http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . All rights reserved. Tue, 14 May 2013 15:46:06 +0000 http://www.hindawi.com/journals/ijmc/2013/743139/ Human estrogen receptor (ER) isoforms, ERα and ERβ, have long been an important focus in the field of biology. To better understand the structural features associated with the binding of ERα ligands to ERα and modulate their function, several QSAR models, including CoMFA, CoMSIA, SVR, and LR methods, have been employed to predict the inhibitory activity of 68 raloxifene derivatives. In the SVR and LR modeling, 11 descriptors were selected through feature ranking and sequential feature addition/deletion to generate equations to predict the inhibitory activity toward ERα. Among four descriptors that constantly appear in various generated equations, two agree with CoMFA and CoMSIA steric fields and another two can be correlated to a calculated electrostatic potential of ERα. Ying-Hsin Chang, Jun-Yan Chen, Chiou-Yi Hor, Yu-Chung Chuang, Chang-Biau Yang, and Chia-Ning Yang Copyright © 2013 Ying-Hsin Chang et al. All rights reserved. Thu, 02 May 2013 09:07:53 +0000 http://www.hindawi.com/journals/ijmc/2013/793260/ Thiazolidines are five-member heterocyclic having sulfur, nitrogen, and oxygen atoms in their ring structure and exhibiting potent as well as wide range of pharmacological activities. In this minireview, recent updates on synthesis and pharmacological evaluations of molecules based on 2,4-thiazolidine and rhodanine are discussed. Ravinder Singh Bhatti, Sakshi Shah, Suresh, Pawan Krishan, and Jagir S. Sandhu Copyright © 2013 Ravinder Singh Bhatti et al. All rights reserved. Tue, 30 Apr 2013 14:42:38 +0000 http://www.hindawi.com/journals/ijmc/2013/348948/ The chemistry of heterocyclic compounds has been an interesting field of study for a long time. Heterocyclic nucleus 1,3,4-thiadiazole constitutes an important class of compounds for new drug development. The synthesis of novel thiadiazole derivatives and investigation of their chemical and biological behavior have gained more importance in recent decades. The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an active area of intensive investigation in medicinal chemistry. During the recent years, there has been intense investigation of different classes of thiadiazole compounds, many of which possess extensive pharmacological activities, namely, antimicrobial activity, anticonvulsant, antifungal antidiabetic, anti-inflammatory, antioxidant, and antituberculosis activities, and so forth. The resistance towards available drugs is rapidly becoming a major worldwide problem. The need to design new compounds to deal with this resistance has become one of the most important areas of research today. Thiadiazole is a versatile moiety that exhibits a wide variety of biological activities. Thiadiazole moiety acts as “hydrogen binding domain” and “two-electron donor system.” It also acts as a constrained pharmacophore. On the basis of the reported literature, we study here thiadiazole compounds and their synthetic methods chemistry and anticonvulsant activity. Bhawna Sharma, Amita Verma, Sunil Prajapati, and Upendra Kumar Sharma Copyright © 2013 Bhawna Sharma et al. All rights reserved. Mon, 15 Apr 2013 18:27:17 +0000 http://www.hindawi.com/journals/ijmc/2013/197612/ A simple protocol for the efficient preparation of aryl and heteroaryl substituted dihydropyrimidinone has been achieved via initial Knoevenagel, subsequent addition, and final cyclization of aldehyde, ethylcyanoacetate, and guanidine nitrate in the presence of piperidine as a catalyst in solvent-free under microwave irradiation. The synthesized compounds showed a good anti-inflammatory, antibacterial, and antifungal activity. Anjna Bhatewara, Srinivasa Rao Jetti, Tanuja Kadre, Pradeep Paliwal, and Shubha Jain Copyright © 2013 Anjna Bhatewara et al. All rights reserved. Tue, 09 Apr 2013 15:59:45 +0000 http://www.hindawi.com/journals/ijmc/2013/467383/ Bilirubin is an endogenous product of heme degradation in mammals. Bilirubin has long been considered as a cytotoxic waste product that needs to be excreted. However, increasing evidence suggests that bilirubin possesses multiple biological activities. In particular, recent studies have shown that bilirubin should be a protective factor for several autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. Since these