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Human acrosin is an attractive target for the discovery of male contraceptive drugs. For the first time, structure-based drug design was applied to discover structurally diverse human acrosin inhibitors. A parallel virtual screening strategy in combination with pharmacophore-based and docking-based techniques was used to screen the SPECS database. From 16 compounds selected by virtual screening, a total of 10 compounds were found to be human acrosin inhibitors. Compound 2 was found to be the most potent hit (IC(50) = 14 μM) and its binding mode was investigated by molecular dynamics simulations. The hit interacted with human acrosin mainly through hydrophobic and hydrogen-bonding interactions, which provided a good starting structure for further optimization studies.

A drug discovery is characterized by two stages. The first in terms of time is called “lead structure”, followed by a so called “drug candidate” stage. The lead structure stage involves selecting the optimum molecule of the pharmaceutical, while drug candidate stage means selecting the optimum solid form. Usually, five to ten candidates pass to the drug candidate stage and the result is the selection of the final solid API (Active Pharmaceutical Ingredience) for the ensuing formulation of the solid dosage form. The lead structure stage concerns only the discovery of the original drug, the drug candidate stage may concern also generics (a drug which is bioequivalent with original and is produced and distributed after the patent protection of the original).

A few aza analogues of the quinolones have been prepared in the two families of the 1,4-dihydro-4-oxopyridazino[1,6-a]indole-3-carboxylic acids and the 1,4-dihydro-4-oxopyrido[3′,2′:4,5]pyrrolo[1,2-b]-pyridazine-3-carboxylic acids to check their antibacterial potential. One compound 6c shows antibacterial activities of the level of nalidixic acid and represents a new lead structure differing from the classical quinolones.

Starting from (1S,2R)-5-methoxy-1-methyl-2-N,N-dipropylaminotetralin [(+)-UH-232] as a lead structure, a series of novel 6-substituted 2-aminotetralins have been discovered which show high affinity for dopamine D3 receptors. One compound, GR218231, exhibits ca. 400 fold selectivity for the dopamine D3 receptor over the D2 receptor and ca. 10,000 fold selectivity with respect to D1 and D4 receptors.

In order to find new biorational pesticides, eight new 6-substituted ether derivatives of Celangulin-V were synthesized. The structures were confirmed by IR, 1H NMR and 13C NMR spectroscopic and HRMS analyses. The insecticidal activities of these compounds were tested against third-instar larvae of Mythimna separata. Four derivatives (b, c, f, g) showed higher insecticidal activities than Celangulin-V, with KD50 values of 135.9, 101.33, 169.0 and 219.2 μg.g-1, respectively. However, two compounds (a, d) showed lower insecticidal activities and two (e, h) no activity. The results suggest that C-6 substitutions in these compounds are very important for their insecticidal activities. The insecticidal activities of the derivatives with two or three carbon substitutions at C-6 are higher than that of Celangulin-V showing that this compound has the potential to be a lead structure for semi-synthetic, green insecticides.

The reemergence of tuberculosis and closely related diseases as significant public health problems is briefly reviewed with particular emphasis on the exacerbating role of AIDS and multiple drug resistance. Screening methods available for discovering new chemical entities active against resistant strains are discussed and their use in screening extracts and compounds for activity is illustrated with a number of newly discovered structures being presented. In particular, the properties of the potent and structurally novel indoloquinazolinone alkaloid, tryptanthrin, is described. Many analogs of this lead structure were synthesized by combinatorial and multiple parallel synthetic techniques and evaluated in vitro and in vivo for their potential in the chemotherapy of human infections.

The lack of agents for infections caused by pathogenic fungi has demanded further investigation of a key lead structure which has shown promise, echinocandin B. In recent years, two analogs of this cyclic hexapeptide are proceeding through the clinic exhibiting proof of concept for the target of these drugs. This target, the ss-1,3-glucan synthesis complex, produces the majority of fungal cell wall glucan in many of the most pathogenic fungi such as Candida. A methodical structure-activity relationship review of several major fragments of these highly functionalized molecules is described. This information is useful for determination of the minimum functional/structural requirements for design of an optimal compound in this series. Analogs are presented with their accompanying whole cell antifungal activities.

