Buspirone structure activity relationship of indole

buspirone structure activity relationship of indole

Dopamine D3 receptor addiction treatment BP, buspirone, [11C] PHNO, – molecular determinants, N-n-butyl-indoleamide, – small-molecule structure-activity relationship (SAR) enantioselectivity, . STRUCTURE-ACTIVITY RELATIONSHIP OF 5-HT1A AGONISTs Overview. its activity indicated that an intact indole nucleus was not required for 5-HT1A C: /- N->~~ CH3 2-NC-7 N M2-N-3 N CH 3 O O Buspirone Gepirone O C#,G) £& --~. · 61, Synthesis and structure-activity relationship studies of .. Synthesis, structure-activity relationships and molecular modeling studies of new indole .. molecular interactions of buspirone analogues with the serotonin transporter.

Antigen presentation is thought to be effected primarily by Langerhans' cells, whereas much of the local expression of the response is thought to be regulated by cytokines derived from both T cells and accessory cells. Pharmacological studies have indicated that a number of mediators in addition to cytokines may contribute to the expression of contact hypersensitivity and other forms of cell-mediated immunity. There has been particular interest in the role of serotonin 5-hydroxytryptamine, 5-HT in these reactions.

For example, serotonin has been shown to have a wide range of actions on T cells and other effector cells in vitro or in vivo, and pharmacological agents that deplete or antagonize serotonin can diminish expression of cell-mediated immunity. Early studies raised the possibility that such agents might reduce cell-mediated immunity by antagonizing or depleting mast cell-associated serotonin. However, more recent findings indicate that at least one of these drugs, reserpine, can inhibit contact hypersensitivity independently of mast cells, probably through direct effects on T cells.

Although experimental contact hypersensitivity represents a classical example of an immune response, and is the experimental model for the common clinical disorder, contact dermatitis, many other pathological conditions in mammals are solely or in part the result of immune responses. Various therapeutics have been utilized as immunosuppressants including steroid hormones, anti-metabolites such as methotrexate and azathioprine, cyclosporine, alkylating agents such as cyclophosamide and busulfan, and antibiotics.

As a result, there still remains a strong need to provide new immunosuppressive agents that can minimize or prevent pathogenic immune responses. In contrast to the immune response, an inflammatory response is a pathologic condition that can occur in response to immunologically non-specific injury, either from physical such as traumachemical, or biologic agents.

Unlike immune responses, inflammatory responses do not respond adaptively to the inciting stimulus, do not show specificity and do not exhibit long term memory.

Cellular products of lymphocytes may contribute to or induce an inflammatory response. However, because of the differences in mechanisms, a compound can function as an antiinflammatory agent without having immunosuppressive properties. Phenylbutazone, indomethacin, aspirin, ibuprofen, and acetaminophen are examples of antiinflammatory compounds which have no significant immunosuppressive activity, as demonstrated by their lack of a significant effect on immunologically mediated responses, such as contact hypersensitivity.

Buspirone 8-[4-[4- 2-pyrimidinyl piperaziny]butyl]azaspiro[4,5]decane-7,9-dione is a neuroleptic agent with central nervous system CNS dopamine and serotonin 5-HT receptor antagonist properties. There remains a need for additional compounds that are immunosuppressants but do not exhibit significant neuroleptic activity.

It is therefore an object of the present invention to provide a method and compositions for suppressing pathogenic immune responses. It is another object of the present invention to provide a method and compositions for suppressing pathogenic immune responses that are without significant neuroleptic effect.

Although the parent buspirone has a strong neuroleptic effect when administered systemically but not when administered topicallyit is used in the examples as a model of an active immunosuppressant.

In the preferred method of administration, the buspirone derivatives are administered systemically, for example, by injection, in a pharmaceutical carrier such as saline, in an amount effective to immunosuppress the patient. In a second embodiment, the derivatives are administered topically in a suitable carrier to immunosuppress the patient effectively at the site of application without producing a significant neuroleptic effect.

Other pharmaceutical compositions include a buspirone derivative combined with a cycloamylose, such as cyclodextrin, which can used to modify the pharmokinetics of the compound.

US5484788A - Buspirone as a systemic immunosuppressant - Google Patents

In a preferred embodiment, buspirone or its derivative is administered as a quaternary salt. The change in ear thickness post-challenged value minus baseline pre-challenge value was measured 24 hours after oxazolone challenge.

