Different synthetic routes to the preparation of 4-ethyl-2,6,7-trioxa-1-phosphabicyclo[2,2,2]octane-1-thioxide labelled with sulfur-35 have been investigated since it is of considerable interest as radioligand for neurochemistry. The thiophosphate was successfully synthesized by sulfuration of the corresponding bicyclophosphite by elemental sulfur-35, however the radiochemical purity of the material obtained in this way proves to be low. Convenient methods for synthesis of the thioxide from [ 35 S] thiourea, based on the results of the autoradiolysis of the starting [ 35 S] thiourea, has been discovered giving rise to thioxide with high radiochemical purity. The autoradiolytic stability of the labelled thiophosphate has been studied.

The essential coenzyme NAD plays important roles in metabolic reactions and cell regulation in all organisms. As such, NAD synthesis has been investigated as a source for novel antibacterial targets. Cross-species genomics-based reconstructions of NAD metabolism in group A streptococci (GAS), combined with focused experimental testing in Streptococcus pyogenes, led to a better understanding of NAD metabolism in the pathogen. The predicted niacin auxotrophy was experimentally verified, as well as the essential role of the nicotinamidase PncA in the utilization of nicotinamide (Nm). PncA is dispensable in the presence of nicotinate (Na), ruling it out as a viable antibacterial target. The function of the "orphan" NadC enzyme, which is uniquely present in all GAS species despite the absence of other genes of NAD de novo synthesis, was elucidated. Indeed, the quinolinate (Qa) phosphoribosyltransferase activity of NadC from S. pyogenes allows the organism to sustain growth when Qa is present as a sole pyridine precursor. Finally, the redundancy of functional upstream salvage pathways in GAS species narrows the choice of potential drug targets to the two indispensable downstream enzymes of NAD synthesis, nicotinate adenylyltransferase (NadD family) and NAD synthetase (NadE family). Biochemical characterization of NadD confirmed its functional role in S. pyogenes, and its potential as an antibacterial target was supported by inhibition studies with previously identified class I inhibitors of the NadD enzyme family. One of these inhibitors efficiently inhibited S. pyogenes NadD (sp.NadD) in vitro (50% inhibitory concentration [IC(50)], 15 μM), exhibiting a noncompetitive mechanism with a K(i) of 8 μM.

High-throughput screening of a specific set (focused library) of heterocyclic compounds containing alkylsulfonyl moiety (a total of 2827 compounds from 78 combinatorial libraries), has been performed and highly effective 5-HT6 receptors antagonists were discovered. The structure of most substances corresponds to the PhM2 pharmacophore model, which confirms its potential in the search for effective 5-HT6 receptor antagonists. It is established that the structure of a substituent introduced in the vicinity of the sulfonyl moiety in PhM2 ligands can affect their pharmacological activity, including the ability to block serotonin-induced 5-HT6 receptor-mediated cell responses. In particular, bulky electron-donor groups reduce the activity, whereas methylamine group significantly increases the 5-HT6 receptor antagonist ability of compounds. Based on these findings, a new conceptual pharmacophore model, PhM3, is proposed. It is shown that compounds from the combinatorial libraries with (i) sulfonyl moiety separated from the heterocyclic and/or aromatic moiety by one (or more) methylene carbon(s), (ii) heterocyclic compounds containing alkylsulfonyl moiety or endocyclic sulfonyl group, (iii) (5-arylsulfonyl-3H-[1,2,3]triazol-4-yl)-amines, and (iv) azoles substituted simultaneously with arylsulfonyl and alkylsulfonyl groups-all have low hit rate and, hence, are not promising for discovery of new 5-HT6 receptor antagonists.

