Synthesis of New Arylpiperazinylalkylthiobenzimidazole, Benzothiazole, or Benzoxazole Derivatives as Potent and Selective 5-HT_1A Serotonin Receptor Ligands

Abstract

A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT 1A and 5-HT 2A serotonergic, alpha 1 adrenergic, D1, and D2 dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT 1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT 1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT 1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT 1A receptor was used to explain the influence of spacer length on ligands affinity.

Synthesis and Experimental Validation of New Designed Heterocyclic Compounds with Antiproliferative Activity versus Breast Cancer Cell Lines MCF-7 and MDA-MB-231

“…The .mol2 files for 176 new molecules were generated and classified in 7 different classes based on their different chemical features for a better classification and identification: pyrrolopyrimidindione, pyrimidinketones, benzyloxyindole, indole, LCAPs, quinoline, and thiophene derivatives [15][16][17][18][19][20][21][22][23][24][25]. The structures of all compounds were reported in Supporting Information (SI).…”

“…In the present paper, in order to verify further the robustness of this model and to apply the drug-repositioning concept, we report the results of the projection of 176 derivatives. Among them, 167 were previously synthesized for other applications such as 1 adrenergic, 5-HT 1A serotonergic, or endothelin receptor ligands and antiproliferative compounds active in prostate tumor cell lines [15][16][17][18][19][20][21][22][23][24][25]. Moreover, 9 compounds were designed and synthesized based on the recent literature [26][27][28] reporting the activity of pyrimidinketones against MCF-7 cell line.…”

Regioselective synthesis and preliminary cytotoxic activity properties of tetrazole appendage N-substituted piperazine derivatives

“…16 Siracusa et al reported that arylpiperazine moiety was linked to a benzoxazole, benzothiazole, or benzimidazole system by an ethylthio or propylthio unit showed to be high affinity towards 5-HT1A receptor. 20 Recently, as part of our on-going programme to discover and develop potential new anticancer agents, we have been reported alkyl chain arylpiperazine containing heterocyclic hybrids that includes benzoxazole/benzothiazole, triazoles and oxadiazoles moieties. 21,22 Thus, in continuation of our lasting interest in chemistry and pharmacological properties of tetrazole and substituted arylpiperazine, we incorporated the structural features of 5-thio substituted tetrazole and along with alkyl chain arylpiperazine by well-known using molecular hybridization approach 23,24 for drug like molecules build-up, which allows achieving new pharmacological profile.…”

Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

“…On the basis of the binding affinity results, a series of compounds possessing affinity below 3 nM for 5-HT 1A R (5,8,9,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) and below 50 nM for 5-HT 7 receptors (9,12,15,17,18,20,21) was selected for functional profile characterization. Intrinsic activity studies were performed using in vitro measures of receptor activation.…”

“…A very important class of 5-HT receptors ligands are derivatives of 1,4-disubstituted arylpiperazine ( Figure 1). Such arylpiperazine derivative with longchain substituents incorporated on the basic nitrogen of the phenylpiperazine ring -long-chain arylpiperazines (LCAPs) -are commonly studied classes of bioactive compounds [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] . Despite the enormous progress in central nervous system (CNS) drug discovery, particularly in the areas of mood disorders and schizophrenia, new drugs are still being sought.…”