The term aryl, as used herein, and unless otherwise specified, refers to phenyl or substituted phenyl, wherein the substituent is independently halo, alkyl, or oxy alkyl for example, methyoxy, ethoxy, etc. The term heterocycle refers to a cyclic moiety that has O, S, or N in the aromatic ring, including but not limited to, pyrryl, furyl, pyridyl, thiophenyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbozolyl, and isoxazolyl and the like, optionally substituted with halo Cl, Br, I, or Falkyl, oxyalkyl, aryl or oxyaryl.

The term aralkyl refers to an aryl group with an alkyl substituent. The term alkaryl refers to an alkyl group that has an aryl substituent. The term alkene, as referred to herein, and unless otherwise specified, refers to an alkene group of C2 to C10, and specifically includes vinyl, and allyl. Buspirone derivatives As used herein, buspirone derivatives without significant neuroleptic effect are identified by their ability to inhibit or prevent cutaneous contact hypersensitivity, as described in detail in Example 1.

Measurement of a compound's ability to bind to serotonin or dopamine receptors can be evaluated by assessing its lack of ability to act as a tranquilizer or neuroleptic in mammals, for example, by demonstrating that it is no different than placebo, for example, in the hot plate test of Eddy, et al.

The chemically unrelated serotonin receptor antagonists, trazadone and mianserin, and the dopamine receptor antagonist, haloperidol, are not effective in suppressing contact hypersensitivity. On this basis, it appears that the mechanism of action of buspirone and buspirone derivatives in suppressing the immune response is independent of their serotonin or dopamine receptor blocking properties.

Therefore, buspirone derivatives with immunosuppressive effects yet without neuroleptic effects can be provided by the method of selection disclosed generally herein. As used herein, the term "buspirone derivative" refers to 1 a molecule of the formula: Structure and Synthesis of Buspirone Derivatives The parent buspirone is 8-[4-[4- 2-pyrimidinyl piperaziny]butyl]azaspiro[4.

STR4 As demonstrated in Example 1, the parent buspirone has significant immunosuppressive activity. However, uncomplexed or unmodified buspirone also has significant neuroleptic effect when administered systemically. However, buspirone can be complexed, or chemically modified without undue experimentation using methods known to those skilled in the art, to retain its immunosuppressive activity and eliminate the undesired neuroleptic effect by decreasing the ability of the compound to bind to dopamine or serotonin receptors.

buspirone structure activity relationship of indole

The potential utility of any one of the above-described forms of buspirone to act as an immunosuppressant can be conveniently determined by synthesizing the compound and testing it in the biological assay described in Example 1. The neuroleptic activity of the buspirone derivatives can be estimated as described in Example 3. Methods of synthesis of buspirone or its derivatives are disclosed in, or can be easily adapted by one of ordinary skill in organic synthesis, from procedures disclosed in Wu, et al.

Complexation or Modification of the Buspirone Nucleus to Prevent Significant Neuroleptic Effect As discussed above, immunosuppressive compounds with a buspirone nucleus that have a neuroleptic effect can be complexed or modified to eliminate that effect, by one or more of the following processes.

Decreasing the Lipophilicity, Equivalent to Increasing the Hydrophilicity of the Compound Compounds with a buspirone nucleus that exhibit an immunosuppressive effect yet also exhibit a neuroleptic effect can be modified to minimize the neuroleptic effect by decreasing the lipophilicity equivalent to increasing the hydrophilicity of the molecule. This can be done by adding one or more charged side chain s onto the molecule or by altering the existing side chain to make it more polar.

The hydrophilicity of buspirone derivatives will in general increase when charged substituents are added. Increasing the Size of the Molecule Another technique for reducing the central nervous system CNS effects of compounds that contains a buspirone nucleus is to increase the size of the molecule via a covalent linkage to a large moiety e.

Complexing the Buspirone Nucleus with a Cyclic Molecule A fourth method for reducing the central nervous system CNS effects of a compound that contains a buspirone nucleus includes forming a non-covalent complex of the compound with a cyclic molecule such as a cycloamylose e.

Such complexes may be prepared by any method known to the art, including those described in U. Buspirone altered or complexed by any of the above methods with the effect of reducing the CNS effects of the compound to an acceptable leveland which exhibits the ability to suppress an immune response, is referred to herein as "a buspirone derivative without significant neuroleptic effect.