Indole-containing compounds are found to interact with many therapeutically-relevant targets, which belong to different types of cell membrane receptors, and represent a very promising class of potential drugs. Synthesis of novel 1,2,3,4,5,5a,6,10b-octahydroazepino[4,3-b]indoles and their interaction profiles measured on a series of 66 therapeutic targets is described. The target recognition patterns of the compounds are compared with those of their bioisosteric analogs, diazolin I and DimebonTM II, representing 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, as well as with 1,2,3,4,5,6-hexahydroazepino[4,3-b]indoles VIII and X. We show that different therapeutic targets exhibit different level of discriminatory sensitivity towards cis- and trans-configurations of the new structures. The newly synthesized compounds exhibit predominant affinity towards histamine H1 and serotonin 5-HT2C receptors.

High-throughput screening of a specific set (focused library) of heterocyclic compounds containing an alkylsulfonyl moiety (a total of 2827 compounds from 78 combinatorial libraries) was performed in order to discover highly effective 5-HT 6 receptor antagonists. The screening identified several compounds that exhibited pronounced inhibiting properties for 5-HT 6 receptors that enabled them to be used to develop new highly effective drugs for treating central nervous system disturbances. The structures of most antagonists corresponded to the PhM2 pharmacophore model, which confirmed its potential in the search for effective 5-HT 6 receptor antagonists. It was established that the structure of the substituent introduced in the vicinity of the sulfonyl moiety in the PhM2 ligands could affect their pharmacological activity, including the ability to block serotonin-induced 5-HT 6 receptor-mediated cell responses. In particular, bulky electron-donating substituents decreased the activity whereas a methylamino group increased statistically significantly the 5-HT 6 antagonistic activity. Based on these findings, a new pharmacophore model for 5-HT 6 antagonists, PhM3, was proposed. It was shown that compounds from the combinatorial libraries with a sulfonyl moiety separated from the heterocyclic and/or aromatic moiety by one (or more) methylenes and heterocyclic compounds containing an alkylsulfonyl moiety or endocyclic sulfonyl, (5-aryl-sulfonyl-3 H -[1,2,3]triazol-4-yl)amines, and azoles substituted simultaneously by arylsulfonyl and alkylsulfonyl moieties all had low hit rates and were not promising for discovery of new 5-HT 6 receptor antagonists.

Indole-containing compounds are found to interact with many therapeutically relevant targets that belong to different types of cell membrane receptors. They represent a very promising class of potential drugs. The synthesis of novel 1,2,3,4,5,5a,6,10b-octahydroazepino[4,3-b]indoles and their interaction profiles measured on a series of 66 therapeutic targets including receptors, enzymes, and neuromediator transporters are described. The target recognition patterns of the compounds are compared with those of their bioisosteric analogs, diazoline (I) and Dimebon™ (II), which are 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, in addition with those of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indoles VIII and X. We show that different therapeutic targets exhibit different levels of sensitivity toward cis- and trans-configurations of the new structures. The new compounds exhibit affinity predominantly toward histamine H1 and serotonin 5-HT2C receptors.

Syntheses, biological evaluation, and structure-activity relationships for a series of novel 2-substituted 3-benzenesulfonyl-5,6-dimethyl-pyrazolo[1,5-a]pyrimidines are disclosed. In spite of a wide, four orders of magnitude, SAR range (K(i) varied from 260 pM to 2.96 μM), no significant correlation of 5-HT(6)R antagonistic potency was observed with major physiochemical characteristics, such as molecular weight, surface polar area, cLogP, or number of rotatable bonds. Statistically significant trend was only observed for size of substitute group, which was not enough to explain the deep SAR trend. Besides with the substitute group size, another factor that presumably plays a role in defining the compound potencies is a relative position of the heterocycle and sulfophenyl moieties. Among all synthesized derivatives, (3-benzenesulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 18 is the most potent (K(i) = 260 pM) and extremely selective, 5000 to >50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT(6) receptor.

