboxylic acid, 2-oxo-2H-chromene-3-carboxylic acid and (7-hydroxy-2-oxo-2H-chromen-4-yl)acetic acid have been studied. Due to difficulties in obtaining complexes as monocrystals the combination of laboratory based methods with X-ray absorption spectroscopy supported with density functional theory calculations has been employed. Complexes were found to be mono- and dinuclear. Different coordination modes were also observed: monodentate, bidentate chelating and carboxylate bridges. The octahedral geometry was found for complex with 2-carboxylic acid whereas for the other two the tetragonal pyramid was formed around copper cations.

Four Cu(II) complexes with 2- and 3-benzo[ b ]furancarboxylic acids have been synthesized and characterized using combination of two spectroscopic techniques. These techniques were: ( i ) FTIR and ( ii ) XAFS. FTIR analysis confirmed that complexes were formed and gave insight into identification of possible coordinating groups to the metallic center. XANES analysis indicated that the oxidation state of Cu is +2. EXAFS analysis allowed to identify that the first coordination sphere is formed by 4–5 oxygen atoms with the Cu–O distances around 2 A. Combining these techniques it was possible to structurally describe novel Cu(II) complexes with benzo[ b ]furancarboxylic acids.

The solid state structure of 3-(4-phenyl-5-oxo-1,2,4-triazolin-1-ylmethyl)-4-cyclohexyl-1,2,4-triazolin-5-thione ( 1 ) was characterized by FT-IR and X-ray diffraction experiment. Additionally, molecular and crystal structure of its DMSO solvate ( 1DMSO ) has been determined by X-ray diffraction method. The influence of DMSO molecules incorporation to the crystal lattice on geometry of triazolin-5-thione derivative molecule and crystal packing was analyzed. Non-covalent bonds within the crystals are additionally visualized by determination of Hirshfeld surfaces. According to results of conformational analysis in gas, molecule of triazolin-5-thione derivative adopts the lowest energy conformation in 1DMSO crystal. The crystal structure of 1 and 1DMSO were compared with previously described structurally similar compounds, in which the cyclohexyl substituent was replaced by aromatic one (phenyl/methoxyphenyl). Very interesting differences in molecules association were found by comparing the crystal structures of 1 and 1DMSO with their, mentioned above, aromatic derivatives. Interesting properties of triazolin-5-thione derivatives are connected with their π-electron delocalization effects, thus aromaticity of heterocyclic fragments has been investigated by means of the HOMA index. Comparison of aromaticity calculations results with association tendency of molecules shows that triazolin-5-one fragments reach higher aromaticity when nitrogen atom from this moiety acts as a donor in strong N H⋯N hydrogen bonds.

Seselin and alloxanthoxyletin, naturally occurring pyranocoumarins, were recently isolated from a number of plant sources, such as family of Rutaceae. It was previously reported that their natural and synthetic derivatives show cytotoxic and antitumor activity. In the present study new series of O-aminoalkyl substituted alloxanthoxyletins and seselins were synthesized and evaluated for their anticancer toxicity. Microwave assisted synthesis was used, and the structures of the compounds were confirmed by 1H NMR, 13C NMR and MS spectroscopic data. The molecular and crystal structure of 3a was analyzed by single crystal X-ray diffraction. Alloxanthoxyletin derivatives 2a, 2b, and 2d showed the highest cytotoxic potential against HTB-140 cells with IC50 of 2.48, 2.80 and 2.98μM, respectively. In vitro drug sensitivity testing in HaCaT, A549 and HTB-140 cells were also performed. Tumor cells showed a higher sensitivity to tested compounds than normal cells. Compounds 2a, 2b and 2d inhibited cell migration and exerted stronger effect on A549 and HTB-140 cells than on HaCaT cells. In order to explain the basic mechanism of cell death induction we have investigated the effect of derivatives 2a, 2b and 2d on early and late apoptosis using annexin V-FITC/7-AAD flow cytometry analysis. Derivatives 2a and 2b were much more potent inducers of early apoptosis in HTB-140 cells compared to HaCaT and A549 cells.