Whether the same entity is capable of inducing the neuropharmacological side effects observed for buspirone can be assayed by, for example, the hot plate test of Eddy et al. The dopamine and serotonin receptors are well characterized and strategies for estimating binding of drugs to these receptors are well established.

For example, Schmidt, et al. Also, a composite pharmacophore analysis and chemical database screening strategy is described by Sleight, et al, Naunyn-Schmiedebergs Arch.

Administration as a Quaternary Salt Buspirone or its above-defined derivative can be administered in the form of a nontoxic pharmaceutically acceptable quaternary salt.

Quaternary salts are typically less lipophilic than the corresponding unquaternized compound, and therefore have a decreased effect on the central nervous system. Nonlimiting examples of quaternary salts that may be used include salts prepared from methyl chloride, methyl bromide, methyl iodide, methyl sulfate, ethyl sulfate, methyl benzene-sulfonate, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-butyl bromide, isobutyl bromide, sec-butyl bromide, n-amyl bromide, n-hexyl chloride, benzyl chloride, and benzyl bromide.

Therapeutic Compositions Mammals, and specifically humans, suffering from pathogenic immune responses can be treated by administering to the patient an effective amount of the buspirone derivative or its salt in the presence of a pharmaceutically acceptable carrier or diluent.

The buspirone derivative is administered subcutaneously, intravenously, intraperitoneally, intramuscularly, parenterally, orally, submucosally, by inhalation, transdermally via a slow release patch, or topically, in an effective dosage range to cause immunosuppression.

Typical dosages for topical application for all of the above-identified conditions are those ranging from 0. In general, local immunosuppression can be achieved by administering topically lower doses of buspirone derivatives than would be required if the agents were administered systemically. The effective dosage of the parent compound, buspirone, for systemic immunosuppression is believed to be higher than the effective dosage of buspirone for inducing a neuroleptic effect. The buspirone derivative is administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated.

The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound of the buspirone derivative in vivo in the absence of serious toxic effects. The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art.

It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.

Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.

The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. The buspirone derivative or its salts can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.

A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The buspirone derivative can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, antiinflammatories, antivirals, or other immunosuppressive agents. These results indicate that the replacement of one acetate pendant arm of H4teta by a methylphosphonate one does not provide promising chelators to stabilize radiolanthanides for in vivo application.

buspirone structure activity relationship of indole

The results indicate that the replacement of one acetate pendant arm of H4teta by a methylphosphonate one does not provide promising chelators for in vivo application. Cyclam derivative; TETA analogue; Lanthanide complexes; Thermodynamic stability constants; Radiolabelling; Biodistribution; Efficient synthesis of 6- hetero arylthieno[3,2-b]pyridines by Suzuki—Miyaura coupling.

The coupling products obtained were evaluated for their growth inhibitory effect on three human tumor cell lines, representing different tumor models, MCF-7 breast adenocarcinomaAC5 melanoma and NCI-H non-small cell lung cancer.

USA - Buspirone as a systemic immunosuppressant - Google Patents

The effect of these two compounds on cell cycle progression was analyzed in the NCI-H cell line. Results showed that both compounds interfered with the normal cell cycle distribution. Bi hetero aryl derivatives of the thieno[3,2-b]pyridine were obtained by Suzuki—Miyaura cross-coupling of the methyl 3-aminobromothieno[3,2-b]pyridinecarboxylate with aryl or heteroaryl pinacolborane esters or potassium trifluoroborates, in good to excellent yields.

The coupling products were evaluated for their growth inhibitory effect on three representative human tumor cell lines. For the two most promising compounds, cell cycle analysis was performed in one of the cell lines in study. Suzuki—Miyaura coupling; Hetero aryl potassium trifluoroborates; Hetero arylpinacolboranes; Hetero arylthieno[3,2-b]pyridines; Tumor cell growth inhibition; Cell cycle analysis; Convenient synthesis and biological profile of 5-amino-substituted 1,2,4-oxadiazole derivatives by Maria Ispikoudi; Michalis Amvrazis; Christos Kontogiorgis; Alexandros E.

We describe herein a convenient straightforward synthesis of 5-amino-substituted 1,2,4-oxadiazoles, upon the reactions of amidoximes with carbodiimides, as well as their further derivatization to acetamides, in good yields. Most of the compounds exhibited in general low interaction with the stable radical 1,1-diphenylpicryl-hydrazyl. Compounds 32 and 39 inhibited significantly soybean lipoxygenase. The ability of the compounds to release NO in the presence of a thiol factor has been also investigated.