A fungus that grows on pinecones yields a compound with antifungal activity that has become the natural model for a significant innovation in crop protection. Variation and optimization of the lead structure of strobilurin A (1) and selection of derivatives which fulfill all practical requirements, for example, kresoxim-methyl (2), led to an exciting and pan-industrial competition for the development of the strobilurines as a new, highly active, and broadly applicable class of fungicides—a fascinating success story.

The synthesis of (2 R,S )-1-(6-methoxy-4-(methoxymethyl)-1 H -indol-5-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and (2 R,S )-1-(4-methoxy-6-(methoxy-methyl)-1 H -indol-5-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol is described. The compounds were tested for electrographic, antiarrhythmic, hypotensive, and spasmolytic activity, as well as for α 1 -, α 2 - and β 1 -adrenoceptor binding affinity. Keywords: α 1 -andrenoceptor antagonist; synthesis; pharmacology 1. Introduction In our search for new aminopropan-2-ol derivatives with cardiovascular activity among, we obtained the compound (2 R,S )-1-(1 H -indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol, ( R,S )-9 (Figure 1) [1] which became a lead structure for further investigations. The compound ( R,S )-9 possesses α 1 - and β 1 -adrenolytic, antiarrhythmic, and hypotensive activities similar to carvedilol, which is a very effective compound in the treatment of such cardiovascular diseases as OPEN ACCESS

We have developed the 4-nitrocinnamoyl substituted benzophenone 4a as a novel non-thiol farnesyltransferase inhibitor. Replacement of the p-tolyl moiety of our initial lead structure 4a by different para and ortho substituted phenyl residues as well as by 1-naphthyl resulted in derivatives with considerably enhanced activity displaying IC(50) values between 42 and 52 nM. These compounds represent novel, readily accessible non-thiol farnesyltransferase inhibitors being more active than the corresponding thiol-containing analogues.

5-Hydroxyalkyl-4-phenylpyridines have been identified as a novel class of glucagon antagonists with potential utility for the treatment of diabetes. A lead structure with moderate activity was discovered through a high throughput screening assay. Structure–activity relationships led to the discovery of a potent antagonist, IC 50 =0.11 μM, more than 60-fold improvement over the lead structure.

Readily available chiral phosphoramidites are a promising class of ligands for nickel-catalyzed asymmetric hydrovinylation of vinyl arenes. Cooperative effects are operative when ligands with more than one element of chirality are used. Choosing the proper stereochemistry in each part of the modular ligand system leads to high chemoselectivities and excellent enantioselectivities up to 94%. Moreover, the catalysts derived from these ligands proved extremely efficient and remarkably robust performing up to 8300 catalytic turnovers at an initial turnover frequency beyond 1000 h-1. The large potential for structural variation and their straightforward synthesis make the phosphoramidites currently the best lead structure for catalyst development in this field.

Radioligand binding studies indicate a down-regulation of myocardial beta(1)-adrenoceptors (beta(1)-AR) in cardiac disease which may or may not be associated with a decrease in beta(2)-ARs. We have chosen ICI 89,406, a beta(1)-selective AR antagonist, as the lead structure to develop new beta(1)-AR radioligands for PET and have synthesised a fluoro-ethoxy derivative (F-ICI).(S)-N-[2-[3-(2-Cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]-N'-[4-(2-[(18)F]fluoro-ethoxy)-phenyl]-urea ((S)-[(18)F]F-ICI) was synthesised. Myocardial uptake of radioactivity after intravenous injection of (S)-[(18)F]F-ICI into adult CD(1) mice or Wistar rats was assessed with positron emission tomography (PET) and postmortem dissection. Metabolism was assessed by high-performance liquid chromatography analysis of plasma and urine.The heart was visualised with PET after injection of (S)-[(18)F]F-ICI but neither unlabelled F-ICI nor propranolol (non-selective beta-AR antagonist) injected 15 min after (S)-[(18)F]F-ICI affected myocardial radioactivity. Ex vivo dissection demonstrated that predosing with propranolol or CGP 20712 (beta(1)-selective AR-antagonist) did not affect myocardial radioactivity. Radiometabolites rapidly appeared in plasma and both (S)-[(18)F]F-ICI and radiometabolites accumulated in urine.Myocardial uptake of (S)-[(18)F]F-ICI after intravenous injection was mainly at sites unrelated to beta(1)-ARs. (S)-[(18)F]F-ICI is not a suitable beta(1)-selective-AR radioligand for PET.

