Search

Substituted thiourea derivatives possess confirmed cytotoxic activity towards cancer but also normal cells. To develop new selective antitumor agents, a series of 3-(trifluoromethyl)phenylthiourea analogs were synthesized, and their cytotoxicity was evaluated in vitro against the cell line panel. Compounds 1–5, 8, and 9 were highly cytotoxic against human colon (SW480, SW620) and prostate (PC3) cancer cells, and leukemia K-562 cell lines (IC50 ≤ 10 µM), with favorable selectivity over normal HaCaT cells. The derivatives exerted better growth inhibitory profiles towards selected tumor cells than the reference cisplatin. Compounds incorporating 3,4-dichloro- (2) and 4-CF3-phenyl (8) substituents displayed the highest activity (IC50 from 1.5 to 8.9 µM). The mechanisms of cytotoxic action of the most effective thioureas 1–3, 8, and 9 were studied, including the trypan blue exclusion test of cell viability, interleukin-6, and apoptosis assessments. Compounds reduced all cancerous cell numbers (especially SW480 and SW620) by 20–93%. Derivatives 2 and 8 diminished the viability of SW620 cells by 45–58%. Thioureas 1, 2, and 8 exerted strong pro-apoptotic activity. Compound 2 induced late apoptosis in both colon cancer cell lines (95–99%) and in K-562 cells (73%). All derivatives acted as inhibitors of IL-6 levels in both SW480 and SW620 cells, decreasing its secretion by 23–63%.

Spectroscopic analysis of 1-(2-fluorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (FPTT) is reported. Experimental and theoretical analyses of FPTT, with molecular dynamics (MD) simulations, are reported for finding different parameters like identification of suitable excipients, interactions with water, and sensitivity towards autoxidation. Molecular dynamics and docking show that FPTT can act as a potential inhibitor for new drug. Additionally, local reactivity, interactivity with water, and compatibility of FPTT molecule with frequently used excipients have been studied by combined application of density functional theory (DFT) and MD simulations. Analysis of local reactivity has been performed based on selected fundamental quantum-molecular descriptors, while interactivity with water was studied by calculations of radial distribution functions (RDFs). Compatibility with excipients has been assessed through calculations of solubility parameters, applying MD simulations. Graphical abstract Reactive sites identified.

Spectroscopic analysis of 1-(2-fluorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (FPTT) is reported. Experimental and theoretical analysis of FPTT, with Molecular Dynamics (MD) simulations, are reported for finding different parameters like: identification of suitable excipients, interactions with water, and sensitivity towards autoxidation. Molecular dynamics and docking show that FPTT can act as a potential inhibitor for new drug. Additionally, local reactivity, interactivity with water, and compatibility of FPTT molecule with frequently used excipients have been studied by combined application of density functional theory (DFT) and MD simulations. Analysis of local reactivity has been performed based on selected fundamental quantum-molecular descriptors, while interactivity with water was studied by calculations of radial distribution functions (RDFs). Compatibility with excipients has been assessed through calculations of solubility parameters, applying MD simulations.

Spectroscopic analysis of 1-(2-fluorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (FPTT) is reported. Experimental and theoretical analyses of FPTT, with molecular dynamics (MD) simulations, are reported for finding different parameters like identification of suitable excipients, interactions with water, and sensitivity towards autoxidation. Molecular dynamics and docking show that FPTT can act as a potential inhibitor for new drug. Additionally, local reactivity, interactivity with water, and compatibility of FPTT molecule with frequently used excipients have been studied by combined application of density functional theory (DFT) and MD simulations. Analysis of local reactivity has been performed based on selected fundamental quantum-molecular descriptors, while interactivity with water was studied by calculations of radial distribution functions (RDFs). Compatibility with excipients has been assessed through calculations of solubility parameters, applying MD simulations. Graphical abstract Reactive sites identified.

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’ growth, when applied at the amount of 4 µg/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 µg/mL. Finally, a pharmacophore model was established based on lead compounds from this and our previous work.

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.

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.

Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by molecular docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.

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).