Subsequent acetylation provided the corresponding acetamides. Known drug space KDS was analysed for the occurrence of natural products and their derivatives. A database of marketed drugs was compiled. In regard to the molecular descriptors the natural products had larger statistical means and standard deviations than their synthetic counterparts. It was found that KDS occupies a larger volume in chemical space with respect to drug-like chemicals, i. The definition of KDS gives drug designers a larger volume to work in compared to drug-like chemical space.

However, the bulk of known drugs are found within the volume of drug-like chemical space. The 1,3-dipolar cycloaddition of azomethine ylides derived from substituted isatins and 1,3-thiazolanecarboxylic acid to a series of 2- arylmethylene -2,3-dihydro-1H-indenones afforded twenty nine novel spiro-pyrrolothiazolyloxindoles regio- and stereoselectively in moderate yields.

These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv MTB using agar dilution method. Among 29 compounds screened, spiro[5. Antitubercular activity; Mycobacterium tuberculosis; Azomethine ylide; 1,3-Dipolar cycloaddition; 2- Arylmethylene -2,3-dihydro-1H-indenones; Spiro-pyrrolothiazolyloxindoles; Mitogen-activated protein kinase 4 of Leishmania parasite as a therapeutic target by Parameswaran Saravanan; Santhosh K. Protein kinases are important regulators of many different cellular processes such as transcriptional control, cell cycle progression and differentiation, and have drawn much attention as potential drug targets.

Leishmania mexicana mitogen-activated protein kinase 4 LmxMPK4 is crucial for the survival of the parasite. As the crystal structure of the enzyme is not known, we have used bioinformatics techniques to model LmxMPK4 structure. The current study reveals conservation of all sequence and structural motifs of LmxMPK4.

Study shows mitogen-activated protein kinases are highly conserved throughout different Leishmania species and significant divergence is observed towards mammalian mitogen-activated protein kinases.

Additionally, using virtual docking methods, we have identified inhibitors for LmxMPK4. The sequence and structure analysis results were helpful in identifying the ligand binding sites and molecular function of the Leishmania specific mitogen-activated protein kinase. Mitogen-activated protein kinases; Leishmania; Motif; Virtual screening; Docking; Chemotherapy; 2-Acetylpyridine thiosemicarbazones: Cytotoxic activity in nanomolar doses against malignant gliomas by Josane A.

buspirone structure activity relationship of indole

Barreiro; Heloisa Beraldo SAR studies suggested that stereo properties are critical to define the potential activity of the studied compounds against the RT2 cell line, while electronic properties seem to be important for interaction with the biological target in T98 cells.

SAR studies were carried out. The synthesis of new 4-amino-tetrahydroquinazolino[3,2-e]purine derivatives along with their activity in cell-free enzymatic assays on Src is reported. Some compounds emerged as moderately active inhibitors of the enzyme and showed antiproliferative effects on the murine leukemia L cell line.

buspirone structure activity relationship of indole

Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction. Therefore, this study provides a new promising scaffold with moderate enzymatic inhibitory activities for further development of new anticancer drugs targeting Src tyrosine kinase.

A series of 4-amino-tetrahydroquinazolino[3,2-e]purine derivatives was synthesized and evaluated for its Src cell-free enzymatic inhibitory and antiproliferative activity on the murine leukemia L cell line. Aminopurine; Src; Cytotoxic; Docking; Synthesis and antitumor activity of novel benzimidazolecarboxylic acid derivatives and their transition metal complexes as topoisomerease II inhibitors by Shadia A.

N-Aminomethyl-1H-benzimidazolecarboxylic acid derivatives 2—5 and the ligand, 1- 5 or 6- -carboxy-1H-benzimidazolylmethyl pyridinium chloride 6; H2L1 have been synthesized. The growth-inhibitory against a panel of 21 human cancer cell lines of the synthesized compounds 1—9 was studied. Compounds 6—9 showed potent growth-inhibitory activity against the studied cell lines.

buspirone structure activity relationship of indole

The correlation coefficients according to COMPARE analysis of the National Cancer Institute screening protocol showed that the pattern of the growth-inhibitory effect of the compounds 6—9 was similar to that of etoposide and doxorubicin but different from that of SN and cisplatin. The topoisomerase II inhibitory activity of the tested compounds 6—9 was studied.