Rooted in the early days of organic dye chemistry, the phenothiazine structure and its derivatives have since held a prominent place in pharmacology and biomedicine. Initially used for histochemical stains of plasmodia by Paul Ehrlich, anthelmintic and antibiotic properties of phenothiazines were globally exploited in the 1930s and 1940s. Clinical use of N-substituted phenothiazines as antihistaminics (1940s), sedatives and antipsychotics (1950s) followed and continues to this day. Recently, interest in these structures has re-emerged for a variety of fascinating features in relation to neurodegenerative disease, spearheaded by the unique redox chemistry of phenothiazine--arguably the most potent chain-breaking antioxidant ever identified.

In order to investigate the evolution of binding efficiency in successful drug discovery programs, a data set of 60 lead/drug pairs with known binding affinities has been compiled and analyzed. Low-end thresholds for the binding efficiencies of viable leads and drugs have been derived. On average, the drugs in the set are significantly larger and more potent but have similar lipophilicity relative to their originating leads, suggesting that the ability to maintain low levels of lipophilicity while increasing molecular weight is one of the keys to a successful drug discovery program. A number of examples demonstrate that large increases in binding efficiency from leads to more elaborate drugs sharing the same scaffold can be achieved. The importance of dissecting a lead structure to identify the most efficient fragments and the option of sacrificing binding efficiency to optimize other properties are discussed, and relevant examples are highlighted.

Bean pods (Phaseolus vulgaris) are among the most widely used traditional remedies against diabetes mellitus. Historical knowledge is summarized and compared to recent study results. Reports dating from the first half of the 20th century as well as recent publications show contradictory results. It seems that Phaseolus preparations should not be considered the first choice in phytopharmaceutical treatment of diabetes or lead structure research. To be effective, fairly high doses of aqueous extracts need to be given. Because of their fiber content and an α-amylase inhibitory effect, beans might be more useful as food components in preventing or ameliorating type 2 diabetes.

This chapter outlines the processes involved in the screening of natural product (NP) extracts for biological activity. The topics covered include biological diversity, the collection of biota samples, the preparation of NP extracts for screening, high-throughput screening, biochemical assays and technology, the isolation and structure determination of bioactive NPs (hits) and lead-like and drug-like molecules, and converting leads into drugs.

If you are contemplating setting up a business in China, you will need to consider what structure to use. But before deciding on the structure, you need to be sure of your strategy—strategy must lead structure. You must first consider why you want to make an investment in China, and find out just what you should be doing, before determining exactly how to do it.

Magnetic Resonance Imaging (MRI) induced heating on patients with pacemaker (PM) or implantable cardioverter-defibrillator (ICD) can pose severe health risks. Experimental studies in this field have shown a great variability in results and revealed that several aspects can affect the amount of heating induced at the lead tip. The structural parameters of the lead are one of these. In this study we performed in-vitro temperature measurements of PM/ICD leads inside a human trunk simulator exposed to the RF field of a 1.5T MRI scanner. A total of 26 leads were tested (23 PM leads, 3 ICD leads) and the temperature increases induced by the RF field ranged from 2.1°C to 15.0°C. Significant heating was observed not only at the lead tip, but also at the ring (as high as 4.2°C), even if not in all the bipolar leads tested. Active-fix leads showed higher temperature increases than passive-fix ones (4.7°C versus 7.4°C).

Computer-assisted molecular design supports drug discovery by suggesting novel chemotypes and compound modifications for lead structure optimization. While the aspect of synthetic feasibility of the automatically designed compounds has been neglected for a long time, we are currently witnessing an increased interest in this topic. Here, we review state-of-the-art software for de novo drug design with a special emphasis on fragment-based techniques that generate druglike, synthetically accessible compounds. The importance of scoring functions that can be used to predict compound reactivity and potency is highlighted, and several promising solutions are discussed. Recent practical validation studies are presented that have already demonstrated that rule-based fragment assembly can result in novel synthesizable compounds with druglike properties and a desired biological activity.

The development of an aminopyridazine lead structure (minaprine) yielded compound SR 46559 A 3-[N-(2-diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, a novel and potent muscarinic agonist with no cholinergic syndrome.

