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Research studies have been performed on cosmetic creams for the treatment of acne, cleansing, bio-moisturizing and epidermis whitening as well as for reducing bacterial growth and preventing papulopustular lesions. There were used analytical methods recommended by the Polish Pharmacopoeia (PP X and XI) as well as Polish Standard (PN-ISO) for estimating morphological and pharmacotherapeutic properties of cosmetic preparations. The determined high content of water and volatile components allowed to determine the morphological structure of cosmetic creams. They are „HIPRE”- type hydrogel emulsions. The thermodynamic parameters of therapeutic agents and phytochemicals contained in plant extracts and essential oils (Ʃ∆Ei, Ʃ∆Vi, δ1/2, HLBRequ.) allowed to calculate the particle radius (r) with the bioavailability coefficient=1.0, owing to which the Einstein-Smoluchowski equation was solved in the application system (D= k·T/σπr·η). The practical viscosity determined by Casson’s method enabled to calculate the diffusion coefficient (D) and to estimate the proces of mass exchange at the phase boundary, which decides about the pharmacotherapeutic effectiveness of the tested preparations. The effective process of mass exchange at the phase boundary is evidenced by the calculated numerical values of the diffusion coefficients, and above all, the topological radius of diffusing molecules (r

About 40% of newly-discovered entities are poorly soluble in water, and this may be an obstacle in the creation of new drugs. To address this problem, the present review article examines the structure and properties of cyclodextrins and the formation and potential uses of drug – cyclodextrin inclusion complexes. Cyclodextrins are cyclic oligosaccharides containing six or more D-(+)- glucopyranose units linked by α-1,4-glycosidic bonds, which are characterized by a favourable toxicological profile, low local toxicity and low mucous and eye irritability; they are virtually non-toxic when administered orally. They can be incorporated in the formulation of new drugs in their natural form (α-, β-, γ-cyclodextrin) or as chemically-modified derivatives. They may also be used as an excipient in drugs delivered by oral, ocular, dermal, nasal and rectal routes, as described in the present paper. Cyclodextrins are promising compounds with many beneficial properties, and their use may be increasingly profitable for pharmaceutical scientists.

Quinazoline nucleus is found in many bioactive molecules exhibiting anticancer activity. Herein we report crystallographic investigation, as well as in vitro determination of the biological activity of symmetrical molecules containing two quinazoline systems tethered by various polyamine linkers e.g. 4-bis(3-aminopropyl)piperazine (I), 4,9-dioxa-1,12-dodecanediamine (II), 3,3′-diamino-N-methyldipropylamine (III). Three new crystal structures are determined that differ in the linker. Molecules of compounds I and II adopt stretched conformations and molecules of III adopt bent conformation in the crystal state. The arrangement of molecules in the crystal structures is determined by weak hydrogen bonds and stacking interactions. Geometry optimization for the molecules was carried out with ab initio calculations. Cytotoxic activity of quinazoline derivatives differs markedly depending upon the cancer cell line. Endometrial cancer cells are more sensitive to examined compounds than prostate or breast cancer cells. Investigated quinazoline derivatives are able to induce HEC1A cell death in concentration and time-dependent manner while they exhibit relatively low cytotoxicity to peripheral blood mononuclear cells (PBMCs). The most promising compound is quinazoline derivative with 4,9-dioxa-1,12-dodecanediamine as the linker (II) which induced HEC1A cells apotosis in a significant manner.

Summary Introduction: The broad spectrum of pharmacological properties of linden inflorescence extracts results from polarity and the level of hydrophilic-lipophilic balance of solvents (medium) used to separate compatible phytochemical structures with the expected pharmacotherapeutic profile. Objective: The use of the general Hildebrand-Scatchard-Fedors theory of solubility to calculate the predicted solubility of classes of phytochemicals contained in linden inflorescences (Tiliae flos) and the indication of those structures which, due to their high solubility in the medium, are responsible for the profile of pharmacological activity. Material and methods: The Hildebrand, Scatchard equation, supported with computational technique proposed by Fedors, allows calculation of the solubility parameters of the extraction medium. Despite application reservations, it is a fundamental tool for estimating the predictable solubility of phytochemicals in real solution. Results: The structure of phytochemicals isolated from linden inflorescences (Tiliae flos) owing to the use of solvents of significantly diversified polarity (–dielectric constant – εM) was the basis for calculating the molar evaporation energy – ΣΔEi (cal/mol) and molar volume – ΣΔVi (cm3/mol) by Fedors method, which are fundamental quantities necessary to estimate the solubility parameter – δ1/2 and required solubility level of hydrophilic-lipophilic balance – HLBRequ. Conclusions: Results of the presented research indicate that basing on the parameters characterizing the structure of phytochemicals and the calculated ideal (–logxi 2) and predicted real (– log x2) solubility, it is possible – using the general Hildebrand-Scatchard-Fedors theory of solubility – to choose selectively the cascade of extraction media in order to distinguish in the plant material chemical and structural individuals of different polarity.

Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.

Information protection is an essential safety issue in many human activity fields. The development of computerisation (informatisation) brings new challenges in the area of non-invasive information processing in information technology (IT) systems. The known fact is that VGA, DVI/HDMI interfaces, for example, or formatter systems of laser printers that process video signals are sources of effective disclosing electromagnetic emission. Emission safety of the more and more common three-dimensional (3D) printers is less known. The selected 3D printer with the ME3DP (Material Extrusion 3D Printing) technology was tested to analyse the existing risk. Simple objects were printed during its operation to identify the stepping motor operation that are emission sources in the secondary channels. The analysis carried out focused on finding the correlation between the registered emissions and the printer head (printhead) movements when printing an object. It was shown that the analysis of the registered sensitive signal runtimes and their spectrograms allows us to recreate the printed object shape. The studies focused on measuring the acoustic signals that came from the stepping motors. The analysis of the possibilities of identifying the shapes of printed objects was based on the visual method. The article presents the study results and their analyses.

The cinnoline nucleus is a very important bicyclic heterocycle that is used as the structural subunit of many compounds with interesting pharmaceutical properties. Cinnoline derivatives exhibit broad spectrum of pharmacological activities such as antibacterial, antifungal, antimalarial, anti-inflammatory, analgesic, anxiolytic and antitumor activities. Some of them are under evaluation in clinical trials. In the present review, we have compiled studies focused on the biological properties of cinnoline derivatives conducted by many research groups worldwide between 2005 and 2019. Comprehensive and target oriented information clearly indicate that the development of cinnoline based molecules constitute a significant contribution to the identification of lead compounds with optimized pharmacodynamic and pharmacokinetic properties.

The protection of information processed electronically involves a large number of IT devices from computer sets or laptops to monitors, printers, servers, etc. In many cases, classified information processing might be associated with the use of projectors, which are an indispensable element of meetings for a limited group of people. Such devices are connected to computers through interfaces of various analogue and digital standards and can become an additional source of unwanted emissions, and the distinctive features of these emissions allow the information displayed to be unwantedly reproduced. This paper offers evidence of the existing threat related to electromagnetic infiltration of several projectors, by showing images reconstructed from registered revealing emissions. The paper presents an analysis of several solutions that can be used to reduce the level of infiltration susceptibility of projectors or to highlight this property in the device assessment process. The possibilities of using special computer fonts and the so-called method of colors—background color and text color—is analyzed. The tests were carried out on randomly selected projectors in two independent laboratories, and, based on these results, a number of interesting conclusions have been highlighted at the end.

The aim of this study was to expand our knowledge about anticancer activity of some polyamine derivatives with quinoline or chromane as terminal moieties. Tested compounds were evaluated in vitro towards metastatic human prostate adenocarcinoma (PC3), human carcinoma (DU145) and mammary gland adenocarcinoma (MCF7) cell lines. Cell viability was estimated on the basis of mitochondrial metabolic activity using watersoluble tetrazolium WST1 to establish effective concentrations of the tested compounds under experimental conditions. Cytotoxic potential of polyamine derivatives was determined by the measurement of lactate dehydrogenase activity released from damaged cells, changes in mitochondrial membrane potential, the cell cycle distribution analysis and apoptosis assay. It was revealed that the tested polyamine derivatives differed markedly in their antiproliferative activity. Bischromane derivative 5a exhibited a rather cytostatic than cytotoxic effect on the tested cells, whereas quinoline derivative 3a caused changes in cell membrane integrity, inhibited cell cycle progression, as well as induced apoptosis of prostate and breast cancer cells which suggest its potential application in cancer therapy.

Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC-3, DU-145 and MCF-7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure and the type of cancer cell line. Noncovalent DNA-binding properties of the most active compounds have been examined using ds-DNA thermal melting studies and topo I activity assay. The promising biological activity, DNA intercalative binding mode and favorable drug-like properties of bis(naphthalene-2-carboxamides) make them a good lead for further development of potential anticancer drugs.

