Design and Syntheses of a Series of Novel Serotonin3 Antagonists.

Abstract

From a structural comparison study between serotonin and serotonin3 (5-HT3) antagonists using a two-dimensional grid template composed of regular hexagons, we deduced structural modification patterns from agonists to antagonists, and designed new 5-HT3 antagonist prototypes. Among them, 2-(4-methyl-1-piperazinyl)-1-butylbenzimidazole (6) was identified as a lead compound which has potent 5-HT3 antagonistic activity comparable to that of granisetron. Using a quantitative structure-activity relationships method, we optimized the structure of 6 and selected 6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole dimaleate (69, KB-6933), one of the most potent and long-acting 5-HT3 antagonists, as a candidate drug.

Novel Selective and Partial Agonists of 5-HT3Receptors. Part 1. Synthesis and Biological Evaluation of Piperazinopyrrolothienopyrazines

“…Recently some new 5-HT 3 antagonists which are structurally related to the quipazine have been published, among which are piperazinylquinoxaline, 2-piperazinylbenzothiazole, benzoxazole, and 2-piperazinylbenzimidazole derivatives. These compounds have in common with the quipazine a bicyclic aromatic moiety linked to a piperazine via a “pseudoamidinic” bond as key pharmacophoric elements for high 5-HT 3 affinity.…”

Synthesis and potent antifungal activity against Candida species of some novel 1H‐benzimidazoles

“…3-Chloro-2-nitrobenzonitrile (12). The mixture of 0.5 g (2.48 mmol) of 3-chloro-2-nitrobenzoic acid toluene (3 mL) and thionyl chloride (2 mL) were heated at 80 C for 4 h. Excess of thionyl chloride and solvent were evaporated, then the residue was stirred in ammonium hydroxide (5 mL) at room temperature for 1 h. The formed precipitate 3-chloro-2-nitrobenzamide was collected.…”

Serotonin 5-HT3 and 5-HT4 receptor antagonists

“…11) for which functional data has been quoted includes KB-6933. 49,113 Using an interesting approach of converting agonists to antagonists using a 2-D representation of molecules on a polyhexagon matrix, piperazinylbenzimidazoles, originally investigated as H 1 antagonists and bearing remarkable similarity to quipazine, were identified as possible prototype structures. SAR showed groups larger than N-methyl on the piperazine were not tolerated and 1-substitution on the benzimidazole was optimized with C5 alkyl side chains, smaller and larger being less potent.…”