© 2017 Elsevier B.V. A novel thiourea derivative, 1-(3-bromophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (ANF-22) is synthesized and characterized by FTIR, FT-Raman and NMR spectroscopy experimentally and theoretically. A detailed conformational analysis of the title molecule has been conducted in order to locate the lowest energy geometry, which was further subjected to the detailed investigation of spectroscopic, reactive, degradation and docking studies by density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Time dependent DFT (TD-DFT) calculations have been used also in order to simulate UV spectra and investigate charge transfer within molecule. Natural bond orbital analysis has been performed analyzing the charge delocalization and using HOMO and LUMO energies the electronic properties are analyzed. Molecular electrostatic potential map is used for the quantitative measurement of active sites in the molecule. In order to determine the locations possibly prone to electrophilic attacks we have calculated average local ionization energies and mapped them to the electron density surface. Further insight into the local reactivity properties have been obtained by calculation of Fukui functions, also mapped to the electron density surface. Possible degradation properties by the autoxidation mechanism have been assessed by calculations of bond dissociation energies for hydrogen abstraction. Atoms of title molecule with significant interactions with water molecules have been determined by calculations of radial distribution functions. The title compound can be a lead compound for developing new analgesic drug.

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.

The wavenumbers, molecular structure, molecular electrostatic potential, nonlinear optical properties and natural bond orbital analysis of a thiourea derivative, 1-(3,4-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (ANF-6) were reported. For the title molecule, HOMO is all over the molecule except the CF 3 group and LUMO is over the 1,3-substituted phenyl ring PhII, CF 3 group and C S group. The most reactive sites of the molecule are identified with the help of MEP plot analysis. The first hyperpolarizability of the title compound is 38.69 times that of the standard NLO material urea. This study also encompassed the investigation of local reactivity properties by calculation of average local ionization energies and Fukui functions, which values have been mapped to the electron density surface. Bond dissociation energies have been calculated for all single acyclic bonds in order to assess the possibilities for autoxidation process and to determine where degradation could start. Radial distribution functions after molecular dynamics simulations have been calculated in order to determine the atoms with the most pronounced interactions with water. Within Marcus semi-empiric approach, charge hopping properties of the title molecule have been assessed and compared with urea and thiourea molecules. From the molecular docking study, the docked title compound forms a stable complex with cytochrome reductase and got a binding affinity value of −6.3 kcal/mol and hence the title compound can be a lead compound for developing new antifungal agent.

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 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.

Isonicotinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT 1A , 5-HT 2A and 5-HT 2C receptors were evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to play critical roles in affinity for serotoninergic receptors and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT 1A , 5-HT 2A and 5-HT 2C receptors and moderate or no affinity for other relevant receptors (D 1 , D 2 , α 1 and α 2 ). N -(3-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)propyl)isonicotinamide ( 4s ) with Ki = 0.130 nM, was the most active and selective derivative for the 5-HT 1A receptor compared to other serotoninergic, dopaminergic and adrenergic receptors. Compound 4o , instead, showed 5-HT 2A affinity values in subnamolar range. Moreover, the compounds having better affinity and selectivity binding profile towards 5-HT 1A and 5-HT 2A receptors were selected in order to be tested by in vitro and in vivo assays to determine their functional activity.

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.

The title compound 1-(3-chloro-4-fluorophenyl)-3-[3-(trifluoromethyl) phenyl]thiourea (ANF-2) was synthesized and structurally characterized by single crystal XRD. The optimized molecular structure, vibrational frequencies, and corresponding vibrational assignments of ANF-2 have been investigated experimentally and theoretically using Gaussian 09 and Schrodinger Materials Science Suite software packages. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. Gauge-including atomic orbital NMR chemical shifts calculations were carried out and compared with experimental data, while the first hyperpolarizability is 48 times that of the standard NLO material. The maximum negative region is localized over the C=S group and 1,3-disubstituted phenyl ring, while the maximum positive region is localized on NH groups indicating a possible site for nucleophilic attack. Average local ionization energies have been mapped to the electron density surface in order to detect molecule sites where electrons are least tightly bound. Other possible reactive centers of the title molecule have been detected by calculation of Fukui functions. In order to investigate the possibility for autoxidation and hydrolysis of the investigated molecule, we have calculated bond dissociation energies and radial distribution functions. Charge hopping properties have been assessed using the Marcus semi-empiric approach and the results were compared with urea and thiourea molecules. The docked ligand forms a stable complex with prostaglandin E synthase and has a binding affinity value of -6.5 kcal mol(-1) and the title compound can be a lead compound for developing new analgesic drugs.

