It has been recently reported that compounds composed of an imidazole connected through an alkyl ... more It has been recently reported that compounds composed of an imidazole connected through an alkyl spacer to a 2-aminobenzimidazole showed high affinity towards the H(3)-receptor. The guanidine fragment of the 2-aminobenzimidazole is probably involved in hydrogen bond interactions at the binding site, and is referred to as the 'polar fragment'. In the present work, starting from 2-aminobenzimidazole derivatives with a di-methylene spacer 1 (pK(i)=7.25) or a tri-methylene one 2 (pK(i)=8.90), we investigated the importance of the hydrogen bond (HB) donor groups at the polar fragment in the interaction with the H(3)-receptor. The replacement of 2-aminobenzimidazoles with different moieties [2-aminobenzothiazole, 3, 4; 2-thiobenzimidazole, 5, 6; 2-thiobenzothiazole, 7, 8; 2-thio-4-phenyl- or 2-thio-5-phenyl-N-methylimidazoles, 9-12] highlighted the effect of the polar group basicity on the optimal length of the alkyl chain: longer spacers were preferred with polar groups of moderate basicity whereas, in the presence of neutral polar groups, the best affinity values were obtained with di-methylene chains. Moreover, N-methylation at the 2-aminobenzimidazole moiety 13-16 revealed different behaviour for compounds having different spacer lengths. In fact, methylation of the exocyclic NH group maintained high affinity for the tri-methylene 2-aminobenzimidazole derivative, while a drop in affinity was observed for the annular N-methylation. An opposite trend characterised di-methylene derivatives. These observed SAR suggest that, within this class of compounds, the number of HB-donor groups can be lowered while maintaining high receptor affinity. Since the presence of HB-donor groups strongly affects brain access, this observation could be useful to design and prepare new H(3)-antagonists.
It has been recently reported that compounds composed of an imidazole connected through an alkyl ... more It has been recently reported that compounds composed of an imidazole connected through an alkyl spacer to a 2-aminobenzimidazole showed high affinity towards the H(3)-receptor. The guanidine fragment of the 2-aminobenzimidazole is probably involved in hydrogen bond interactions at the binding site, and is referred to as the 'polar fragment'. In the present work, starting from 2-aminobenzimidazole derivatives with a di-methylene spacer 1 (pK(i)=7.25) or a tri-methylene one 2 (pK(i)=8.90), we investigated the importance of the hydrogen bond (HB) donor groups at the polar fragment in the interaction with the H(3)-receptor. The replacement of 2-aminobenzimidazoles with different moieties [2-aminobenzothiazole, 3, 4; 2-thiobenzimidazole, 5, 6; 2-thiobenzothiazole, 7, 8; 2-thio-4-phenyl- or 2-thio-5-phenyl-N-methylimidazoles, 9-12] highlighted the effect of the polar group basicity on the optimal length of the alkyl chain: longer spacers were preferred with polar groups of moderate basicity whereas, in the presence of neutral polar groups, the best affinity values were obtained with di-methylene chains. Moreover, N-methylation at the 2-aminobenzimidazole moiety 13-16 revealed different behaviour for compounds having different spacer lengths. In fact, methylation of the exocyclic NH group maintained high affinity for the tri-methylene 2-aminobenzimidazole derivative, while a drop in affinity was observed for the annular N-methylation. An opposite trend characterised di-methylene derivatives. These observed SAR suggest that, within this class of compounds, the number of HB-donor groups can be lowered while maintaining high receptor affinity. Since the presence of HB-donor groups strongly affects brain access, this observation could be useful to design and prepare new H(3)-antagonists.
It has been recently reported that compounds composed of an imidazole connected through an alkyl ... more It has been recently reported that compounds composed of an imidazole connected through an alkyl spacer to a 2-aminobenzimidazole showed high affinity towards the H(3)-receptor. The guanidine fragment of the 2-aminobenzimidazole is probably involved in hydrogen bond interactions at the binding site, and is referred to as the 'polar fragment'. In the present work, starting from 2-aminobenzimidazole derivatives with a di-methylene spacer 1 (pK(i)=7.25) or a tri-methylene one 2 (pK(i)=8.90), we investigated the importance of the hydrogen bond (HB) donor groups at the polar fragment in the interaction with the H(3)-receptor. The replacement of 2-aminobenzimidazoles with different moieties [2-aminobenzothiazole, 3, 4; 2-thiobenzimidazole, 5, 6; 2-thiobenzothiazole, 7, 8; 2-thio-4-phenyl- or 2-thio-5-phenyl-N-methylimidazoles, 9-12] highlighted the effect of the polar group basicity on the optimal length of the alkyl chain: longer spacers were preferred with polar groups of moderate basicity whereas, in the presence of neutral polar groups, the best affinity values were obtained with di-methylene chains. Moreover, N-methylation at the 2-aminobenzimidazole moiety 13-16 revealed different behaviour for compounds having different spacer lengths. In fact, methylation of the exocyclic NH group maintained high affinity for the tri-methylene 2-aminobenzimidazole derivative, while a drop in affinity was observed for the annular N-methylation. An opposite trend characterised di-methylene derivatives. These observed SAR suggest that, within this class of compounds, the number of HB-donor groups can be lowered while maintaining high receptor affinity. Since the presence of HB-donor groups strongly affects brain access, this observation could be useful to design and prepare new H(3)-antagonists.
It has been recently reported that compounds composed of an imidazole connected through an alkyl ... more It has been recently reported that compounds composed of an imidazole connected through an alkyl spacer to a 2-aminobenzimidazole showed high affinity towards the H(3)-receptor. The guanidine fragment of the 2-aminobenzimidazole is probably involved in hydrogen bond interactions at the binding site, and is referred to as the 'polar fragment'. In the present work, starting from 2-aminobenzimidazole derivatives with a di-methylene spacer 1 (pK(i)=7.25) or a tri-methylene one 2 (pK(i)=8.90), we investigated the importance of the hydrogen bond (HB) donor groups at the polar fragment in the interaction with the H(3)-receptor. The replacement of 2-aminobenzimidazoles with different moieties [2-aminobenzothiazole, 3, 4; 2-thiobenzimidazole, 5, 6; 2-thiobenzothiazole, 7, 8; 2-thio-4-phenyl- or 2-thio-5-phenyl-N-methylimidazoles, 9-12] highlighted the effect of the polar group basicity on the optimal length of the alkyl chain: longer spacers were preferred with polar groups of moderate basicity whereas, in the presence of neutral polar groups, the best affinity values were obtained with di-methylene chains. Moreover, N-methylation at the 2-aminobenzimidazole moiety 13-16 revealed different behaviour for compounds having different spacer lengths. In fact, methylation of the exocyclic NH group maintained high affinity for the tri-methylene 2-aminobenzimidazole derivative, while a drop in affinity was observed for the annular N-methylation. An opposite trend characterised di-methylene derivatives. These observed SAR suggest that, within this class of compounds, the number of HB-donor groups can be lowered while maintaining high receptor affinity. Since the presence of HB-donor groups strongly affects brain access, this observation could be useful to design and prepare new H(3)-antagonists.
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