autoimmune diseases are closely associated with specific types of human leukocyte antigens (HLAs), we have hypothesized that bilirubin might bind to the antigenic peptide-binding groove of the HLA molecules and exert its immunosuppressive actions. In order to evaluate the hypothesis, theoretical docking studies between bilirubin and the relevant HLA molecules have been undertaken. The in silico studies have clearly shown that bilirubin may bind to the antigenic peptide-binding groove of the HLA molecules relevant to the autoimmune diseases with significant affinity. The bound bilirubin may block the binding of antigenic peptides to be presented to T cell receptors and lead to suppression of the autoimmune responses. Based on this hypothesis new drug discovery research for autoimmune diseases will be conducted. Hideto Isogai and Noriaki Hirayama Copyright © 2013 Hideto Isogai and Noriaki Hirayama. All rights reserved. Thu, 04 Apr 2013 14:07:06 +0000 http://www.hindawi.com/journals/ijmc/2013/203606/ DHEA, 17α-AED, 17β-AED, and 17β-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED, and 17β-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERβ may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR, only in the presence of high dexamethasone concentrations. These results underscore the major difference between androstene hormone interactions with these nuclear receptors and their biological effects. Thomas L. Shaak, Dayanjan S. Wijesinghe, Charles E. Chalfant, Robert F. Diegelmann, Kevin R. Ward, and Roger M. Loria Copyright © 2013 Thomas L. Shaak et al. All rights reserved. Sun, 31 Mar 2013 16:11:26 +0000 http://www.hindawi.com/journals/ijmc/2013/725673/ A series of new 1,3,4-oxadiazole derivatives, 4(a–h), containing 5-chloro-2-methoxy benzohydrazide moiety were synthesized by the reaction of 5-chloro-2-methoxybenzoate with different aromatic carboxylic acids. These newly synthesized compounds were characterized by FT-IR, 1H NMR, mass spectra, and also by elemental analysis. All the newly synthesized compounds were screened for their antibacterial and antifungal activities. Antimicrobial studies revealed that compounds 4c, 4f, and 4g showed significant activity against tested strains. Basavapatna N. Prasanna Kumar, Kikkeri N. Mohana, Lingappa Mallesha, and Kikkeri P. Harish Copyright © 2013 Basavapatna N. Prasanna Kumar et al. All rights reserved. Tue, 19 Mar 2013 12:08:40 +0000 http://www.hindawi.com/journals/ijmc/2013/495134/ Oral bioavailability of a drug compound is the significant property for potential drug candidates. Measuring this property can be costly and time-consuming. Quantitative structure-property relationships (QSPRs) are used to estimate the percentage of oral bioavailability, and they are an attractive alternative to experimental measurements. A data set of 217 drug and drug-like compounds with measured values of the percentage of oral bioavailability taken from the small molecule ChemBioBase database was used to develop and test a QSPR model. Descriptors were calculated for the compounds using Codessa 2.1 tool. Nonlinear general regression neural network model was generated using the DTREG predictive modeling program software. The calculated percentage of oral bioavailability model performs well, with root-mean-square (rms) errors of 4.55% oral bioavailability units for the training set, 14.32% oral bioavailability units for the test set, and 19.12% oral bioavailability units for the external prediction set. Given the structural diversity and bias of the data set, this is a good first attempt at modeling oral bioavailability using QSPR methods. The model can be used as a potential virtual screen or property estimator. With a larger data supply less biased toward the high end values of the percentage of oral bioavailability, a more successful model could likely be developed. Deepu Bakasta and M. G. Shambhu Copyright © 2013 Deepu Bakasta and M. G. Shambhu. All rights reserved. Tue, 05 Mar 2013 13:46:27 +0000 http://www.hindawi.com/journals/ijmc/2013/256836/ Several new 2,6-bis(substituted)pyridine ligands and 2,6-bis(substituted)pyridine Ag(I) nitrate complexes were synthesized and characterized spectroscopically. The newly synthesized ligands include pyridine-2,6-bis(3-oxopropanenitrile) (1), pyridine-2,6-bis(2-cyano-N-phenyl-3-oxopropanethioamide) (2), and pyridine-2,6-bis((E)-2-(2-phenylhydrazono)-3-oxopropanenitrile) (3). The