© 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.

A total of 31 of thiourea derivatives was prepared reacting 3-(trifluoromethyl)aniline and commercial aliphatic and aromatic isothiocyanates. The yields varied from 35% to 82%. All compounds were evaluated in vitro for antimicrobial activity. Derivatives 3 , 5 , 6 , 9 , 15 , 24 and 27 showed the highest inhibition against Gram-positive cocci (standard and hospital strains). The observed MIC values were in the range of 0.25–16 μg/ml. Inhibitory activity of thioureas 5 and 15 against topoisomerase IV isolated from Staphylococcus aureus was studied. Products 5 and 15 effectively inhibited the formation of biofilms of methicillin-resistant and standard strains of Staphylococcus epidermidis . Moreover, all obtained thioureas were evaluated for cytotoxicity and antiviral activity against a large panel of DNA and RNA viruses. Compounds 5, 6 , 8–12 , 15 resulted cytotoxic against MT-4 cells (CC 50 ≤ 10 μM).

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.

The substituent effect on the supramolecular arrangement in a series of polycyclic monoimide keto derivatives crystals was studied. Single crystal X-ray diffraction and IR spectroscopic experiments were performed for seven related compounds, as well as the Hirshfeld surface analysis and quantum chemical calculations at HF and DFT levels in vacuo, in solution and for small clusters. The presence of C O group at the bridge of the main hydrocarbon skeleton implied the catemer motif of the Nimide H⋯Oimide hydrogen bond in case of smaller substituents (H , MeO , EtO ). For more voluminous groups (iBuO ) or additional hydrogen bond acceptors (AcO , O ) the steric hindrance increased and the imide⋯imide interactions were no longer present in the solid state. The Nimide H⋯Oketo or Nimide H⋯Oester hydrogen bonds were formed instead. The binding energy per one N H⋯O interaction calculated for supramolecular clusters at HF/6-31G(d,p) level was ca. 20 kJ mol−1, indicating moderate strength of this hydrogen bond. The solvation free energies and induced dipole moments were computed at B3LYP/6-311+G(d,p) level using the integral equation formalism model (IEF PCM) considering three solvents of various polarity: non-polar chloroform, polar aprotic dimethyl sulfoxide (DMSO) and polar protic water. The relations between the vibrational spectra and the crystal structure have been discussed. The following sequence of carbonyl stretching modes in IR spectra has been derived from quantum chemical calculations: (1) at the highest frequencies – the symmetric vibration of two imide C O bonds, (2) the vibrations of keto C O bonds attached directly to the polycyclic hydrocarbon skeleton, (3) the asymmetric vibration of two imide C O bonds, and (4) at the lowest frequencies – the vibration of ester C O group. The characteristic peaks observed in imide experimental IR spectra at about 3080 cm−1 have been explained as overtone and combination bands of νC O stretching and γN H out-of-plane bending vibrations.

An overview of docking models of chain arylpiperazines to different subtypes of serotonin receptors belonging to the GPCR family is presented. The theory of a ligand-receptor interaction has been briefly summarized. The review covers more than twenty models, beginning with the early models of a ligand interaction with the 5-HT1A and 5-HT2A receptor, and ending with a ligand-5-HT7 receptor docking studies.

The present paper discusses models of 5-HT(1A) and 5-HT(2A) receptors, developed by conformational analysis and 3D-QSAR methods. Hypotheses concerning the ligand-5-HT(7) receptor interaction were complemented by models constructed on the basis of the receptor's structure. Various pharmacophore concepts are supported by structures of exemplary ligands and groups of compounds, derived from chain polycyclic arylpiperazines, used for models generations.