The new Cu(II) complexes of 1/2/3-(bromophenyl)-3-(1,7,8,9-tetramethyl-3,5-dioxo-4-azatricyclo[5.2.1.0 2,6 ]dec-8-en-4-yl)thiourea derivatives have been synthesized. The spectroscopic studies together with density functional theory calculations of Cu(II) complexes revealed that two parent ligands coordinate to the copper cation in bidentate fashion via thiocarbonyl S and deprotonated N atoms forming rarely observed four-membered chelate ring, with nearly planar [CuN 2 S 2 ] moiety. In solid state, the mononuclear complex is formed for thiourea derivative with 3-bromophenyl, whereas for Cu(II) connection with 2- and 4-bromophenyl-thioureas the formation of dinuclear complexes is observed, the latter formed by the stacking of mononuclear complexes. The microbiological activity of novel compounds has been evaluated. The Cu(II) complex with 4-bromophenyl ring connected to the thiourea moiety showed significant inhibition against standard strains of S. aureus and S. epidermidis . The range of minimal inhibitory concentration values is 2–4 μg/mL. That compound exhibited antibiofilm potency and effectively inhibited the formation of biofilm of methicillin-susceptive strain of S. epidermidis ATCC 12228. Moreover, the cytotoxicity against the MT-4 cells of all obtained complexes has been evaluated. The complexes turned out to be non-cytotoxic for exponentially growing MT-4.

Thiourea derivatives have been reported to possess many biological activities, among them antiviral and antitumoral properties. As part of our continuing effort to develop new active compounds, we report the synthesis and the evaluation of new fifteen thiourea derivatives with 1,3-benzothiazole-2-yl moiety, among them a group of biologically active (1-7) also underwent cyclization to 1,3-thiazolidin-4-ones. Molecular structure of four compounds (4, 13, 15 and 3a) was determined by an X-ray crystallography. We here report the evaluation of their cytotoxicity against human leukaemia/lymphoma- and solid tumour-derived cell lines and of their antiviral activity against HIV-1 and representatives of ssRNA and dsDNA viruses. Derivative 5 showed an interesting activity against HIV-1 wild type and against variants carrying clinically relevant mutations. A colorimetric enzyme immunoassay clarified its mode of action as a non-nucleoside inhibitor of the reverse transcriptase.

Four 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with the corresponding aryl/alkylisothiocyanates in a medium-polarity solvent. Their structures were confirmed by spectral techniques, and the molecular structure of 3 was determined by X-ray crystal analysis. For all derivatives, the binding affinities at the 5-HT2A and 5-HT2C receptors, as well as their functional activities at the 5-HT1A and D2 receptors, were determined. The arylthioureas 1 and 4 were the most active at the 5-HT1A receptor, showing, at the same time, significant selectivity over the studied 5-HT2 and D2 receptor subtypes. The compounds were tested for their pharmacological activities within the central nervous system in relevant mouse models. The involvement of the serotonergic system in the activity of 1 and 4 was indicated. The antinociceptive action of 4 was linked to its anti-inflammatory activity.

A series of halogenated (4-methoxyphenyl)-1H-tetrazol-5-amine regioisomers (1a-9a, 1b-9b) were synthesized from their corresponding thiourea analogues (1–9). The synthesis pathway was confirmed by an X-ray crystallographic studies of 1a, 1b and 5a. Title derivatives were tested for their in vitro antitubercular activity against standard, “wild-type” and atypical mycobacteria. The highest therapeutic potential was attributed to isomeric N-(bromophenyl)tetrazoles 8a and 9a. Their growth-inhibitory effect against multidrug-resistant Mycobacterium tuberculosis Spec. 210 was 8-16-fold stronger than that of the first-line tuberculostatics. Other new tetrazole-derived compounds were also more or equally effective towards that pathogen comparing to the established pharmaceuticals. Among non-tuberculous strains, Mycobacterium scrofulaceum was the most susceptible to the presence of the majority of tetrazole derivatives. The synergistic interaction was found between 9a and streptomycin, as well as the additivity of both 8a and 9a in pairs with isoniazid, rifampicin and ethambutol. None of the studied compounds displayed antibacterial or cytotoxic properties against normal and cancer cell lines, which indicated their highly selective antimycobacterial effects.