The activity of several 3-(v-(4-arylpiperazin-1-yl)alkyl)pyrimido(5,4-c) quinolin-4(3H)-ones (LCAPs) with well-defined serotonin 1A (5-HT1A) receptor affinity was described by using chromatographic and calcu- lated physicochemical parameters in quantitative structure-activity relationship analysis. Normal-phase thin-layer chromatography plates impregnated with solutions of L-aspartic acid, L-serine, L-phenylalan- ine, L-tryptophan, L-tyrosine, L-asparagine, L-threonine and their mix- tures (denoted as S1-S11 biochromatographic models) were used with two mobile phases as a model of the interaction between LCAP and 5-HT1A receptors. Molecular descriptors for the investigated com- pounds were calculated by using HyperChem and ACD/Labs programs. The significant relationship explains that 82% of the variance was suc- cessfully validated by leave-one-out and leave-many-out tests. The results demonstrated that this model has significant predictive ability and can be used for the preliminary screening of newly synthesized po- tential 5-HT1A receptor ligands.

The interaction of polyamine conjugates with DNA double helix has been studied. Binding properties were examined by ethidium bromide (EtBr) displacement and DNA unwinding/topoisomerase I/II (Topo I/II) activity assays, as well as dsDNA thermal stability studies and circular dichroism spectroscopy. Genotoxicity of the compounds was estimated by a comet assay. It has been shown that only compound 2a can interact with dsDNA via an intercalative binding mode as it displaced EtBr from the dsDNA-dye complex, with Kapp = 4.26 × 106 M−1; caused an increase in melting temperature; changed the circular dichroism spectrum of dsDNA; converted relaxed plasmid DNA into a supercoiled molecule in the presence of Topo I and reduced the amount of short oligonucleotide fragments in the comet tail. Furthermore, preliminary theoretical study has shown that interaction of the discussed compounds with dsDNA depends on molecule linker length and charge distribution over terminal aromatic chromophores.

The synthesis of new bischromone derivatives (4a-c and 5a-c) as potential anticancer drugs is described. The difference in the reactivity between 4-oxo-4H-chromene-3-carboxylic acid 2 (or its methyl ester 3) and 4-oxo-4H-chromene-3-carbonyl chloride 1 with three different polyamines: 3,3'-diamino-N-methyldipropylamine (a), 1,4-bis(3-aminopropyl)piperazine (b), 4,9-dioxa-1,12-dodecanediamine (c) resulted in the formation of two different groups of products, compounds 4a-c and 5a-c, designed in agreement with the bisintercalators' structural requirements. The transformation of 4-oxo-4H-chromene-3-carboxylic acid into 2H-chromene-2,4(3H)-diones (5) was confirmed by the NMR and XRD experiments. Compounds 4a and 5a were evaluated in vitro in the highly aggressive melanoma cell line A375. An enhanced induction of apoptosis and cell cycle arrest clearly revealed that compound 5a was more potent than 4a. Compound 5a was also more active in diminishing the adhesive potential of melanoma cells. Current studies support the notion that small changes in the three-dimensional structure of molecules might have a substantial impact on their biological activity.

The expiration date is a guarantee from the manufacturer that a drug product will remain chemically stable - and thus maintain its full potency and safety - prior to that date. Authors of this study have checked whether tested drug product has a similar dissolution profile beyond and within expiration date. In this paper, dissolution study of Zyprexa (Olanzapine as an Active Pharmaceutical Ingredient) 10 mg tablets was conducted in three different mediums, in the same way as comparison in-vitro and in-vivo tests during investigation of bioavailability and bioequivalence at clinical trials phase. Obtained results demonstrated that dissolution profiles of tested and reference product are essentially similar, which was statistically confirmed by means of similarity factor.

The paper presents the concept of integration of INSIGMA Event Reporting System (INSIGMA ERS) and national emergency notification system, SPR in polish (System Powiadamiania Ratunkowego). The concept is based on the logical interface between systems as a tool of proposed integration. The resulting integration may present the synergy effect which would provide faster and timely delivery of emergency information from society to public security services. It may significantly increase the security of citizens.