We developed the Pharmacophore Alignment Search Tool (PhAST), a text-based technique for rapid hit and lead structure searching in large compound databases. For each molecule, a two-dimensional graph of potential pharmacophoric points (PPPs) is created, which has an identical topology as the original molecule with implicit hydrogen atoms. Each vertex is coloured by a symbol representing the corresponding PPP. The vertices of the graph are canonically labelled. The symbols associated with the vertices are combined to a so-called PhAST-Sequence beginning with the vertex with the lowest canonical label. Due to the canonical labelling the created PhAST-Sequence is characteristic for each molecule. For similarity assessment, PhAST-Sequences are compared using the sequence identity in their global pairwise alignment. The alignment score lies between 0 (no similarity) and 1 (identical PhAST-Sequences). In order to use global pairwise sequence alignment, a score matrix for pharmacophoric symbols was developed and gap penalties were optimized. PhAST performed comparably and sometimes superior to other similarity search tools (CATS2D, MOE pharmacophore quadruples) in retrospective virtual screenings using the COBRA collection of drugs and lead structures. Most importantly, the PhAST alignment technique allows for the computation of significance estimates that help prioritize a virtual hit list.

In this article, in the first part, we propose an artificial neural network-based intelligent technique to determine the quantitative structure-activity relationship (QSAR) among known aldose reductase inhibitors (ARIs) for diabetes mellitus using two molecular descriptors, i.e., the electronegativity and molar volume of functional groups present in the main ARI lead structure. We have shown that the multilayer perceptron-based model is capable of determining the QSAR quite satisfactorily, with high R-value. Usually, the design of potent ARIs requires the use of complex computer docking and quantum mechanical (QM) steps involving excessive time and human judgement. In the second part of this article, to reduce the design cycle of potent ARIs, we propose a novel ANN technique to eliminate the computer docking and QM steps, to predict the total score. The MLP-based QSAR models obtained in the first part are used to predict the potent ARIs, using the experimental data reported by Hu et al. (J Mol Graph Mod 2006, 24, 244). The proposed ANN-based model can predict the total score with an R-value of 0.88, which indicates that there exists a close match between the predicted and experimental total scores. Using the ANN model, we obtained 71 potent ARIs out of 6.25 million new ARI compounds created by substituting different functional groups at substituting sites of main lead structure of known ARI. Finally, using high bioactivity relationship and total score values, we determined four potential ARIs out of these 71 compounds. Interestingly, these four ARIs include the two potent ARIs reported by Hu et al. (J Mol Graph Mod 2006, 24, 244) who obtained these through the complex computer docking and QM steps. This fact indicates the effectiveness of our proposed ANN-based technique. We suggest these four compounds to be the most promising candidates for ARIs to prevent the diabetic complications and further recommend for wet bench experiments to find their potential against AR in vitro and in vivo. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009

The antifungal lead structure α-trichloromethyl-3-pyridinemethanol (1 a) was modified and esters, (thio-)carbamates, and sulfonates as well as other derivatives incorporating the pyridylcarbinol structure were prepared. The optical resolution as well as the N-oxidation of1 a are described.

The p38 MAP kinase is implicated in the release of the pro-inflammatory cytokines TNFα and IL-1b. Inhibition of cytokine release may be a useful treatment for inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. A new lead structure for p38 MAP kinase inhibition was identified. Herein, we report the SAR of this new class of p38 inhibitors.

Many of the ligands in use today to investigate serotonin receptors and serotonin receptor pharmacology were serendipitous discoveries; this includes ligands that are commonly regarded as being “selective” for a given population of serotonin receptors. Nevertheless, there still remains a number of serotonin receptor types that lack a truly selective agonist and/or antagonist. Over the past 20 yr, there have been various attempts to rationally develop ligands with greater selectivity, or selective ligands for serotonin receptor types for which such agents were lacking. To this end, we describe some of our efforts to develop selective serotonergic agents by presenting a series of case studies. Several different strategies have been employed to achieve this goal. In particular, the “deconstruction-reconstruction-elaboration” approach is shown to be useful for aiding the development of selective ligands where a lead structure is already known, and the utility of the “standard series” approach is illustrated where a lead structure is not known. The discussion is focused on these and other methods that could have general applicability for the development of other selective serotonergic and nonserotonergic agents.