Ciprofloxacin (CP) has a confirmed cytotoxic action on some cancerous cells, but in high, non-pharmacological concentrations. Considering features of natural fatty acids, such as biocompatibility, biodegradability and their increased cellular uptake by cancer cells, it seems that combining them with a drug could improve its bioavailability, and thus cytotoxicity. Therefore, the aim of this study was coupling of CP with saturated and unsaturated fatty acids, and evaluation of their cytotoxicity, apoptosis-inducing effects and inhibition of IL-6 release in human primary (SW480) and metastatic (SW620) colon cancer, metastatic prostate cancer (PC3) and normal (HaCaT) cell lines. The PC3 cell line was the most sensitive to the presence of the obtained conjugates. The value of IC50 for oleic acid conjugate (4) was 7.7 μM, and it was 12 times lower than for CP alone (101.4 μM). The studied derivatives induced late apoptosis in all cancer cell lines, but not in normal cells. The most potent apoptosis inducer was conjugate 4, that resulted in the highest percentage of PC3 cells in late apoptosis (81.5% ± 3.9), followed by elaidic acid amide 5 (75% ± 4.8). The strongest pro-apoptic effects on SW480 cells were demonstrated by conjugates of DHA (8) and sorbic (2) acids, whereas in SW620 cell lines, compounds 2 and 5 appeared to be the most effective. To establish the mechanism of cytotoxic action of derivatives 2, 4, 5, the level of interleukin-6 (IL-6) was measured. The compounds with the highest cytotoxic potential significantly decreased the release of IL-6 by cancer cells. Additionally, all conjugates were evaluated for their in vitro antimicrobial activity. Short chain amides - crotonic (1) and sorbic (2) - were the most active against Staphyloccoci. The second-mentioned amide has shown both strong antistaphylococcal and antitumor properties.

A heterocyclic compound commonly known as “indanocyclon” undergoes an unexpected Diels-Alder addition with maleimide. The resulting product has been isolated and characterized in order to get an information about its structure and possible mechanism of the reaction. Extensive comparison of single crystal properties of 3-(2,8-dioxo-1,3-diphenyl-2,8-dihydrocyclopenta[a]inden-8a(1H)-yl)pyrrolidine-2,5-dione and favorable product of the reaction has been also performed.

A new series of norbornene and exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide derivatives was prepared, and their affinities to the 5-HT1A , 5-HT2A , and 5-HT2C receptors were evaluated and compared with a previously synthesized series of derivatives characterized by the same nuclei, to identify selective ligands for the subtype receptors. Arylpiperazines represent one of the most important classes of 5-HT1A R ligands, and the research of new derivatives has been focused on the modification of one or more portions of this pharmacophore. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4-substituted piperazine), known to be critical for the affinity to 5-HT1A receptors, and the proper selection of substituents resulted in compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that 3e, 4j, and 4n were the most active and promising derivatives for the serotonin receptor considered in this study.

Twelve novel derivatives of N-(furan-2-ylmethyl)-1H-tetrazol-5-amine were synthesized. For obtained compound 8, its corresponding substrate single crystals were isolated and X-ray diffraction experiments were completed. In the initial stage of research, in silico structure-based pharmacological prediction was conducted. All compounds were screened for their antibacterial and antimycobacterial activities using standard and clinical strains. The cytotoxic activity was evaluated against a panel of human cancer cell lines, in contrast to normal (HaCaT) cell lines, by using the MTT method. All examined derivatives were found to be noncytotoxic against normal cell lines. Within the studied group, compound 6 showed the most promising results in antimicrobial studies. It inhibited four hospital S. epidermidis rods&rsquo, growth, when applied at the amount of 4 &micro, g/mL. However, the most susceptible to the presence of compound 6 was S. epidermidis T 5501 851/19 clinical strain, for which the MIC value was only 2 &micro, g/mL. Finally, a pharmacophore model was established based on lead compounds from this and our previous work.