Compounds 6 and 8 inhibited topoisomerase II activity at 10 times lower concentration than etoposide in relaxation assay. Benzimidazoles; Benzimidazolyl methyl pyridinium salts; Transition metals complexes; Antitumor activity; Growth-inhibitory activity; Topoisomerase II inhibitory activity; Synthesis, crystal structures, biological activities and fluorescence studies of transition metal complexes with 3-carbaldehyde chromone thiosemicarbazone by Yong Li; Zheng-Yin Yang; Jin-Cai Wu Zn II complex exhibits blue fluorescence under UV light and its fluorescent property in solid state was investigated.

Antioxidant tests in vitro show the compounds possess significant antioxidant activity against superoxide and hydroxyl radicals, and the scavenging effects of Cu II complex are stronger than Zn IINi II complexes and some standard antioxidants, such as mannitol and vitamin C. Their DNA binding properties and antioxidant activity were investigated systematically.

A series of 2-[N-aryloxo 4-chlorophenyl ethanehydrazonoyl]methyl-4 3H -pyrimidinones 5 were prepared by coupling the diazonium salt of aniline derivatives with 2- 4-chlorobenzoylmethylene methyl-4 3H -pyrimidinone 4 in sodium hydroxide solution. The structures of these newly synthesized compounds were confirmed by IR, NMR, mass spectrometry and elemental analyses and the tautomeric structure of these compounds was discussed.

All the newly synthesized compounds were screened for their antibacterial and antifungal activities, some of which exhibited moderate activity. Compounds 5b, 5d and 5i showed good cytotoxic activities against the tested cell lines. A large number of chemical structures that interact with G-protein coupled receptors GPCRs have been disclosed in patents or published papers. Most of these compounds are selective for a given protein target; however, it is well recognized that some GPCR-drugs interact with multiple targets.

Using a literature database, we have identified compounds that act on different GPCRs. These protein targets are usually divided in three main classes, A, B and C, based on sequence similarity, but they can also be grouped pharmacologically based on endogenous ligand characteristics.

In this paper, we specifically focus on compounds able to recognize two different classes or different pharmacological clusters within the same class. Despite the large number of GPCR ligands described in the literature, we identified a limited number of molecules acting on both classes A and B, only few acting on classes A and C and none acting on class B and C receptors. A search for bi- or multi-potent compounds exhibiting activities on different pharmacological clusters of class A receptors revealed cases of cross reactivity, the most frequent concerning amine and peptide receptor clusters.

Aminoalkyl substituted derivatives were synthesized starting from glycyrrhetinic acid methyl ester and screened for antitumor activity in a panel of 15 human cancer cell lines by an SRB assay.

The most compound 7 possesses an aminohexyl side chain, induces apoptosis and shows IC50 values of 0. Glycyrrhetinic acid; Antitumor activity; Apoptosis; Design and synthesis of novel tetrahydro-2H-Pyrano[3,2-c]Pyridazin-3 6H -one derivatives as potential anticancer agents by Taleb H. Polyfunctional tetrahydro-2H-pyrano[3,2-c]pyridazin-3 6H -one derivatives were synthesized and biologically evaluated as novel anticancer agents.

These motifs were produced by a five-step reaction sequence in which the Achmatowicz oxidative cyclization, is the basic core for such synthesis.

Compounds 15f, 16c, and 16d showed antiproliferative activity against the SK-BR-3 breast cancer cell line. These compounds form the foundation for further investigation in our continuing efforts to develop potent anticancer agents. Several novel 6-[ hetero arylamino]thieno[3,2-b]pyridines were prepared by palladium-catalyzed C—N Buchwald—Hartwig coupling of the methyl 3-aminobromothieno[3,2-b]pyridinecarboxylate with aryl and heteroarylamines, using different reaction conditions.

The antitumoral activity of the di hetero arylamines obtained was evaluated against three representative human tumor cell lines, namely breast adenocarcinoma MCF-7melanoma AC5and non-small cell lung cancer NCI-H and some structure—activity relationships were established within each series.

The most promising compounds were shown to be a benzothiazole derivative with GI50 3. The novel di hetero arylamines derivatives of the thieno[3,2-b]pyridine moiety were submitted to in vitro antitumoral evaluation and some structure—activity relationships SARs were established. With an intention to synergize the anti-bacterial activity of chalcones and rhodanineacetic acid, several hybrid compounds possessing chalcone and rhodanineacetic acid moieties were synthesized and tested for their anti-bacterial activity.

