Evaluation of the anxiolytic properties of benzimidazole-2-thioethanones, 2-alkylthio- and 2-alkylsulfonylbenzimidazoles

Abstract

Introduction: Fabomotizole is an anxyolytic drug produced in Russia, a 2-mercaptobenzimidazole derivative. The pleiotropic effects of the benzimidazole scaffold, combined with proven neuropsychotropic properties, make fabomotizole a promising target for the synthesis of its analogs to obtain new derivatives with pronounced biological activity.

Materials and Methods: The study involved 125 white outbred male mice, randomly divided into 25 experimental groups (n=5). Twenty-one derivatives of benzimidazole-2-thioethanone, 2-alkylthio-, and 2-alkylsulfonylbenzimidazole were studied. The screening dose was calculated at the level of 1/100 of LD₅₀, determined in silico by the consensus ADMET prediction. The behavioral patterns of the animals were assessed in vivo in Light/Dark Box and Open Field in comparison with etifoxine (50 mg/kg), fabomotizole (20 mg/kg), and phenazepam (0.01 mg/kg). In the final stage, the studied structures were optimized using quantum chemistry methods for subsequent analysis of the structure-activity relationship.

Results and Discussion: The most active derivatives of 2-mercaptobenzimidazole were derivatives of 5-unsubstituted-2-mercaptobenzimidazole: ZH-2, ZH-3, ZH-4, and ZH-41. Among all the studied compounds, a decrease in anxiolytic effect was observed in sequence: 5-unsubstituted – 5-chloro-substituted – 5-methoxy-substituted 2-mercaptobenzimidazoles. A study of the mercaptobenzimidazole fragment using molecular mechanics and quantum chemistry methods revealed that the addition of a substituent to the benzene ring leads to a redistribution of the electron density of cyclic structures.

Conclusion: The synthesis of new molecules with a putative anxiolytic effect based on 2-mercaptobenzimidazole is a promising direction in medicinal chemistry. The most active compounds are those without a substituent at position 5 of the benzimidazole ring.

Graphical Abstract