A series of nine copper complexes were synthesized by reacting 1,3-disubstituted thioureas with copper(II) chloride. The new compounds were characterized by elemental analysis, infrared, ultraviolet-visible and X-ray absorption spectroscopies as well as molecular modelling. The molecular structure of complexes in the solid state consists of two thiourea ligands chelated to the Cu(II) ion through the S and deprotonated N atoms (CuN2S2). The coordination polyhedron of metal cation in powdered samples exhibits two different geometries. Pseudo-tetrahedral structure is observed for noncentrosymmetric complexes with cis-N2S2 arrangement around Cu(II). A distorted square planar geometry is characteristic for centrosymmetric compounds with trans arrangements of chelating atoms around the central ion. All complexes after dissolving in dimethyl sulfoxide adopt a centrosymmetric coordination, while after diluting this solution with water, the reorganization of atoms around the metal cation is observed, leading to the formation of a tetrahedral compounds. Initial ligands and Cu(II) complexes were evaluated for their cytotoxicity. Two complexes with 4- and 3-bromophenyl attached to the (1,7,8,9,10-pentamethyl-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl)thiourea moiety (Cu1, Cu3) are cytotoxic against SW480 and PC3 cells (IC50 4–19 μm), and non-cytotoxic against HaCaT cells (IC50 ≥ 84 μm), being more selective than doxorubicin and cisplatin used as references. The compounds induced apoptosis in cancer cells, however, Cu3 was estimated to be highly active inducer of late apoptosis in SW480 and PC3 cells at lower toxicity against normal cells. The likely mechanism of action of complexes is correlated with decreasing release of IL-6 in cancer cell lines.

On the basis of the structures of serotonin modulators or drugs (NAN-190, buspirone, aripiprazole) and phosphodiesterase 4 (PDE4) inhibitors (rolipram, RO-20-1724), a series of novel multitarget 5-arylidenehydantoin derivatives with arylpiperazine fragment was synthesized. Among these compounds, 5-(3,4-dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (13) and 5-(3-cyclopentyloxy-4-methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (18) were found to be the most promising showing very high affinity toward 5-HT1A and 5-HT7 receptors (Ki = 0.2–1.0 nM) but a negligible inhibitory effect on PDE4. The high affinity of the compounds for 5-HT1A and 5-HT7 receptors was further investigated by computer-aided studies. Moreover, compounds 13 and 18 showed no significant cytotoxicity in the MTT assay, but high clearance in the in vitro assay. In addition, these compounds behaved like 5-HT1A and 5-HT7 receptor antagonists and exhibited antidepressant-like activity, similar to the reference drug citalopram, in an animal model of depression.

© 2019 Elsevier B.V. This manuscript presents the computational and experimental studies of a new thiourea derivative 1-(4-chloro-3-nitrophenyl)-3-(3,4-dichlorophenyl)thiourea (CNDCT). Scaled simulated and experimental IR and Raman spectra were compared and the vibrational modes are assigned to proper vibrations followed by potential energy distribution study. Weakening of N-H bond is observed from the red shift in NH stretching mode values from the theoretical wavenumber values. Natural bond orbital studies provide the stability of the molecule and predict the change properties upon the charge delocalization. Reactive sites in the molecule were identified using molecular electrostatic potential figures. According to QTAIM analysis, the locations of noncovalent interactions in CNDCT-1 and CNDCT-3 are practically the same. The difference in case of the CNDCT-2 is that noncovalent interaction is formed between atoms N7-H30, instead between atoms O20-C12. Average Local Ionization Energy (ALIE) and Fukui functions provide information about the exact atoms susceptible to various attacks. The tendency of the molecule to undergo air autoxidation was found from the bond dissociation energies (BDE) values and the interaction of the molecules with solvent system was analyzed using and radial distribution functions (RDF) obtained from molecular dynamics (MD) simulations. NLO studies indicate that the candidate molecule is a good NLO material compared to that of urea. Docking studies reveal that the title compound shows the inhibitory activity against Farnesoid X receptor.

