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Serotonin, or 5-hydroxytryptamine (5-HT), is a biogenic amine most noted as a neurotransmitter, an activator of the utmost subtype family of G-protein- coupled receptors (GPCR). Drugs targeting 5-HT1A and other 5-HT receptors treat central nervous system diseases such as schizophrenia and depression. Recent advances in serotonin receptor structure research gave us several crystal 5-HT1A receptor structures, most notably 5-HT1A bound to the antipsychotic drug aripiprazole (Abilify®). This discovery prompted us to evaluate a series of newly synthesized ligands for serotonergic activity since those arylpiperazine derivatives share minimal general structure with aripiprazole. The results of molecular docking analysis of unsubstituted starting substances encouraged us to propound further modifications of the tail and head parts of the parent molecules to maximize receptor binding affinity. Intrigued by the results of molecular analysis, all foreseen derivatives were synthesized. The pharmacological activity of all nine (5a and 6a are synthesized previously) compounds was assessed by the in vitro tests and in silico pharmacokinetics predictions for the most promising candidates. All tested ligands have improved affinity compering to parent compounds (10a and 11a), 8b and 9b expressed the best pharmacological profile with an improved binding affinity toward serotonin 5-HT1A receptors (Ki 12.1 and 4.8 nM, respectively).

The synthetic route toward novel tricyclic, nitrogen-containing system is disclosed. Three novel compounds possessing structural features of 1,2,3,4-tetrahydroquinoxaline and decahydropyrido[3,4-b]pyrazine are synthesized starting from readily available precursors in six or seven steps, of which the last three or four steps respectively are diastereoselective. Key reaction steps include N-acylation, Hofmann rearrangement and ring-closing Buchwald– Hartwig reaction. Compounds trans-8, cis-12 and trans-12 are synthesized in order to prove that this novel, tricyclic system can be functionalized with various groups. Synthetic significance of this heterocyclic system lies in the possibility for the orthogonal functionalization of three different amino groups, allowing fine structural tuning.

Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172032]

A scalable, cost-efficient and simple synthetic pathway towards potential bivalent opioid/dopamine receptor ligands was developed and optimized. Three novel compounds that contain both opioid and dopamine pharmacophores linked by the four methylene group chain were synthesized in 33, 35 and 39 % overall yield after a four-step synthetic route starting from three commercially available N-aryl piperazines. The anilino piperidine precursor was easily prepared in three steps, as previously published, starting from 4- piperidone. The synthesis presented in this paper could be of interest for heterocyclic and general organic chemistry. The newly designed compounds possessing two pharmacophores, opioid and D2/D3, are potentially useful pharmacological probes. Of particular interest would be the simultaneous binding to both opioid and D2/D3 receptors, and the resulting pharmacological responses may be useful for the further understanding of tolerance and dependence phenomena in opioid clinical use and/or abuse. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172032]

A total of 14 novel arylpiperazines were synthesized, and pharmacologically evaluated by measuring their affinities towards the D2 dopamine receptor (DRD2) in a [3H]spiperone competition assay. All the herein described compounds consist of a benzimidazole moiety connected to N-(2-methoxyphenyl)piperazine via linkers of various lengths. Molecular docking analysis and molecular dynamics simulations were performed on the DRD2–arylpiperazine complexes with the objective of exploring the receptor–ligand interactions and properties of the receptor binding site. The recently published crystal structure of DRD2 was used throughout this study. The major finding is that high affinity arylpiperazines must interact with both the orthosteric binding site and the extended binding pocket of DRD2 and therefore should contain a linker of 5 or 6 methylene groups long. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172032]

A series of sixteen novel substituted piperidines and (2-methoxyphenyl)piperazines were synthesized, starting from the key intermediates 1-(2-methoxyphenyl)-4-(piperidin-4-yl)piperazine and 1-(2-methoxyphenyl)-4-(piperidin-4-ylmethyl)piperazine. Biological evaluation of the synthesized compounds was pointed out for seven compounds, of which 1-(2-methoxyphenyl)-4-{[1-(2-nitrobenzyl)piperidin-4-yl]methyl}piperazine had the highest affinity for the dopamine D2 receptor. For all seven selected compounds docking analysis was performed in order to establish their structure-to-activity relationship. [Projekat Ministarstva nauke Republike Srbije, br. 172032]

Series of eight novel 5-substituted derivatives of benzimidazole were synthesized by condensation of corresponding diamine with ethyl-4-[4-(2-chlorophenyl)piperazin-1-yl] butanoate in refluxing 4N hydrochloric acid. In vitro antibacterial activity against ten strains namely, Bacillus subtilis, Clostridium sporogenes, Streptosporangium longisporum, Micrococcus flavus, Sarcina lutea, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis and Proteus vulgaris and antifungal activity against two fungal strains namely, Candida albicans and Saccharomyces cerevisiae, were evaluated. Of all the compounds screened for activity 2-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-iodo-1H-benzimidazole and 2-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-methyl-1H-benzimidazole were associated with higher antifungal activity than commercial drugs. [Projekat Ministarstva nauke Republike Srbije, br. 172032]