Crystal structures of hydrochlorides of 7-chloro- and 7-methyl-4-iminecinnoline analogs of antibacterial quinolones have been determined by X-ray diffraction methods. The cell parameters for the 7-chloro (1) analog in the space group P21/c are a = 9.061(1), b = 19.062(1), c = 7.310(1)A, β = 104.92(1)°, Z = 4, and Dcalc = 1.569 g/cm3 and for the 7-methyl (2) analog in the space group P\({\bar 1}\) are a = 7.277(5), b = 9.080(5), c = 10.058(5) A, α = 106.10(1), β = 102.38(1), γ = 90.18(1)°, Z = 2, and Dcalc = 1.429 g/cm3. Despite geometrical equivalency of methyl and chlorine and some resemblance of their packings, the crystal structures are not isostructural. Each compound forms a strong intramolecular hydrogen bond between protonated 4-imine (a donor) and 3-carboxylic (an acceptor) groups. Compounds with a similar bond, but with reversed functionality and orientation of the 3-carboxylic group, form common quinolones, being mostly 4-oxoquinoline-3-carboxylic acids. The difference should exclude chemical affinity of 4-imine analogs to the guanine base of a bacterial DNA in DNA-gyrase complex, as proposed by Shen et al.2 for 4-oxoquinoline-3-carboxylic acids showing antibacterial activity. Also the free acidic function of a carboxyl group may significantly lower permeability of 4-imine-3-carboxylic analogs of quinolones. Surprisingly, they have demonstrated antibacterial activity comparable with that of nalidixic acid.

Cross-sectional survey study was done, investigating whether information included in SmPC (changing often due to safety reasons) is actually used, properly used or not used at all by cardiologists, GP's (general practitioners), internists and internal diseases physicians. Conducting readability test of Patient Information Leaflet, required by European Commission improved utilization of medical information included in it by European patients. Since there was no such requirement on Summary of Product Characteristics (SmPC), we examined utilization of information presented in Summary of Product Characteristics by physicians. Investigated were six drugs used in antiplatelet therapies, ATC (Anatomical, Therapeutic Chemical classification system) code B01AC. A random sample of 800 physicians took part in the study. They were physicians (300 cardiologists and 300 GP's) chosen from The Polish Chamber of Physicians and Dentists (PCPD) database interviewed using regular mail and 200 physicians interrogated during the XV International Congress of Polish Cardiac Society.Physicians. They were asked to complete a questionnaire consisting of 20 questions (13 concerning active substances, 6 general questions and one open question "Indicate the best way of receiving safety information"). Questions were constructed on the basis on new safety information included in actualized SmPC after submission of Periodic Safety Update Reports (PSURs) for medicinal products concerned. The overall response rate was 16.5% (132 filled in of 800 questionnaires). Of the respondents there were 65 and 67 from group I (cardiologists) and group II (GP's, internists and internal diseases), respectively. Eligible questionnaires (85) were obtained during the Congress (64.4%). Only 47 were received via regular mail (35.6%). Most correct answers were noted for clopidogrel and ASA (acetylsalicylic acid). 72.98% and 72.73%, respectively. The less known substance appeared eptifibatide, only 34.47% of answers were correct. Analyzing both groups (I and II), there were no significant differences regarding percent of correct answers, however, a statistical tendency level has been reached for "drugs for hospital use only" (abciximab, eptifibatide and tirofiban). For the open question, concerning best pipeline for receiving safety information according to respondents, both groups were relatively similar. Most popular were e-mail alerts, web pages/portals and drug compendiums, 44.37 and 24 indications, respectively. Study has limitation of a small sample size. The results are based on small amount of received questionnaires. Due to small sample size, it can be assumed that there are no significant differences between two compared groups (I--cardiologists; II--GP's, internists and internal diseases physicians) with regard to utilization of information from SmPC; however, beside two substances--clopidogrel and ASA, the level of knowledge is below expected. It also should be emphasized that "drugs for hospital use only" pointed out tendency that cardiologists can have better knowledge regarding these substances.

C12H12N2O3,Mr=232.24. (1): C2/c,Z=8,a=14.658(1),b=4.9375(4),c=31.859(4) A, β=91.710(6)°. (2): P21/c,Z=4,a=11.422(2),b=4.8864(2),c=21.176(3)A, β=103.29(3)°. The study confirms significant contribution of quinoid diazine ring form in anhydrobase of 1-substituted 4-hydroxycinnolinium hydroxides. The phenomenon corresponds with a negative net charge at formerly positively charged N(1) atom, with fewer hydrogen contacts of less negatively charged O(4) and with increased stacking in 1-substituted derivative, in comparison with 2-substituted structure.