Syntheses of a series of novel 3-sulfonyl-pyrazolo[1,5-a]pyrimidines and their 5-HT(6) receptor antagonistic structure-activity relationship are disclosed. The nature and position of substituents, which affect their receptor antagonistic activity, are analyzed. Among all synthesized derivatives, {3-(3-chlorophenylsulfonyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl}-methyl-amine 33 (K(i)=190 pM), (3-phenylsulfonyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 44 (K(i)=240 pM), (3-phenylsulfonyl-5-metoxymethyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 50 (K(i)=270 pM), and (3-phenylsulfonyl-5-methyl-7-metoxymethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 52 (K(i)=280 pM) are the most potent antagonists of the 5-HT(6) receptors.

A method for the chemoselective reduction of Ugi-type lactam amides at the lactam carbonyl functionality with borane complexes has been developed. The novel reduction products can be further manipulated synthetically to yield various novel N- and C-terminally active unnatural amino acid building blocks.

Syntheses, biological evaluation as 5-HT(6) receptor (5-HT(6)R) antagonists, and structure-activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT(6)R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT(6)R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT(6)R ligands with modified ADME characteristics without grossly affecting efficiency of their interaction with the receptor. In respect to the structure-activity relationship (SAR), among other physiochemical parameters, only the molecule size and shape (described by gyration radii) showed a clear tendency for more compact molecules to be more potent antagonists of this receptor.

Multi-component and domino reactions are efficient and effective methods in the sustainable and diversity-oriented synthesis of heterocycles. In particular, transition metal-catalyzed multi-component sequences have recently gained considerable interest. Based upon the Sonogashira entry to alkynones, alkenones, and intermediate allenes, we have opened new avenues to the one-pot synthesis of numerous classes of heterocyclic frameworks in an MCR fashion. This methodological approach has now found various applications in one-pot syntheses of functional chromophores, pharmaceutically active compounds, and marine alkaloids and derivatives.

5-HT6 receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.

Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure with a 5-HT6 receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive binding. We have found highly active and selective 5-HT6R antagonists. The most active 5-HT6R antagonists have IC50 < 100 nM in a functional assay, and K-i < 10 nM in a binding assay, which is 100 times higher than the activity with respect to other serotonin receptors.

IMPORTANCE OF THE FIELD:Among the GPCR subclasses that have been discovered to date, 5-HT receptors are especially attractive as key biological targets with enormous clinical importance. In particular, during the last decade, the 5-HT(6) receptor has gained increasing attention due to extensive cellular functions. It has also been suggested that its activity can be mediated by inverse agonists.AREAS COVERED IN THIS REVIEW:Summarizing the points listed above, the current review primarily focuses on patent literature within the title field, evolution and trends that have not yet been covered in such depth in other published papers.WHAT THE READER WILL GAIN:To obtain a clear understanding of the situation and dynamics within the field of 5-HT(6) ligands, having an obvious pharmaceutical potential in terms of related patents, we provide a comprehensive search through several key patent collections. We have covered promising small molecule compounds which are being evaluated in different clinical trials as well as drugs currently available in the pharmaceutical market. In addition, readers will gain a deep insight into the patent specification, geographic distribution, tendency and patent holders presented.TAKE HOME MESSAGE:Several of 5-HT(6)-targeted compounds are reasonably regarded as powerful drug candidates for the treatment of a range of neuropathological disorders, including Alzheimer's disease and Huntington's disease.

Multicomponent reactions of primary 1,2- and 1,3-diamines with carbonyl compounds and isocyanides resulting in the formation of diverse 2-amino-1,4-diazaheterocycles are described. Lewis acids (LAs) promote the reactions effectively, and chlorotrimethylsilane (TMSCl) has been found to be a promoter of choice. The scope and limitations of the reactions with regard to each of the components are evaluated and discussed. Post-IMCR modifications of the synthesized heterocycles have been elaborated.

Data on the methods of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles synthesis has been surveyed. The synthetic accessibility of various derivatives of these heterocycles has been demonstrated. It has been shown that such compounds exhibit a broad spectrum of pharmacological activity and hold interest for medicinal chemistry.