This Account provides an overview and examples of function-oriented synthesis (FOS) and its increasingly important role in producing therapeutic leads that can be made in a step-economical fashion. Biologically active natural product leads often suffer from several deficiencies. Many are scarce or difficult to obtain from natural sources. Often, they are highly complex molecules and thus not amenable to a practical synthesis that would impact supply. Most are not optimally suitable for human therapeutic use. The central principle of FOS is that the function of a biologically active lead structure can be recapitulated, tuned, or greatly enhanced with simpler scaffolds designed for ease of synthesis and also synthetic innovation. This approach can provide practical access to new (designed) structures with novel activities while at the same time allowing for synthetic innovation by target design. This FOS approach has been applied to a number of therapeutically important natural product leads. For example, b...

Publisher Summary The aim of this chapter is to provide some guidelines and strategies rendering easier and more efficacious the decision on which compounds to prepare and which ones to reject. Depending on the lead structure's size and on its degree of complexity, the strategy may involve a simplification (disjunctive approach), conservation of the same level of complexity (analogical approach), or enlargement through additional elements (conjunctive approach). Examples of drugs resulting from associative synthesis (nonsymmetrical twin drugs) and of duplication of the parent drug (symmetrical twin drugs) are summarized. Conservation of the lead compound's degree of complexity proceeds usually through isosteric exchanges or functional inversions and can be considered the analogical approach. The strategy of hit optimization heavily depends on the amount of information available at the start of the study. If some knowledge of the 3D structure of the target is available, the synthesis program can take the corresponding information immediately into account. This will also be the case if some earlier structure–activity relationship (SAR) studies are available. A structural guide is also available for drugs designed to bind to the neurotransmitters of the central nervous system (CNS).

Publisher Summary pKa has been studied for many years, providing a solid body of research and quality measurements upon which reliable tools for pKa prediction for compounds can be based for application in medicinal chemistry. Knowledge of the pKa of substructures in the lead structure allows the “tuning” of ionizability in order to modify its permeability and solubility. Databases can provide a useful source of comparison pKa data for compounds that have been reported. Software for the prediction of pKa from structure has greatly progressed. pKa software can provide more advanced information for chemists. Software can be applied when planning the synthesis of structural series analogs, when the goal is to modify permeability or solubility by the substitution of substructures with varying pKa values in order to optimize absorption. Two higher-throughput methods are introduced in this chapter. Each can be implemented in drug discovery laboratories with the proper equipment, and each has been offered as an integrated commercial instrument.

This Account provides an overview and examples of function-oriented synthesis (FOS) and its increasingly important role in producing therapeutic leads that can be made in a step-economical fashion. Biologically active natural product leads often suffer from several deficiencies. Many are scarce or difficult to obtain from natural sources. Often, they are highly complex molecules and thus not amenable to a practical synthesis that would impact supply. Most are not optimally suitable for human therapeutic use. The central principle of FOS is that the function of a biologically active lead structure can be recapitulated, tuned, or greatly enhanced with simpler scaffolds designed for ease of synthesis and also synthetic innovation. This approach can provide practical access to new (designed) structures with novel activities while at the same time allowing for synthetic innovation by target design. This FOS approach has been applied to a number of therapeutically important natural product leads. For example, bryostatin is a unique natural product anticancer lead that restores apoptosis in cancer cells, reverses multidrug resistance, and bolsters the immune system. Remarkably, it also improves cognition and memory in animals. We have designed and synthesized simplified analogs of bryostatin that can be made in a practical fashion (pilot scale) and are superior to bryostatin in numerous assays including growth inhibition in a variety of human cancer cell lines and in animal models. Laulimalide is another exciting anticancer lead that stabilizes microtubules, like paclitaxel, but unlike paclitaxel, it is effective against multidrug-resistant cell lines. Laulimalide suffers from availability and stability problems, issues that have been addressed using FOS through the design and synthesis of stable and efficacious laulimalide analogs. Another FOS program has been directed at the design and synthesis of drug delivery systems for enabling or enhancing the uptake of drugs or drug candidates into cells and tissue. We have generated improved transporters that can deliver agents in a superior fashion compared with naturally occurring cell-penetrating peptides and that can be synthesized in a practical and step-economical fashion. The use of FOS has allowed for the translation of exciting, biologically active natural product leads into simplified analogs with superior function. This approach enables the development of synthetically innovative strategies while targeting therapeutically novel structures.