A series of new pyrimido[5,4-c]quinolin-4(3H)-ones with variable length of the spacer between amide and 4-arylpiperazine moiety were prepared to further explore the role of a terminal portion in the serotonergic activity. The majority of compounds demonstrated high in vitro affinity for 5-HT(1A) receptor, and moderate-to-low affinity for 5-HT(2A) and 5-HT(7) receptors. X-ray analysis, two-dimensional NMR, conformational studies and docking into the 5-HT(1A) receptor model were conducted to investigate conformational preferences of selected 5-HT(1A) receptor ligands in different environments. The extended conformation of tetramethylene derivatives was found in a solid state, in DMSO (for a protonated form) and as a global energy minimum during conformational analysis in simulated water environment. Ligand geometry in top-scored complexes, obtained by docking to a set of 100 receptor models, were either fully extended or with central spacer torsion in synclinal conformation.

The synthesis of new polyamine derivatives containing dimeric quinoline (3a-c), cinnoline (4a-c) and phthalimide (7a-c and 8a-c) moieties is described. Three different polyamines: (1,4-bis(3-aminopropyl)piperazine (a), 4,9-dioxa-1,12-dodecanediamine (b), 3,3'-diamino-N-methyldipropylamine (c) were used as linkers. The new compounds were obtained according to known procedures. Their biological activity was assessed in vitro in a highly aggressive melanoma cell line A375. Polyamine diimides containing phthalimide moieties demonstrated no inhibitory activities against melanoma cells. Quinoline diamides were more efficient than cinnoline ones. Mainly cytostatic activity exerted as altered cell cycle profiles was observed at the concentrations causing about 50% reduction of adherent cell proliferation. Based on their structure as well as their biological activity, we assume that some of the newly synthesized compounds may act as DNA bisintercalators. This study might be useful for further designing and developing anticancer drugs with potent activities.

A series of substituted 3-aminopyrimido[5,4-c]cinnolines 3, 7 was prepared. 6,7-Substituted 4-amino-3-cinnolinecarboxylic acid 1 were condensed with acetic anhydride to give the respective 1,3-oxazino[5,4-c]cinnolines 2. The obtained derivatives reacted with hydrazines and gave 3-aminopyrimido[5,4-c]cinnolines. Reaction of the esters 5 with hydrazines produced hydrazides 6, which upon treatment with N,N-dimethylformamide dimethyl acetal gave 3-aminopyrimido[5,4-c]cinnolines 7. Treatment of 6b with bromocyan produced 2-amino-3,4-dihydro-3,10-dimethyl-5 H-1,3,4-triazepino[7,6-c]cinnolin-5-on (8b). Some of the synthesized compounds were screened for their effect on the CNS.

Although cinnoline belongs to a family of fairly well known heterocycles, the interest in the study of its derivatives continues. Cinnoline compounds demonstrate interesting bioactivity and many research papers have discussed the biological property, structure-activity relationship, and applications in medicinal science. Attention has been paid to the synthesis of heterocyclic compounds bearing a cinnoline moiety, mainly because of the interest in their broad spectrum of pharmacological activities. This chronological work summarizes almost all synthetic papers and patents concerning the biological properties of 107 cinnoline derivatives published over the last 50 years with 117 references.

This review focuses on a new approach to the development of drugs, namely on prodrugs and soft drugs. Nowadays, we try to design drugs that heal sick people having the best acceptance of patients. They must be efficient and selective on their site of action and must be metabolized to non-toxic derivatives. Both, prodrugs and soft drugs should have good distributive properties to enhance their quality. They are designed to maximize the amount of an active drug that reaches its target, through changing the physicochemical, biopharmaceutical or pharmacokinetic properties of drugs. Prodrugs are changed into the active drug within the body through enzymatic or non-enzymatic reactions. Soft drugs are novel and active analogues of already known therapeutic agents. It is expected that continued studies will improve drug properties so as to achieve the best drug delivery system.

Pyrimido[5,4-c]cinnoline and pyrimido[5,4-c]quinoline derivatives have been tested as potential intercalators. All of them embody stuctural properties alike to afford intercalating activity. Their cytotoxicity was determined on the two human leukemia cell lines, the promyelocytic HL-60 and the lymphoblastic NALM-6. The viability of cells exposed continuously to tested compounds was estimated by the trypan-blue exclusion assay. IC50 data for the NALM-6 cell line are lower than for the HL-60 cell line, what suggested that the HL-60 leukemia cells are more resistant to toxic action of tested compounds. All compounds exerted moderate cytotoxic activity. The compounds were analyzed with the HyperChem/ChemPlus software trying to find basic structure-activity relationships.