4-Chloro-3-nitrophenylthioureas 1&ndash, 30 were synthesized and tested for their antimicrobial and cytotoxic activities. Compounds exhibited high to moderate antistaphylococcal activity against both standard and clinical strains (MIC values 2&ndash, 64 &mu, g/mL). Among them derivatives with electron-donating alkyl substituents at the phenyl ring were the most promising. Moreover, compounds 1&ndash, 6 and 8&ndash, 19 were cytotoxic against MT-4 cells and various other cell lines derived from human hematological tumors (CC50 &le, 10 &mu, M). The influence of derivatives 11, 13 and 25 on viability, mortality and the growth rate of immortalized human keratinocytes (HaCaT) was observed.

A series of 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with appropriate aryl/alkylisothiocyanates in anhydrous media. The structures of the newly synthesized compounds were confirmed by spectroscopic analysis and the molecular structures of 8 and 28 were confirmed by X-ray crystallography. All obtained compounds were tested for antimicrobial activity against Gram-positive cocci, Gram-negative rods and for antifungal activity. Microbiological evaluation was carried out over 20 standard strains and 30 hospital strains. Compound 6 showed significant inhibition against Gram-positive cocci and had inhibitory effect on the S. aureus topoisomerase IV decatenation activity and S. aureus DNA gyrase supercoiling activity. Compounds were tested for cytotoxicity and antiviral activity against a large panel of DNA and RNA viruses, including HIV-1 and other several important human pathogens. Interestingly, derivative 8 showed potent activity against HIV-1 wild type and variants bearing clinically relevant mutations. Newly synthesized tryptamine derivatives showed also a wide spectrum activity, proving to be active against positive- and negative-sense RNA viruses.

Thirty new derivatives of palmitic acid were efficiently synthesized. All obtained compounds can be divided into three groups of derivatives: Thiosemicarbazides (compounds 1–10), 1,2,4-triazoles (compounds 1a–10a) and 1,3,4-thiadiazoles (compounds 1b–10b) moieties. 1H-NMR, 13C-NMR and MS methods were used to confirm the structure of derivatives. All obtained compounds were tested in vitro against a number of microorganisms, including Gram-positive cocci, Gram-negative rods and Candida albicans. Compounds 4, 5, 6, 8 showed significant inhibition against C. albicans. The range of MIC values was 50–1.56 μg/mL. The halogen atom, especially at the 3rd position of the phenyl group was significantly important for antifungal activity. The biological activity against Candida albicans and selected molecular descriptors were used as a basis for QSAR models, that have been determined by means of multiple linear regression. The models have been validated by means of the Leave-One-Out Cross Validation. The obtained QSAR models were characterized by high determination coefficients and good prediction power.

Five of thiourea derivatives were prepared using as a starting compound 3-(trifluoromethyl)aniline, 4-chloro-3-nitroaniline, 1,3-thiazol- 2-amine, 2H-1,2,3-triazol-4-amine and commercial isothiocyanates. All compounds were evaluated in vitro for antimicrobial activity. Derivatives 2 and 3 showed the highest inhibition against Gram-positive cocci (standard and hospital strains). The observed MIC values were in the range of 0.5–8 μg/ml. The products effectively inhibited the formation of biofilms of methicillin-resistant and standard strains of Staphylococcus epidermidis. Inhibitory activity of thioureas 2 and 3 against Staphylococcus aureus topoisomerase IV was studied. The examined compounds were nongenotoxic.