newly synthesized ligands and silver(I) complexes were evaluated for their in vitro anticancer activity against four human cancer cell lines including hepatocellular carcinoma (HePG2), lung adenocarcinoma (A549), colon carcinoma (HT29), and breast adenocarcinoma (MCF7). Most of the newly synthesized silver(I) complexes exhibited better activity than the ligands, and the results have been compared with doxorubicin as a reference drug. Korany A. Ali, Mokhles M. Abd-Elzaher, and Khaled Mahmoud Copyright © 2013 Korany A. Ali et al. All rights reserved. Thu, 14 Feb 2013 15:00:23 +0000 http://www.hindawi.com/journals/ijmc/2013/273534/ A green, efficient synthesis of 5-arylidene rhodanine and 2,4-thiazolidinedione derivatives without using any external catalyst in polyethylene glycol (PEG) at 80°C has been described. Reaction procedure is very simple, short, and obtained yields are very high. Dhruva Kumar, Suresh Narwal, and Jagir S. Sandhu Copyright © 2013 Dhruva Kumar et al. All rights reserved. Tue, 08 Jan 2013 15:42:10 +0000 http://www.hindawi.com/journals/ijmc/2013/984329/ Novel substituted chromenopyridones (3a–j and 6a–d) were synthesized and evaluated in vitro for the cytotoxic activity against various human cancer cell lines such as prostate (PC-3), breast (MCF-7), CNS (IMR-32), cervix (Hela), and liver (Hep-G2). preliminary cytotoxic screening showed that all the compounds possess a good to moderate inhibitory activity against various cancer cell lines. Particularly, compound 6b bearing allyl moiety displayed a significant cytotoxic potential in comparison to standard drugs. Balwinder Singh, Vishal Sharma, Gagandeep Singh, Rakesh Kumar, Saroj Arora, and Mohan Paul Singh Ishar Copyright © 2013 Balwinder Singh et al. All rights reserved. Tue, 18 Dec 2012 10:29:37 +0000 http://www.hindawi.com/journals/ijmc/2012/730239/ The purpose of this study is to understand the interactions of some antibacterial cationic amphipathic cyclooctapeptides with calcium(II) and their secondary structural preferences. The thermodynamic parameters associated with calcium(II) interactions, between the antibacterial active cyclooctapeptides (COP 1–6) and those that did not exhibit significant activities (COP 7–9), were studied by isothermal titration calorimetry. Calcium(II) binding in the absence and presence of micellar dodecylphosphocholine (DPC), a membrane mimicking detergent, was conducted by circular dichroism (CD). Both groups of cyclopeptides showed weak binding affinities for calcium(II) (Kb ca. 10−3 M−1). However, CD data showed that the antimicrobial peptides COP 1–6 adopted a twisted beta-sheet structure (positive CD absorption band at ca. 203 nm) in the presence of calcium(II) in micellar DPC. In contrast, COP 7–9, which lacked antibacterial activity, adopted a different conformational structure (negative CD absorption band at ca. 203 nm). These results indicate that these cyclopeptides could adopt secondary structural preferences in the presence of calcium(II) amidst a hydrophobic environment to elicit their antibacterial activity. These findings could be useful in facilitating the design of cyclopeptide derivatives that can adopt this beta-sheet-like secondary structure and, thereby, provide a useful molecular template for crafting antibacterial compounds. Tarshona Stevens, Nykia McNeil, Xiuli Lin, and Maria Ngu-Schwemlein Copyright © 2012 Tarshona Stevens et al. All rights reserved. Tue, 18 Dec 2012 09:47:32 +0000 http://www.hindawi.com/journals/ijmc/2012/682495/ We report the results of a search for model-based relationships between mu, delta, and kappa opioid receptor binding affinity and molecular structure for a group of molecules having in common a morphine structural core. The wave functions and local reactivity indices were obtained at the ZINDO/1 and B3LYP/6-31 levels of theory for comparison. New developments in the expression for the drug-receptor interaction energy expression allowed several local atomic reactivity indices to be included, such as local electronic chemical potential, local hardness, and local electrophilicity. These indices, together with a new proposal for the ordering of the independent variables, were incorporated in the statistical study. We found and discussed several statistically significant relationships for mu, delta, and kappa opioid receptor binding affinity at both levels of theory. Some