Some compounds presented great anti-microbial activities against Gram-positive bacteria including the multidrug-resistant clinical isolates. The synthesis of new polyamine derivatives containing dimeric quinoline 3a—ccinnoline 4a—c and phthalimide 7a—c and 8a—c moieties is described.

The new compounds were obtained according to known procedures. Their biological activity was assessed in vitro in a highly aggressive melanoma cell line A Polyamine diimides containing phthalimide moieties demonstrated no inhibitory activities against melanoma cells. Quinoline diamides were more efficient than cinnoline ones. 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. Synthesis, antiproliferative activity and tubulin targeting effects by Miriam Carr; Lisa M. The 1,4-diarylazetidinones are unsubstituted at C-3, or contain methyl substituent s at C The most potent compounds 12d and 12e display antiproliferative activity at nanomolar concentrations when evaluated against the MCF-7 and MDA-MB human breast carcinoma cell lines.

Triosephosphate isomerase from Trypanosoma cruzi TcTIMan enzyme in the glycolytic pathway that exhibits high catalytic rates of glyceraldehydephosphate- and dihydroxyacetone-phosphate-isomerization only in its dimeric form, was screened against an in-house chemical library containing nearly compounds belonging to different chemotypes. After secondary screening, twenty-six compounds from eight different chemotypes were identified as screening positives.

Curcumin is a multifunctional natural product with regulatory effects on inflammation. However, a major limitation for the application of curcumin is its poor bioavailability. We previously demonstrated that the mono-carbonyl analogues of curcumin possessed improved pharmacokinetic profiles.

Based on the screening data, quantitative structure—activity relationship was conducted, indicating that electron-withdrawing groups in benzene ring are favourable to anti-inflammatory activities of B-class compounds.

Furthermore, compounds AN1 and B82 demonstrated anti-inflammatory abilities in a dose-dependent manner. These raise the possibility that these compounds might serve as potential agents for the treatment of inflammatory diseases. The quantitative SAR indicates that electron-withdrawing groups benefit anti-inflammatory activities of B-class compounds. The biological importance of microtubules in mitosis, as well as in interphase, makes them an interesting target for the development of anticancer agents.

Small molecules such as benzo[b]thiophenes are attractive as inhibitors of tubulin polymerization. Moreover, 4e perturbed mitochondrial membrane potential and caused activation of caspase-3 and cleavage of poly ADP-rybose polymerase PARPevents that are involved in 4e-induced apoptosis.

European Journal of Medicinal Chemistry (v.45, #12)

A series of novel 2- 5- hydroxymethyl phenyl-1H-pyrazolyl phenylethanol derivatives 4 was synthesized from ethyl 1- 2-oxophenylethyl phenyl-1H-pyrazolecarboxylate derivatives 3 and characterized by means of IR, 1H NMR, HRMS and X-ray crystal diffraction. Structures of 4a, 4d, 4e and 4f were also determined by 13C NMR. Isomeric intermediates, 3a and 5a, were unambiguously confirmed by X-ray crystal structure analysis and successfully differentiated with 1H NMR chemical shifts of methylene bonded to pyrazole ring.

Preliminary biological evaluation showed that compounds 4d and 4e could suppress A lung cancer cell growth through cell cycle arrest and autophagy. Biological evaluation showed that compounds 4d and 4e could suppress A lung cancer cell growth through cell cycle arrest and autophagy.

In this study, we first described the two configurations of cephalosporins by cefozopran, then determined their molecular structure and finally evaluated the stability and biological activity of the two configurations. Our results showed that cefozopran existed as two different configurations in the aqueous solution with acetonitrile. Using mass spectrometry with liquid chromatography, nuclear magnetic resonance with liquid chromatography and optical rotation detection technology, we determined the spatial structures of both configurations and the detailed mechanism for change.

By molecular docking and determining their antimicrobial activities, we showed that the biological activity of cis-isomer was stronger than that of trans-isomer. We reported two kinds of configurations of cefozopran, determined their molecular structures and evaluated their stability and biological activity. In the PCA, a separation between active and inactive compounds was obtained by six descriptors topological and geometrical.

Leave-N-out cross validation and y-randomization test showed that the model presented robustness and no chance correlation, respectively, and the descriptors indicated that the FAS inhibition depends on electronic distribution of the investigated compounds.

The model obtained in this study may provide a guidance for proposition of new FAS inhibitors.