- Structure-activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods
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In order to probe structure-activity relationships of association with ferriprotoporphyrin IX (log K) and inhibition of β-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 (π) 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% β-hematin inhibitory activity (log BHIA50) was found to correlate with log K and either meta (σm) or para (σp) 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 β-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.
- Nsumiwa, Samkele,Kuter, David,Wittlin, Sergio,Chibale, Kelly,Egan, Timothy J.
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p. 3738 - 3748
(2013/07/19)
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- Microwave-assisted synthesis of 4-quinolylhydrazines followed by nickel boride reduction: a convenient approach to 4-aminoquinolines and derivatives
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Nickel(II) chloride/sodium borohydride combination was employed for the reduction of 4-hydrazinoquinoline derivatives to the corresponding anilines. This reductive protocol was efficiently applied for the reductive cleavage of monosubstituted hydrazines. We described herein the microwave-assisted synthesis of 4-hydrazinoquinolines, which furnished a high yielding and rapid two-step procedure for the synthesis, under mild conditions, of 4-aminoquinolines as antimalarial precursors.
- Gemma, Sandra,Kukreja, Gagan,Tripaldi, Pierangela,Altarelli, Maria,Bernetti, Matteo,Franceschini, Silvia,Savini, Luisa,Campiani, Giuseppe,Fattorusso, Caterina,Butini, Stefania
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p. 2074 - 2077
(2008/09/18)
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