of the new local reactivity indices incorporated in the theory appear in several equations for the first time in the history of model-based equations. Interaction pharmacophores were generated for mu, delta, and kappa receptors. We discuss possible differences regulating binding and selectivity in opioid receptor subtypes. This study, contrarily to the statistically backed ones, is able to provide a microscopic insight of the mechanisms involved in the binding process. Tamara Bruna-Larenas and Juan S. Gómez-Jeria Copyright © 2012 Tamara Bruna-Larenas and Juan S. Gómez-Jeria. All rights reserved. Thu, 13 Dec 2012 15:25:19 +0000 http://www.hindawi.com/journals/ijmc/2012/530392/ New functionalized terphenyl derivatives incorporating various heterocyclic rings are prepared by using 4,4′′-difluoro-5′-hydroxy-1,1′:3′,1′′-terphenyl-4′-carbohydrazide as a key intermediate derived from 4,4′-difluoro chalcone, a versatile synthone. All the derivatives are characterized by 1H NMR, IR, and mass spectral data. All the synthesized products are screened for their in vitro antimicrobial and antioxidant properties. The majority of the tested compounds exhibited significant antioxidant activity and some of them showed good antimicrobial activity. Seranthimata Samshuddin, Badiadka Narayana, Balladka Kunhanna Sarojini, Divya N. Shetty, and Nalilu Suchetha Kumari Copyright © 2012 Seranthimata Samshuddin et al. All rights reserved. Thu, 06 Dec 2012 09:25:35 +0000 http://www.hindawi.com/journals/ijmc/2012/316972/ Activator protein-1 (AP1) is a transcription factor that consists of the Jun and Fos family proteins. It regulates gene expression in response to a variety of stimuli and controls cellular processes including proliferation, transformation, inflammation, and innate immune responses. AP1 binds specifically to 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element 5′-TGAG/CTCA-3′ (AP1 site). It has been found constitutively active in breast, ovarian, cervical, and lung cancers. Numerous studies have shown that inhibition of AP1 could be a promising strategy for cancer therapeutic applications. The present in silico study provides insights into the inhibition of Jun-Fos-DNA complex formation by curcumin derivatives. These derivatives interact with the amino acid residues like Arg155 and Arg158 which play a key role in binding of Jun-Fos complex to DNA (AP1 site). Ala151, Ala275, Leu283, and Ile286 were the residues present at binding site which could contribute to hydrophobic contacts with inhibitor molecules. Curcumin sulphate was predicted to be the most potent inhibitor amongst all the natural curcumin derivatives docked. Anil Kumar and Utpal Bora Copyright © 2012 Anil Kumar and Utpal Bora. All rights reserved. Wed, 28 Nov 2012 17:09:20 +0000 http://www.hindawi.com/journals/ijmc/2012/237965/ Benzodiazepines have a various behavioral effects in addition to their anxiolytic action. There is every reason to believe that the BZ/GABA receptor complex is involved in these effects, since GABAmimetic manipulations modify the effect of BZ in tests of convulsive activity, motor function, and appetitive behavior. 1,5-Benzodiazepines are biologically important molecules and are extensively used clinically as analgesic, hypnotic, sedative, and antidepressive agents. Hence, 1,5-Benzodiazepines were synthesized by condensation of o-phenylenediamine and ketones, for example, cyclohexanone and acetone in presence of sulfated zirconia (catalyst). Mannich bases were synthesized with acetophenone, p-nitroacetophenone, p-chloroacetophenone, and formaldehyde. Schiff bases were synthesized using Mannich base of 1,5-benzodiazepines with p-chloroaniline and p-chlorophenylsemicarbazide in the presence of glacial acetic acid. All the synthesized compounds were characterized by 1H NMR and IR spectral analyses. All the synthesized derivatives were evaluated at the dose of 30 mg/kg b.w for anticonvulsant activity by isoniazid induced convulsion model, and the compounds NBZD-3 and NBZD-8 were found to be the most active among all compounds. Among all the synthesized derivatives, compounds NBZD-13 and NBZD-17 were found to be the most active among all compounds using thiosemicarbazide induced model. Although NBZD-8, NBZD-10, and NBZD-18 are the compounds which had shown good anticonvulsant activity and have an advantage over that, they were not sedative. Surendra