hERG blockade is one of the major toxicological problems in lead structure optimization. Reliable ligand-based in silico models for predicting hERG blockade therefore have considerable potential for saving time and money, as patch-clamp measurements are very expensive and no crystal structures of the hERG-encoded channel are available. Herein we present a predictive QSAR model for hERG blockade that differentiates between specific and nonspecific binding. Specific binders are identified by preliminary pharmacophore scanning. In addition to descriptor-based models for the compounds selected as hitting one of two different pharmacophores, we also use a model for nonspecific binding that reproduces blocking properties of molecules that do not fit either of the two pharmacophores. PLS and SVR models based on interpretable quantum mechanically derived descriptors on a literature dataset of 113 molecules reach overall R(2) values between 0.60 and 0.70 for independent validation sets and R(2) values between 0.39 and 0.76 after partitioning according to the pharmacophore search for the test sets. Our findings suggest that hERG blockade may occur through different types of binding, so that several different models may be necessary to assess hERG toxicity.

Complementing organic elements with a metal center provides new opportunities for building three-dimensional structures with unique and defined shapes. Such access to unexplored chemical space may lead to the discovery of molecules with unprecedented properties. Along these lines, this account article describes our successful design of highly potent and selective ruthenium-based inhibitors for the protein kinases GSK-3 and Pim-1 by using the class of indolocarbazole alkaloids as a lead structure. The described ruthenium complexes are kinetically inert scaffolds in which the ruthenium has the function to organize the orientation of the organic ligands in the three-dimensional space.

The development of highly active and selective agonists for the G protein coupled orphan receptor bombesin receptor subtype 3 (BRS-3) with still unknown physiological function is described. Systematic modifications of two unselective agonists, a nonapeptide and octapeptide, were used in order to elaborate structure activity relationships and for the design of a short lead-structure. Low molecular weight peptidomimetics were obtained by the systematic optimization of this lead structure. Furthermore, the synthesis and evaluation of nonpeptide alpha-v-beta-3 integrin receptor antagonists based on the RGD motif is described. Die Entwicklung hochaktiver und selektiver Agonisten für den G Protein gekoppelten orphan receptor Bombesin Rezeptor Subtyp 3 (BRS-3), dessen Funktion noch unbekannt ist, wird beschrieben. Durch systematische Modifizierung zweier unselektiver Agonisten, einem Nonapeptid und einem Oktapeptid, wurden zunächst Struktur-Wirkungsbeziehungen erarbeitet und danach für das Design einer kürzeren Leitstruktur ausgenutzt. Die systematische Optimierung dieser Leitstruktur führte zu den obengenannten niedermolekularen Peptidmimetika. Weiterhin wird die Synthese von nichtpeptidischen Antagonisten, die auf der peptidischen Leitstruktur RGD basieren und auf den alpha-v-beta-3 Integrinrezeptor wirken, beschrieben.

The present review describes the current status of synthetic cyclic peroxides, trioxanes and trioxolanes that show significant promise as antimalarial drugs because of their artemisinin-like activity. The literature from 1996 onwards is critically surveyed to provide an update on how an age-old, persistent, debilitating and frequently deadly disease could be treated by new, affordable and effective medicines possessing the peroxide pharmacophore. The review is not exhaustive and does not cover recent progress on the lead structure artemisinin and its derivatives. Nevertheless, some mechanistic aspects gleaned from artemisinin that have relevance to synthetic peroxides are discussed.

In order to discover lead compounds with novel action mechanism, a series of tetrazolinone derivatives bearing structurally diverse substituents, 1-aryl-4-substituted-1,4-di-hydro-5H-tetrazol-5-ones 2, 1-((5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)-4-(substituted)- phenyl-1H-tetrazol-5(4H)-ones 5, and 1-((5-(alkylthio)-1,3,4-thiadiazol-2-yl)methyl)-4- (substituted)phenyl-1H-tetrazol-5(4H)-ones 7, were designed and synthesized in good yields by a multiple-step synthetic procedure. The results of greenhouse in vivo test indicated that all the target compounds did not displayed herbicidal activity, however, some of them exhibited excellent in vivo insecticidal activity against Tetranychus cinnabarinus at the concentration of 250 mg L−1. To our knowledge, this is the first report about the insecticidal activity of tetrazolinone derivatives, which indicated that the tetrazolinone scaffold could be identified as a novel insecticidal lead structure. The present work demonstrated that optimizing a target-diverse scaffold is an effective way to discover new lead compounds with new action mechanism or biological activity.