A series of halogeno derivatives of thiourea bearing a polycyclic imide core has been efficiently synthesized and evaluated for antimicrobial activity. The structures of the compounds were established by 1H and 13C NMR and MS methods. The molecular structure of 4Clc was determined by an X-ray crystallography. Compounds containing 3-chloro-4-fluorophenyl substituent (3Cl4Fb, 3Cl4Fd) were found to be the most promising against Gram-positive bacteria (MIC values ranged from 8 to 32 pg/mL for standard and 32 - 64 µg/mL for hospital strains). The in vitro cytotoxicity against MT-4 cells of all compounds was evaluated.

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 13 alkyl derivatives of 3-phenylpiperidine-2,6-dione were synthesized. Newly obtained compounds were investigated in vitro against HIV-1 and other selected viruses. The benzyl 3f and fluorophenyl 3g derivatives showed moderate protection against CVB-2 and the compound 3g also against HSV-1. Derivatives were tested also for their antibacterial and antifungal activity. The molecular structures of 3a and 3d were determined by an X-ray analysis.

The preparation of twelve aminoalkanol derivatives of 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione was described. Newly obtained compounds, as well as their propyl and butyl analogues, were evaluated in vitro against selected viruses. Selected derivatives were tested for their antibacterial and antifungal activity. Compounds 3h, 3j, 4b and 5a–d showed moderate to significant protections against CVB-2, HSV-1 and YFV viruses. The molecular structures of 4a, 5c and 5g were determined by an X-ray analysis.

Prezentowana praca zawiera przegląd modeli farmakoforowych receptorów serotoninowych 5-HT1A, 5-HT2A oraz 5-HT7, opisanych w czasie ostatniej dekady. Przedstawiono modele ligandów receptora 5-HT1A i 5-HT2A wyznaczone metodami analizy konformacyjnej i trójwymiarowej analizy QSAR. Hipotezę oddziaływań ligand-receptor 5HT7 uzupełniono o modele skonstruowane na podstawie struktury receptora. Opisy farmakoforów zostały poparte przykładami znanych aktywnych ligandów i grup związków wykorzystanych do wytworzenia modeli.

Prezentowana praca zawiera przegląd literaturowy modeli oddziaływań dokujących długołańcuchowych arylopiperazyn z receptorami serotoninowymi 5-HT1A, 5-HT2A oraz 5-HT7. Wymieniono najważniejsze rodzaje oddziaływań stabilizujących kompleks ligand-receptor serotoninowy. Omówiono szereg hipotez wiązania ligandów do receptorów metabotropowych, proponowanych na podstawie modelowania homologicznego. W celu określenia konformacji znanych pochodnych alkilo- i alkoksypiperazynylowych przeanalizowano również dane strukturalne z Cambridge Structural Database.

Antibacterial and antifungal activity of 10-(diphenylmethylene)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives were examined by the disk diffusion method (growth inhibition zone diameter in agar medium). The minimal inhibitory concentrations (MICs) for the most active agents were determined. Title compounds were also evaluated in vitro against HIV-1 virus and their cytotoxicity was determined. Aminoalkanol derivatives exhibited activity against the majority of microorganisms studied.

Antibacterial and antifungal activity of 10-(diphenylmethylene)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives were examined by the disc-diffusion method (growth inhibition zone diameter in agar medium). The MIC’s for the most active agents were determined. Title compounds were also evaluated in vitro against representatives of different virus classes. Most of the tested compounds exhibit activity against CVB-2 virus.

The synthesis and pharmacological activity of 4-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione is described. The structure of the compound was confirmed by elemental analysis, 1H nuclear magnetic resonance (NMR), 13C NMR, mass spectra, and X-ray crystallography. The compound exhibited significant affinity to both 5-HT1A and 5-HT2A receptors, similarly to aripiprazole, which is an atypical antipsychotic drug.