N. Pandeya and Neha Rajput Copyright © 2012 Surendra N. Pandeya and Neha Rajput. All rights reserved. Mon, 26 Nov 2012 14:52:59 +0000 http://www.hindawi.com/journals/ijmc/2012/498931/ 3D-QSAR approach has been widely applied and proven to be useful in the case where no reliable crystal structure of the complex between a biologically active molecule and the receptor is available. At the same time, however, it also has highlighted the sensitivity of this approach. The main requirement of the traditional 3D-QSAR method is that molecules should be correctly overlaid in what is assumed to be the bioactive conformation. Identifying an active conformation of a flexible molecule is technically difficult. It has been a bottleneck in the application of the 3D-QSAR method. We have developed a 3D-QSAR software named AutoGPA especially based on an automatic pharmacophore alignment method in order to overcome this problem which has discouraged general medicinal chemists from applying the 3D-QSAR methods to their “real-world” problems. Applications of AutoGPA to three inhibitor-receptor systems have demonstrated that without any prior information about the three-dimensional structure of the bioactive conformations AutoGPA can automatically generate reliable 3D-QSAR models. In this paper, the concept of AutoGPA and the application results will be described. Naoyuki Asakawa, Seiichi Kobayashi, Junichi Goto, and Noriaki Hirayama Copyright © 2012 Naoyuki Asakawa et al. All rights reserved. Sun, 25 Nov 2012 10:11:19 +0000 http://www.hindawi.com/journals/ijmc/2012/782058/ In our continued attempts at designing new antibiotics based on the structure of the C-9154 antibiotic, to simultaneously improve activity and lower toxicity, an analogue to the C-9154 antibiotic and six derivatives of this analogue were synthesized. The approach was to significantly reduce the polarity of the synthesized analogue in the derivatives to achieve increased permeability across cell membranes by conversion of the highly polar carboxylic group to an ester functional group. The compounds were synthesized using a two-step reaction which involved an additional reaction between benzyl amine and maleic anhydride and then conversion of the terminal carboxylic acid functional group to an ester functional group using a thionyl chloride mediated esterification reaction. The compounds were fully characterized using Infrared, GC-MS, and 1D and 2D NMR experiments. The in vitro biological activity of the compounds showed that the derivatives were more active than the analogues as was anticipated with minimum inhibitory concentration in the range 0.625–5 μg/mL. The analogue had minimum inhibitory concentration in the range 2.5–10 μg/mL. These values are significantly better than that obtained for the original C-9154 antibiotic which had activity in the range 10–>100 μg/mL. Isaac Asusheyi Bello, George Iloegbulam Ndukwe, Joseph Olorunju Amupitan, Rachael Gbekele Ayo, and Francis Oluwole Shode Copyright © 2012 Isaac Asusheyi Bello et al. All rights reserved. Thu, 18 Oct 2012 15:04:27 +0000 http://www.hindawi.com/journals/ijmc/2012/367815/ Sulfonamide drugs which have brought about an antibiotic revolution in medicine are associated with a wide range of biological activities. We have synthesized a series of α-tolylsulfonamide, 1–11 and their substituted N,N-diethyl-2-(phenylmethylsulfonamido) alkanamide derivatives, 12–22 in improved and excellent yields in aqueous medium at room temperature through highly economical synthetic routes. The chemical structures of the synthesized compounds 1–22 were confirmed by analytical and spectral data such as IR, 1H- and 13C-NMR, and mass spectra. The in vitro antibacterial activity of these compounds along with standard clinical reference, streptomycin, was investigated on two key targeted organisms. It was observed that 1-(benzylsulfonyl)pyrrolidine-2-carboxylic acid, 2 emerged as the most active compound against Staphylococcus aureus at MIC value of 1.8 μg/mL while 4-(3-(diethylamino)-3-oxo-2-(phenylmethylsulfonamido) propyl)phenyl phenylmethanesulfonate, 22 was the most active sulfonamide scaffold on Escherichia coli at MIC value of 12.5 μg/mL. Olayinka O. Ajani, Oluwole B. Familoni, Feipeng Wu, Johnbull O. Echeme, and Zheng Sujiang Copyright © 2012 Olayinka O. Ajani et al. All rights reserved. Tue, 25 Sep 2012 14:28:25 +0000 http://www.hindawi.com/journals/ijmc/2012/157125/ Antioxidant potential of various extracts of Cassia fistula was determined by the DPPH, FRAP, Fe3+ reducing power, and hydrogen peroxide scavenging assay. Methanolic extracts of Cassia fistula showed the highest amount of phenolic and flavonoid content and reducing capacity, whereas hexane extracts exhibited the lowest level of reducing capacity. The order of antioxidant activity in Cassia fistula extracts displayed from higher to lower level as methanolic extracts of pulp, methanolic extracts of seed, hexane extracts of pulp, and hexane extracts of seed. The antioxidant potential of Cassia fistula extracts significantly correlated () with the phenolic content of the methanolic extracts. Ascorbic acid taken as control showed highest antioxidant power in the present study. Md. Irshad, Md. Zafaryab, Man Singh, and M. Moshahid A. Rizvi Copyright © 2012 Md. Irshad et al. All rights reserved. Tue, 25 Sep 2012 12:05:31 +0000 http://www.hindawi.com/journals/ijmc/2012/196921/ A series of (Z)-2-benzylidenebenzofuran-3-(2H)-ones (aurones) bearing a variety of substituents on rings A and B were synthesized and evaluated for their antiparasitic activity against the intracellular amastigote form of Leishmania infantum and their cytotoxicity against human THP1-differentiated macrophages. In general, aurones bearing no substituents on ring A (compounds 4a–4f) exhibit higher toxicity than aurones with 4,6-dimethoxy substitution (compounds 4g–4l). Among the latter, two aurones possessing a 2′-methoxy or a 2′-methyl group (compounds 4i and 4j) exhibit potent antileishmanial activity ( M and  M, resp.), comparable to the activity of the reference drug Amphotericin B, whereas they present significantly lower cytotoxicity than Amphotericin B as deduced by the higher selectivity index. Marina Roussaki, Sofia Costa Lima, Anna-Maria Kypreou, Panagiotis Kefalas, Anabela Cordeiro da Silva, and Anastasia Detsi Copyright © 2012 Marina Roussaki et al. All rights reserved. Tue, 07 Aug 2012 08:50:08 +0000 http://www.hindawi.com/journals/ijmc/2012/148235/ This research was undertaken to design several new antibiotics, by structurally modifying the C-9154 antibiotic, simultaneously improving its activity and lowering toxicity. This was achieved by synthesizing an analogue to the C-9154 antibiotic and seven derivatives of this analogue. The approach was to significantly reduce the polarity of the synthesized analogue in the derivatives to achieve increased permeability across cell membranes by conversion of the highly polar carboxylic group to an ester functional group. The compounds were fully characterized using infrared, GC-MS, and 1D and 2D NMR experiments. The in vitro biological activity of the compounds showed that the derivatives were more active than the analogue as was anticipated and both were more active than the standard drugs used for comparison. Work is ongoing to establish applications for the compounds as antiplasmodials, antivirals, anticancers/tumours, antitrypanosomiasis, anthelminthic, and as general antibiotics for human, veterinary, and even agricultural use as they had marked effect on both Gram-positive and Gram-negative bacteria and some fungi. Isaac Asusheyi Bello, George Iloegbulam Ndukwe, Joseph Olorunju Amupitan, Rachael Gbekele Ayo, and Francis Oluwole Shode Copyright © 2012 Isaac Asusheyi Bello et al. All rights reserved. Sun, 17 Jun 2012 08:30:54 +0000 http://www.hindawi.com/journals/ijmc/2012/208039/ One of the most important functions of the opioid system is the control of pain. Among the three main opioid receptor classes (μ, δ, κ), the μ (MOR) is the main type targeted for pharmacotherapy of pain. Opioid analgesics such as morphine, oxycodone and fentanyl are agonists at the MOR and are the mainstay for the treatment of moderate-to-severe pain. However, adverse effects related to opioid use are severe and often lead to early discontinuation and inadequate analgesia. The development of more effective and safer medications for the management of pain still remains a major direction in pharmaceutical research. Chemical approaches towards the identification of novel MOR analgesics with reduced side effects include structural modifications of 14-alkoxy-N-methylmorphinan-6-ones in key positions that are important for binding, selectivity, potency, and efficacy at opioid receptors. This paper describes a representative