Using advanced numerical technologies, e.g. 3D simulation, is essential for the verification of some critical aspects of design and performance of large power transformers in service. Using such technologies ensures reliable and predictable operation of the transformer, dielectrically, thermally, and electromechanically. These technologies have also proven to be essential in evaluating the condition and insulation life of transformers already in operation as well as evaluating needed cooling system enhancements for increased transformer loadability and higher operational demands. This paper presents a number of applications, where 3D simulation-based analysis has been used. The applications include verifications of hot-spot temperatures of the core and clamping structure of core form transformers, verification of electric field stresses in tap changers' lead structure and HV bushings, analysis and solution of an overheated bus-duct of a large GSU, and determining the overloadability of transformers in operation. The paper demonstrates why 3D analysis is an essential tool in a simulation-based transformer service (SBTS) activity

Mucobromic and mucochloric acid were used as building blocks for the construction of a chemical combinatorial library of 3,4,5-trisubstituted 2(5H)-furanones. With these 2 butenolide building blocks, and eight alcohols a sublibrary of 16 dihalogenated 5-alkoxy-2(5H)-furanones was prepared. This sublibrary of 5-alkoxylated furanones was reacted with 16 amines generating a full size focussed combinatorial library of 256 individual compounds. This three dimensional combinatorial library of 3-halogen-4-amino-5-alkoxy-2(5H)-furanones was prepared around the benzimidazolyl furanone lead structure by applying a solution phase combinatorial chemistry concept. Typical representatives of the library were purified and fully characterized and one x-ray structures was recorded, additionally. The 3-bromo-4-benzimizazolyl-5-methoxy-2(5H)furanone, Br-A-l, showed an MIC of 8 μg/ml against the multiresistant Staphylococcus aureus ( MRSA). © 2006 Bentham Science Publishers Ltd.

This investigation aims to evaluate strategies for an efficient selection of bioactive compounds from the multitude and biodiversity of the plant kingdom. Statistics prove natural products (NPs) as a source leading most consistently to successful development of new drugs. However, there are several reasons why the interest in finding bioactive NPs has generally declined at several major pharmaceutical companies. Their substantial argument is that the research in this field is time-consuming, highly complex and ineffective. A more rational and economic search for new lead structures from nature must therefore be a priority in order to overcome these problems. In this paper, different strategies are described to exploit the molecular diversity of bioactive secondary metabolites, namely classical pharmacognostic approaches and computational methods. The latter include various data mining tools, like virtual screening filtering experiments using pharmacophore models, docking studies, and neural networks, which help to establish a relationship between chemical structure and biological activity. The strengths and weaknesses of these methods will be shown in this review. Focusing on selected targets within the arachidonic acid cascade (phospholipase A2, 5-lipoxygenase, cyclooxygenase-1 and -2), several studies of successful discoveries in the field of anti-inflammatory NPs were scrutinized for the applied strategies. Both the compilation of relevant published data and recent studies supported by our own research clearly demonstrate the benefits of the synergistic effect of a hybridization of these strategies for an effective drug discovery from natural ingredients.

Manzamine A represents an important lead structure for the development of novel antimalarial chemotherapies. The synthesis and biological evaluation of a group of simplified analogues of manzamine A, which were designed to examine the roles of the A and D rings and of both the relative stereochemistry and the orientation of the beta-carboline heterocycle on the antimalarial activity of manzamine A, are described. [structure: see text]

The building blocks fac-[(99m)Tc{kappa(3)-HB(tim(Me))(3)}(CO)(3)] and fac-[(99m)Tc{kappa(3)-R(mu-H)B(tim(Me))(2)}(CO)(3)] [R is H (4a), Ph (5a); tim(Me) is 2-mercapto-1-methylimidazolyl] were obtained almost quantitatively by reacting fac-[(99m)Tc(CO)(3)(H(2)O)(3)](+) with the corresponding scorpionate. These compounds cross the intact blood-brain barrier in mice, with significant retention in the case of 4a and 5a. Using 4a as the lead structure, we have synthesized the functionalized complexes fac-[M{kappa(3)-H(mu-H)B(tim(Bu-pip))(2)}(CO)(3)] [M is Re (8), (99m)Tc (8a); tim(Bu-pip) is methyl[4-((2-methoxyphenyl)-1-piperazinyl)butyl](2-mercapto-1-methylimidazol-5-yl)methanamide] and fac-[M{kappa (3)-H(mu-H)B(tim(Me))(tim(Bu-pip))}(CO)(3)] [M is Re (9), (99m)Tc (9a)] and evaluated their potential as radioactive probes for the targeting of brain 5-HT(1A) serotonergic receptors. The Re complexes exhibit excellent affinity [IC(50)=0.172 +/- 0.003 nM (8); IC(50)=0.65 +/- 0.01 nM (9)] for the 5-HT(1A) receptor. The radioactive congeners ((99m)Tc) have shown an initial brain uptake of 1.38 +/- 0.46%ID g(-1) (8a) and 0.43 +/- 0.12%ID g(-1) (9a), but suffer from a relatively fast washout.

