Structure-activity relationships for ferriprotoporphyrin IX association and ¦Â-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods

详细信息    查看全文

• 作者：Samkele Nsumiwa^a ; David Kuter^a ; Sergio Wittlin^b ; Kelly Chibale^a ; ^c ; Timothy J. Egan^a ; ^{timothy.egan@uct.ac.za}
• 关键词：Hemozoin ; DFT ; Antimalarials ; Quinolines ; Structure&ndash ; activity relationships ; Ferriprotoporphyrin IX
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 July, 2013
• 年：2013
• 卷：21
• 期：13
• 页码：3738-3748
• 全文大小：1377 K

文摘

In order to probe structure-activity relationships of association with ferriprotoporphyrin IX (log K) and inhibition of ¦Â-hematin formation, a series of 4-aminoquinolines with varying substituents at the 7-position (X) have been synthesized. These have been further elaborated by introduction of two different R groups on the 4-amino nitrogen atom in the form of methyl (R = Me) and ethylamine (R = EtNH₂) side chains. Data for a previously investigated series containing an N,N-diethyl-ethylamine side chain were also compared with the findings of this study. Experimentally, log K values for the simple 4-aminoquinoline series (R = H) were found to correlate with the hydrophobicity constant (¦Ð) of the group X. The log K values for the series with R = Me and EtNH₂ were found to correlate with those of the series with R = H. The log of the 50 % ¦Â-hematin inhibitory activity (log BHIA₅₀) was found to correlate with log K and either meta (¦Ò_m) or para (¦Ò_p) Hammett constants for the series with R = Me and EtNH₂, but not the simple series with R = H. To further improve predictability, correlations with ab initio electrostatic parameters, namely Mulliken and CHelpG charges were investigated. The best correlations were found with CHelpG charges which indicated that log K values can be predicted from the charges on atom H-8 and the group X in the quinolinium species computed in vacuum, while log BHIA₅₀ values can be predicted from the CHelpG charges on C-7, C-8 and N-1 for the neutral species in vacuum. These correlations indicate that association and inhibition of ¦Â-hematin formation are separately determined. They also suggest that electron withdrawing groups at the 7-position, but not necessarily hydrophobic groups are required for hemozoin inhibition. The upshot is that the correlations imply that considerably more hydrophilic hemozoin inhibitors are feasible.