strategy to improve the therapeutic usefulness of opioid analgesics from the morphinan class of drugs by targeting position 5. The focus is on chemical and biological studies and structure-activity relationships of this series of ligands. We report on 14-alkoxymorphinan-6-ones having a methyl and benzyl group at position 5 as strong opioid antinociceptive agents with reduced propensity to cause undesired effects compared to morphine although interacting selectively with MORs. Helmut Schmidhammer and Mariana Spetea Copyright © 2012 Helmut Schmidhammer and Mariana Spetea. All rights reserved. Fri, 15 Jun 2012 15:39:03 +0000 http://www.hindawi.com/journals/ijmc/2012/715123/ Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unacceptable side effects. Of the endogenous opioid peptides, endomorphin(EM)-1 and endomorphin(EM)-2 with their high μ-receptor affinity and exceptionally high selectivity relative to δ- and κ-receptors in vitro and in vivo provided a sufficiently sequence-flexible entity in order to prepare opioid-based drugs. We took advantage of this unique feature of the endomorphins by exchanging the N-terminal residue Tyr1 with 2′,6′-dimethyl-L-tyrosine (Dmt) to increase their stability and the spectrum of bioactivity. We systematically altered specific residues of [Dmt1]EM-1 and [Dmt1]EM-2 to produce various analogues. Of these analogues, [N-allyl-Dmt1]EM-1 (47) and [N-allyl-Dmt1]EM-2 (48) exhibited potent and selective antagonism to μ-receptors: they completely inhibited naloxone- and naltrexone-induced withdrawal from following acute morphine dependency in mice and reversed the alcohol-induced changes observed in sIPSC in hippocampal slices. Overall, we developed novel and efficacious opioid drugs without deleterious side effects that were able to resist enzymatic degradation and were readily transported intact through epithelial membranes in the gastrointestinal tract and the blood-brain-barrier. Yoshio Okada, Yuko Tsuda, Severo Salvadori, and Lawrence H. Lazarus Copyright © 2012 Yoshio Okada et al. All rights reserved. Tue, 12 Jun 2012 09:38:59 +0000 http://www.hindawi.com/journals/ijmc/2012/905981/ Six new titanocene compounds have been isolated and characterised. These compounds were synthesised from their fulvene precursors using Super Hydride (LiBEt3H) followed by transmetallation with titanium tetrachloride to yield the corresponding titanocene dichloride derivatives. These complexes are bis-[((1-methyl-3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5a), bis-[((5-methoxy-1-methyl,3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5b), bis-[((1-methyl,3-diethylaminomethyl)indol-4-yl)methylcyclopentadienyl] titanium (IV) dichloride (5c), bis-[((5-bromo-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5d), bis-[((5-chloro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5e), and bis-[((5-fluoro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5f). All six titanocenes 5a–5f were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines using DMSO and Soluphor P as solubilising agents in order to determine their IC50 values. Titanocenes 5a–5f were found to have IC50 values of 10 (±2), 21 (±3), 29 (±4), 140 (±6), and 450 (±10) μM when tested using DMSO. Anthony Deally, Frauke Hackenberg, Grainne Lally, and Matthias Tacke Copyright © 2012 Anthony Deally et al. All rights reserved. Thu, 31 May 2012 08:59:08 +0000 http://www.hindawi.com/journals/ijmc/2012/452325/ Pharmacophore modelling-based virtual screening of compound is a ligand-based approach and is useful when the 3D structure of target is not available but a few known active compounds are known. Pharmacophore mapping studies were undertaken for a set of 50 N3-phenylpyrazinones possessing Corticotropin-releasing Factor 1 (CRF 1) antagonistic activity. Six point pharmacophores with two hydrogen bond acceptors, one hydrogen bond donor, two hydrophobic regions, and one aromatic ring as pharmacophoric features were developed. Amongst them the pharmacophore hypothesis AADHHR.47 yielded a statistically significant 3D-QSAR model with 0.803 as 𝑅2 value and was considered to be the best pharmacophore hypothesis. The developed pharmacophore model was externally validated by predicting the activity of test set molecules. The squared predictive correlation coefficient of 0.91 was observed between experimental and predicted activity values of test set molecules. The