The introduction of combinatorial chemistry and robotics for high throughput screening has changed the way drugs are discovered today compared with 10-15 years ago when fewer compounds were tested in animal or organ models. The introduction of new analytical techniques, especially liquid chromatography/mass spectrometry (LC/MS) has made it possible to characterize the chemical properties, permeability, metabolic stability and metabolic fate of a large number of screening hits for further development in a funnel-like manner. The purpose of this contribution is to discuss principles and recent strategies for metabolite identification and to give an introduction to biotransformation studies. Metabolites are experimentally generated with the use of animal and human recombinant expressed enzymes, and different liver and other tissue fractions like microsomes and slices. For separation and identification of structurally diverse metabolites, LC/MS and tandem mass spectrometry (LC/MS/MS) techniques are commonly used. The LC/MS and LC/MS/MS techniques are rapid, sensitive, easy to automate and robust, and therefore, they are the methods of choice for these studies. The outcome of the metabolite identification studies is detection of metabolites that could be pharmacologically active and contribute to the efficacy of a new chemical entity (NCE), and elimination of compounds that form reactive intermediates and/or toxic metabolites that could cause adverse effects of NCE. If such information is available at an early stage during the drug discovery process, the chemical structure of the compound may be modified to reduce the risk of idiosyncratic and/or adverse drug reactions during clinical development.

Determination of metabolic properties of a new chemical entity (NCE) is one of the most important steps during the drug discovery and development process. Nowadays, in vitro methods are used for early estimation and prediction of in vivo metabolism of NCEs. Using in vitro methods, it is possible to determine the metabolic stability of NCEs as well as the risk for drug-drug interactions (DDIs) related to inhibition and induction of drug metabolic enzymes. Metabolic stability is defined as the susceptibility of a chemical compound to biotransformation, and is expressed as in vitro half-life (t(1/2)) and intrinsic clearance (CL(int)). Based on these values, in vivo pharmacokinetic parameters such as bioavailability and in vivo half-life can be calculated. The drug metabolic enzymes possess broad substrate specificity and can metabolize multiple compounds. Therefore, the risk for metabolism-based DDIs is always a potential problem during the drug development process. For this reason, inhibition and induction in vitro screens are used early, before selection of a candidate drug (CD), to estimate the risk for clinically significant DDIs. At present, most pharmaceutical companies perform in vitro drug metabolism studies together with in silico prediction software and automated high-throughput screens (HTS). Available data suggest that in vitro methods are useful tools for identification and elimination of NCEs with unappreciated metabolic properties. However, the quantitative output of the methods has to be improved. The aim of this review is to highlight the practical and theoretical basis of the in vitro metabolic methods and the recent progress in the development of these assays.

QSAR analysis was done in a group of cinnoline-3-carboxylic acid derivatives with antibacterial properties. Several physicochemical parameters, which characterize the variability of the structure of the 15 studied compounds, were compared as to their activity against gram-positive cocci, gram-negative bacilli and gram-positive bacilli strains. The physicochemical parameters with predictive value were found.

Chemical modification of cinnoxacin was studied with the aim of improving its antibacterial activity and spectrum. A series of 4-imino-1, 4-dihydrocinnoline-3-carboxylic acid derivatives was synthesized and their in vitro antibacterial activity was evaluated. These derivatives were designed as isosteric analogues of fluoroquinolones and are characterized by the presence of an imine group instead of an oxo group at the 4-position and a nitrogen atom in position 2. The crystal structure of one analogue determined by X-ray diffraction shows the dipolar form of the compound in the solid state. The in vitro antibacterial activity of the synthesized compounds against Gram-positive and Gram-negative bacteria was examined. The MIC of the most active compounds lies in the range of the first generation of quinolones such as nalidixic acid. The compounds with dichlorobenzyl substituent show enhanced activity against Gram-positive bacteria.

C 12 H 14 N 2 O 3 cristallise dans P2 1 /c avec a=8,760, b=13,550, c=10,456 A, β=104,62 o , Z=4; affinement jusqu'a R=0,062. Le groupe bicyclique est dans une conformation sofa. L'orientation du groupe acetate d'ethyle est determinee par une liaison hydrogene intramoleculaire entre l'oxygene du carbonyl et l'atome N(1) de l'heterocycle, avec une distance N...O de 3,016 A