Several analogues based on the lead structure of azalanstat were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). A number of these compounds, which are structurally distinct from metalloporphyrin HO inhibitors, were found to be selective for the HO-1 isozyme (stress induced), and had substantially less inhibitory activity on HO-2, the constitutive isozyme.

Virtual screening of large libraries of organic compounds combined with pharmacological high throughput screening is widely used for drug discovery in the pharmaceutical industry. Our aim was to explore the efficiency of using a biased 3D database comprising secondary metabolites from antiinflammatory medicinal plants as a source for the virtual screening. For this study pharmacophore models of cyclooxygenase I and II (COX-1, COX-2), key enzymes in the inflammation process, were generated with structure-based as well as common feature based modeling, resulting in three COX hypotheses. Four different multiconfomational 3D databases limited in molecular weight between 300 and 700 Da were applied to the screening in order to compare and analyze the obtained hit rates. Two of them were created in-house (DIOS, NPD). The database DIOS consists of 2752 compounds from phytochemical reports of antiinflammatory medicinal plants described by the ethnopharmacological source 'De material medica' of Pedanius Dioscorides, whereas NPD contains almost 80,000 compounds gathered arbitrarily from natural sources. In addition, two available multiconformational 3D libraries comprising marketed and development drug substances (DWI and NCI), mainly originating from synthesis, were used for comparison. As a test of the pharmacophore models' capability in natural sources, the models were used to search for known COX inhibitory natural products. This was achieved with some exceptions, which are discussed in the paper. Depending on the hypothesis used, DWI and NCI library searches produced hit rates in the range of 6.6% to 13.7%. A slight increase of the number of molecules assessed for binding was achieved with the database of natural products (NPD). Using the biased 3D database DIOS, however, the average increase of efficiency reached 77% to 133% compared to the hit rates resulting from WDI and NCI. The statistical benefit of a combination of an ethnopharmacological approach with the potential of computer aided drug discovery by in silico screening was demonstrated exemplified on the applied targets COX-1 and COX-2.

The authors review the history of miniature electric field probes. They begin by describing growing environmental concerns about the biological effects of electromagnetic radiation in the mid 1970s. The importance of lead structure and design is discussed, and examples of two lead structures are presented. Design considerations for probes used in electromagnetic pulse measurements are viewed. The discussion indicates that lead bandwidths as high as 16 MHz are required for measurements of very short pulses such as those generated by a nuclear blast. >

Tacrine-huperzine A hybrids (huprines) are a new class of very potent and selective acetylcholinesterase (AChE) inhibitors. Huprines were designed from tacrine and (-)-huperzine A through a conjunctive approach. They combine the 4-aminoquinoline substructure of tacrine with the carbobicyclic substructure of (-)-huperzine A. Structural variations on several parts of a lead structure have allowed to complete a structure-activity relationship exploration of this new structural family and have led to several huprines more active than other known AChE inhibitors.

Symmetrically and dissymmetrically disubstituted imidazole-4,5-dicarboxamides (I45DCs) have diverse bioactivities and therefore represent useful small molecules for lead structure identification in drug discovery. For this reason, an improved synthesis was developed as a first step in the preparation of greater numbers of analogues. The method involves the transformation of imidazole-4,5-dicarboxylic acid into dissymmetrically disubstituted I45DCs in four steps and in a minimum yield of 51%. This reflects an overall reduction of one synthetic step and a greater than 30% improvement in yield over the known method.

Readily accessible, novel, and potent anti-malarial compounds have been developed. Optimization of the initial lead structure resulted in derivatives with IC 50 values from 7 to 35 nM against chloroquine-sensitive and 70–350 nM against chloroquine-resistant strains of Plasmodium falciparum .