geometry and features of pharmacophore were expected to be useful for the design of selective CRF 1 receptor antagonists. Paramjit Kaur, Vikas Sharma, and Vipin Kumar Copyright © 2012 Paramjit Kaur et al. All rights reserved. Mon, 21 May 2012 14:23:10 +0000 http://www.hindawi.com/journals/ijmc/2012/498901/ Two aromatic amino acids, Tyr1 and Phe3 or Phe4, are important structural elements in opioid peptides because they interact with opioid receptors. The usefulness of an artificial amino acid residue 2,6-dimethylphenylalanine (Dmp) was investigated as an aromatic amino acid surrogate for several opioid peptides, including enkephalin, dermorphin, deltorphin, endomorphin, dynorphin A, and nociceptin peptides. In most peptides, substitutions of Phe3 by a Dmp residue produced analogs with improved receptor-binding affinity and selectivity, while the same substitution of Phe4 induced markedly reduced receptor affinity and selectivity. Interestingly, replacement of Tyr1 by Dmp produced analogs with unexpectedly high affinity or produced only a slight drop in receptor affinity and bioactivity for most peptides. Thus, Dmp is also a useful surrogate for the N-terminal Tyr residue in opioid peptides despite the lack of a phenolic hydroxyl group, which is considered necessary for opioid activity. The Dmp1-substituted analogs are superior to 2,6-dimethyltyrosine (Dmt)1-substituted analogs for high receptor selectivity since the latter generally have poor receptor selectivity. Thus, Dmp is very useful as an aromatic amino acid surrogate in opioid peptides and may be useful for developing other novel peptide mimetics with high receptor specificity. Yusuke Sasaki and Akihiro Ambo Copyright © 2012 Yusuke Sasaki and Akihiro Ambo. All rights reserved. Tue, 15 May 2012 14:40:17 +0000 http://www.hindawi.com/journals/ijmc/2012/693903/ Pharmaceutical compounds represent a rapidly emerging class of environmental contaminants. Such compounds were recently classified by the U.S. Geological Survey, including several antibiotics. An LC-MS/MS screening method for the top five antibiotics in drinking water was developed and validated using a Shimadzu LC-MS-IT-TOF. The separation was performed using a Waters Acquity UPLC BEH C18 column with a gradient elution. Sulfamethazine was exposed to conditions intended to mimic drinking water chlorination, and samples were collected and quenched with excess sodium sulfite. Kinetics of sulfamethazine degradation was followed as well as the formation of the major chlorinated byproduct (𝑚/𝑧 313). For the screening method, all five antibiotic peaks were baseline resolved within 5 minutes. Additionally, precision and accuracy of the screening method were less than 15%. Degradation of sulfamethazine upon exposure to drinking water chlorination occurred by first order kinetics with a half-life of 5.3×104 min (approximately 37 days) with measurements starting 5 minutes after chlorination. Likewise, the formation of the major chlorinated product occurred by first order kinetics with a rate constant of 2.0×10−2. The proposed identification of the chlorinated product was 4-amino-(5-chloro-4,6-dimethyl-2-pyrimidinyl)-benzenesulfonamide (C12H13N4O2SCl) using MS𝑛 spectra and databases searches of SciFinder and ChemSpider. Tyler C. Melton and Stacy D. Brown Copyright © 2012 Tyler C. Melton and Stacy D. Brown. All rights reserved. Wed, 02 May 2012 16:14:05 +0000 http://www.hindawi.com/journals/ijmc/2012/412614/ A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2. Stéphane L. Raeppel, Frédéric Gaudette, Hannah Nguyen, Normand Beaulieu, James Wang, Christiane Maroun, Jeffrey M. Besterman, and Arkadii Vaisburg Copyright © 2012 Stéphane L. Raeppel et al. All rights reserved. Sun, 29 Apr 2012 15:58:16 +0000 http://www.hindawi.com/journals/ijmc/2012/327257/ MDAN-21, 7-{2-[(7-{2-[({(5𝛼,6𝛼)-4,5-Epoxy-3,14-dihydroxy-17-methylmorphin-6-yl}-aminocarbonyl)metoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetylamino}-naltrindole, a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphine-dependent monkeys in the remarkably low dose range 0.006–0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032–0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain. Mario D. Aceto, Louis S. Harris, S. Stevens Negus, Matthew L. Banks, Larry D. Hughes, Eyup Akgün, and Philip S. Portoghese Copyright © 2012 Mario D. Aceto et al. All rights reserved.