This paper sets forth a global synthetic strategy based on the Garlanding concept to design and to produce halo-oligopyridines. This strategy allows to prepare an infinite number of these new compounds and hence to create a library of halo-oligopyridines. This article is focused on the basic principle of the Garlanding concept and on the demonstration of its feasibility.

Graphical abstract

The synthesis and the biological evaluation of pyrano[3,2-e]indoles and their reaction intermediates are described. The compounds prepared were evaluated for their inhibition of NO production, antioxidant activity and also for their ability to inhibit in vitro the growth of four human tumor cell lines: large lung carcinoma (COR-L23), alveolar basal epithelial carcinoma (A549), amelanotic melanoma (C32) and melanoma (A375). The two reaction intermediates, 5a and 5b, showed the highest inhibition of NO production in murine monocytic macrophage (IC50=1.1μM and IC50=2.3 μM respectively). Compound 5a was the most active against melanotic melanoma (IC50=11.8μM) while the other compounds exhibited weak cytotoxicity with IC50 values >50μM on all cell lines.

2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was converted into the corresponding 2-(pyrrol-1-yl) derivative, followed by reduction of the latter compound into the corresponding amine. This amine and its acyl, aroyl, and arylidene derivatives were used as synthons in the synthesis of several title compounds

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The reaction between 3-(dimethylamino)/3,3-bis(methylthio)-1-(substituted)prop-2-en-1-ones and 4-substituted-5-amino-1H-pyrazoles afforded new pyrazole[1,5-a]pyrimidines structurally related to Zaleplon. The chemical modifications introduced at the 3-, 5-, and 7-positions of the bicyclic structure revealed new promising candidates for the treatment of sleep disorders.

The syntheses of the title heterocycles were achieved using 5-amino-1-(1-benzyl-1H-indol-3-ylcarbonyl)-1H-pyrazole-4-carbonitrile as starting material. These compounds were converted into the 4-imidazolinyl derivatives which were subjected to cyclization reactions to afford the title compounds.

Starting from the pyrazole-4-carboxylic acid hydrazide 3, a variety of new oxadiazoles 7-9, 11,
13, 17, 18, triazoles 20, 22-25, thiadiazole 21 and pyrazole derivatives 26-29 have been
synthesized

Starting from the 4-amino-3-(1,3-diphenyl-1H-pyrazol-4-yl)-4,5-dihydro-[1,2,4] triazole-5(1H)-
thione 2, a series of new [1,3,4]thiadiazoles 3, 4, 7 and [1,3,4] thiadiazines 8, 10, 11, 12, 14 were
prepared. Also, [1,3,4]thiadiazepines 16-18 could be synthesized. Some of the newly prepared
compounds were evaluated for their antiviral potential.

Here we report our medicinal chemistry approach on the synthesis of the pyrazolo[4,3-e][1,2,4]triazolo[1,5- c]pyrimidines and related compounds that have permitted us to complete the SAR analyses on this class of chemical molecules. Evaluating their pharmacological profiles, we planned several structural modifications to modulate the biological activity versus the different adenosine receptor subtypes. Efforts made by our research group led to the discovery of a variety of selective antagonists for the A2A and A3 receptors, performing modifications at the N7, N8, N5, C9, C2-position of the pyrazolo-triazolo-pyrimidine core and by the replacement of the 2-(2-furyl)[1,2,4]triazole molecular part with substituted 2-thioxotriazole, dioxotriazine, oxotriazine, and 1,2,4-triazepine moieties. Modifications at the N7- pyrazole performed by the introduction of different alkyl or arylalkyl chains, led us to the discovery of very potent and selective A2A receptor antagonists, whereas, functionalisations at the N5-position together with the modulation of the pattern of substitution on the N8-pyrazole nitrogen revealed new A3 antagonists (40, 41) suitable to represent candidate for the pharmacological and clinical investigations. Other modifications performed to the tricyclic nucleus, such as the introduction at the C9-position of thioethyl, aminoalkyl and (cyclo)alkylamino radicals (compounds 50-66) and the replacement of the 2-furyl moiety with substituted aromatic rings (compounds 48 a-f and 49a, b) led to a diminished receptor affinity. Also the replacement of the 2-(2-furyl)triazolo template with new heterocycles revealed inactive molecules but allowed us to real understand what structural modifications introduced on the pyrazolo-triazolo-pyrimidine structure played an important role on ligand-receptor interaction. In this way, we notice what position of the heterocyclic structure is not allowed to be modified and, on the contrary, what position is susceptible of modifications or functionalizations.