On the basis of recently reported biologically active 3-(trifluoromethyl)phenylthioureas, a series of diaryl derivatives incorporating 1 H -tetrazol-5-yl ( 1a–11a , 1a’–11a’ ) and 1,3-thiazolidin-4-one ( 1b–11b ) scaffolds were synthesized. The synthesis pathway was confirmed by an X-ray crystallographic studies of 3a’ , 6a , 8a , 6b and 8b . The cytotoxicity against MT-4 cells and anti-HIV properties of new derivatives were evaluated. As compared to initial thiourea connections, the cyclisation reduced the cytotoxicity of compounds by 2–15 times. The most promising N-(4-nitrophenyl)-1 H -tetrazol-5-amine 7a was found to be more active than the origin thiourea. Its cytotoxicity was evaluated on A549, HTB-140 and HaCaT cell lines using MTT assay. The compound shows significant influence on cancer, but not on normal cells. Obtained results can provide some constructive data for further designing of novel family of potentially bioactive analogs.

Thirty six novel heterocyclic derivatives of ethyl 2-(2-pyridylacetate) were efficiently synthesized. The new compounds involve the linkage of a 2-pyridyl ring with thiosemicarbazide (compounds 1–7), 1,2,4-triazole (compounds 1a–7a), 1,3,4-thiadiazole (compounds 1b–7b), and 1,3,4-oxadiazole (compounds 1f–7f) moieties. The last group of compounds 1e–7e involves the connection of a 2-pyridyl ring with 1,2,4-triazole and thiourea. 1H-NMR, 13C-NMR and MS methods were used to confirm the structures of the obtained derivatives. The molecular structures of 3, 3b, 7a and 7f were further confirmed by X-ray crystallography. All obtained compounds were tested in vitro against a number of microorganisms, including Gram-positive cocci, Gram-negative rods and Candida albicans. In addition, the obtained compounds were tested for cytotoxicity and antiviral activity against HIV-1.

Three novel zinc complexes with benzo[b]furan-carboxylic acids were obtained. The elemental and thermal analyses, and IR spectroscopy were used for basic characterization of compounds. The Zn(II) coordination geometry was studied by X-ray absorption spectroscopy. In microcrystalline powders for all complexes the cation is penta-coordinated (ZnO5) with the Zn–O distances equal to ca. 2 A, as determined by extended X-ray absorption fine structure. For recrystallized Zn(II) complex 1 (with 7-acetyl-6-methoxy-3-methyl-benzo[b]furan-2-carboxylic acid) crystal structure was determined by X-ray crystallography, and this analysis indicated a distorted polyhedron around the cation in which one of the Zn–O distances is above 2.5 A.

Three Cu(II) complexes with derivatives of the benzo[b]furancarboxylic acid have been synthesized and characterized by the elemental and thermal analyses, and IR spectroscopy. The geometry of metal–ligand interaction for all compounds has been described using X-ray absorption spectroscopy and for one of them by X-ray crystallography. Two mononuclear Cu(II) complexes, with 7-acetyl-5-bromo-6-hydroxy-3-methylbenzo[b]furan-2-carboxylic and 6-acetyl-5-hydroxy-2-methylbenzo[b]furan-3-carboxylic acids, exhibit a tetra-fold coordination, CuO4. The Cu(II) cation in crystals with 7-acetyl-6-methoxy-3-methyl-benzo[b]furan-2-carboxylic acid is penta-coordinated; the bridging COO− groups and ethanol molecule stabilize the dinuclear center Cu2O10. The powdered form of this complex is based on the Cu2O8 units, indicating the absence of the ethanol molecules.

