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  2. Synthesis, biological activity, QSAR and QSPR study of 2-aminobenzimidazole derivatives as potent H3-antagonists

Synthesis, biological activity, QSAR and QSPR study of 2-aminobenzimidazole derivatives as potent H3-antagonists

  • Bioorg Med Chem. 2004 Feb 15;12(4):663-74. doi: 10.1016/j.bmc.2003.11.030.
Marco Mor 1 Fabrizio Bordi Claudia Silva Silvia Rivara Valentina Zuliani Federica Vacondio Mirko Rivara Elisabetta Barocelli Simona Bertoni Vigilio Ballabeni Francesca Magnanini Mariannina Impicciatore Pier Vincenzo Plazzi
Affiliations

Affiliation

  • 1 Dipartimento Farmaceutico, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43100 Parma, Italy. [email protected]
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 [(3)H]-(R)-alpha-methylhistamine ([(3)H]-RAMHA) binding to rat brain membranes (pK(i)), for intrinsic activity, evaluating their effect on [(35)S]GTPgammaS binding to rat brain membranes, and for H(3)-antagonist potency, on electrically stimulated guinea-pig ileum (pK(B)). The pK(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 (pK(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 (pK(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 pK(i) on log P, while an additional electronic effect of the substituents on benzimidazole tautomerism is suspected.

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