Structure−Activity Relationships in 4-Aminoquinoline Antiplasmodials. The Role of the Group at the 7-Position

Abstract

Antiplasmodial activities versus the chloroquine sensitive D10 strain of Plasmodium falciparum of a series of N(1),N(1)-diethyl-N(2)-(4-quinolinyl)-1,2-ethanediamines with 11 different substituents at the 7-position on the quinoline ring have been investigated in vitro. Electron-withdrawing groups at the 7-position have been shown to lower the pK(a) of both the quinoline ring nitrogen atom and the tertiary amino nitrogen in the alkyl side chain. The quinoline nitrogen pK(a) ranges from 6.28 in the nitro derivative to 8.36 in the amino derivative, while the tertiary amino nitrogen has a pK(a) ranging between 7.65 in the trifluoromethyl derivative and 10.02 in the amino derivative. Calculation suggests that the resulting pH trapping of these compounds in the parasite food vacuole ranges between about 7% of that observed in chloroquine for the NO(2) derivative and 97% in the amino derivative. A direct proportionality between antiplasmodial activity normalized for pH trapping and beta-hematin inhibitory activity was observed. Activity could not be correlated with any other observed physical parameter. The beta-hematin inhibitory activity of these derivatives appears to correlate with both the hematin-quinoline association constant and the electron-withdrawing capacity of the group at the 7-position (Hammett constant). For the compounds under investigation, the hematin association constant is in turn influenced by the lipophilicity of the group at the 7-position.

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

“…24 In the present work, a similar correlation was found in the series with R = Me (Figure 1d). In addition, log BHIA 50 also correlated with both log K &  p for both the series with R = Me and EtNH 2 (Figure 1e and f).…”

“…The association constants with Fe(III)PPIX and the inhibition of β-hematin formation values were found to be correlated, except in the series with R = H. The parameter π was found to correlate with log K in the case of the series with R = H, similar to that found previously by Kaschula et al for the series with R = EtN(Et) 2 . 24 The parameter  p in combination with log K correlated with log BHIA 50 of the series with R = Me and EtNH 2 , while  m and log K correlated in the case where R = Me, similar to that found by Kaschula et al in the case of the series with R = EtN(Et) 2 . The R = H series was also used to confirm that the quinoline ring is the primary component for the inhibition of β-hematin formation as previously suggested.…”

“…This involved preparation of a series of 4-aminoquinolines in which the group at position 7 of the quinoline ring (X) and the lateral side-chain on the 4-amino group (R) were varied (Scheme 1), as well as comparisons with a previous series (R = EtN(Et) 2 in Scheme 1) prepared in our laboratory. 24 The values of log K and log BHIA 50 were then correlated with empirical properties, namely hydrophobicity and Hammett constants and correlations between log BHIA 50 and measured log K values were also explored. Furthermore, correlations with atomic charges, computed using density functional theory (DFT), were also investigated.…”

“…The conditions used for measurement of these quantities were chosen to facilitate comparison with previously collected data for a related series of compounds with a N,N-diethylaminoethyl side chain (R = EtN(Et) 2 in Scheme 1). 24 Values of log K and the 50% -hematin inhibitory activity (BHIA 50 ) are presented in Table 1.In a previous study of 4-aminoquinolines with R = EtN(Et) 2 , it was found that log K is correlated with the substituent hydrophobicity constant () of the X substituent. 24 A similar correlation is observed for the series prepared here with R = H ( Figure 1a).…”

“…The predicted activities for the series with R = H again cross-correlated with the experimental values for the series with R = Me and EtNH 2 and was even found to predict activities in the series reported by Kaschula et al with R = EtN(Et) 2 . 24 An interesting observation is that the sensitivity of log BHIA 50 to the changes in ESP brought about by altering the X-substituent decreases as the lateral side chain becomes more lipophilic.Several notable features emerge from this investigation. Atomic charges that predict log K are for the most part not the same as those that predict log BHIA 50 and furthermore the correlations involve different species, namely quinolinium and neutral respectively.…”