Synthesis, biological activity, QSAR and QSPR study of 2-aminobenzimidazole derivatives as potent H 3-antagonists

Abstract

We report the design, synthesis, QSPR and QSAR of a new class of H 3-antagonists, having a 2-aminobenzimidazole moiety connected to the 4(5) position of an imidazole ring through di- or tri-methylene chains. Eleven substituents, selected by experimental design to obtain broad and non-correlated variation in their lipophilic, electronic and steric properties, were introduced at the 5(6) position of the benzimidazole nucleus. The compounds were tested for their H 3-receptor affinity, by displacement of [ 3H]-( R)-α-methylhistamine ([ 3H]-RAMHA) binding to rat brain membranes (p K i), for intrinsic activity, evaluating their effect on [ 35S]GTPγS binding to rat brain membranes, and for H 3-antagonist potency, on electrically stimulated guinea-pig ileum (p K B). The p K i values of the derivatives with longer chain ( 5a– k) ranged over 2 orders of magnitude, with the 5(6)-methoxy derivative 5d endowed with sub-nanomolar affinity (p K i =9.37). The series having two methylene groups in the chain spacer ( 4a– k), showing a small variation in affinity, revealed to be somewhat insensitive to ring substitution. Lipophilicity (log P) and basicity (p K a) of the newly synthesized compounds were measured and related to receptor affinity in a QSAR study. Multiple regression analysis (MRA) showed an approximate parabolic dependence of p K i on log P, while an additional electronic effect of the substituents on benzimidazole tautomerism is suspected.