Chemical reactivity descriptors and lipophilicyty (log P) were evaluated via semi-empirical method for the quantum calculation of molecular electronic structure (PM3) in order to clarify the structure-cytotoxic activity relationships of disubstutited thioureas. Analysed compounds were obtained by the linkage of 2-aminothiazole ring, thiourea and substituted phenyl ring. The detailed examination was carried out to establish correlation between descriptors and cytotoxic activity against the MT-4 cells for 11 compounds. For the most active compounds (6 compounds) cytotoxic activity against three cancer cell lines (CCRF-CEM, WIL-2NS, CCRF-SB) and normal human cell (HaCaT) was determined. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release were assessed. Regression analysis revealed that electrophilicity index and chemical potential significantly contributed to expain the thioureas cytotoxic potential.

A series of 10 thiourea derivatives have been synthesized by the reaction of aromatic amine with a substituted aryl (compounds 1–3, 6–8) and alkylphenyl (4, 5, 9, 10) isothiocyanates. Their in vitro and in vivo pharmacological properties were studied. Among the evaluated compounds, two displayed very high affinity for the 5-HT2A receptor (1–0.043 nM and 5–0.6 nM), being selective over the 5-HT2C receptor. Derivatives 3, 5, 9, 10 by 70–89% diminished L-5-HTP-induced head twitch episodes. Compounds 1 and 5 as the 5-HT2A receptor antagonists produced a dose-dependent decrease in the number of DOI-elicited HTR. Compounds 1–5 strongly reduced amphetamine-evoked hyperactivity in rodents. In another test, 1 and 2 caused hyperthermia in mice, whereas 9 and 10 led to hypothermia. Antinociceptive and anticonvulsant properties of selected derivatives were demonstrated. Molecular docking studies using a homology model of 5-HT2A revealed a significant role of hydrogen bonds between both thiourea NH groups and Asp155/Tyr370 residues, as well as π–π interaction with Phe339.

A series of novel 4-chloro-3-nitrophenylthiourea derivatives were synthesized and evaluated for their antimicrobial, antibiofilm and tuberculostatic activities. Most of compounds exhibited high antibacterial activity against both standard and hospital strains (MIC values 0.5-2 μg/mL), as compared to Ciprofloxacin. Derivatives with 3,4-dichlorophenyl (11) and 3-chloro-4-methylphenyl (13) substituents were the most promising towards Gram-positive pathogens. Both of them exhibited antibiofilm potency and effectively inhibited the formation of biofilms of methicillin-resistant and standard strains of Staphylococcus epidermidis. Two N-alkylthioureas (20, 21) showed twofold to fourfold increase in in vitro potency against isolates of Mycobacterium tuberculosis, as compared to Isoniazid. An action of 7, 10, 11, 13, 20 and 21 against activity of topoisomerases isolated from Staphylococcus aureus was studied. Synthesized compounds were found as non-genotoxic.

A set of 21 thiourea derivatives were prepared through reacting 3-amino-1H-1,2,4-triazole with the commercial aliphatic and aromatic isothiocyanates. The aliphatic isothiocyanate was used as reagent leading to substitution on NH atom of 3-aminotriazole ring, whereas the triazole amino group was substituted when isothiocyanate group was bonded to the Csp2 hybridized atom, e.g. an aryl or C=O fragment. All compounds were evaluated in vitro for the antimicrobial activity. The derivatives 1, 2, 4, 8, 9, 10 and 12 showed the highest inhibition against Gram-positive cocci (S. aureus and S. epidermidis). The observed MIC values were in the range of 4-32 μg/mL. Compounds were also tested for their in vitro antimicrobial activity against the hospital methicillin-resistant strains of S. aureus. The observed MIC values varied from 4 to 64 μg/mL. The products 4 and 10 effectively inhibited the formation of biofilms of the methicillin-resistant and standard strains of S. epidermidis. The compound 10 was found to be more promising with IC50 values of 2-6 μg/mL as compared to the control. Moreover, the cytotoxicity against the MT-4 cells of all studied thioureas was evaluated. The compound 18 was significantly cytotoxic (CC50 = 8 μM).