Structural Analysis of Chloroquine Resistance Reversal by Imipramine Analogs

Abstract

For imipramine, desipramine, and eight analogs of these well-known drugs, an N-5-aminoalkyl substitution was a minimum but insufficient structural feature associated with chloroquine resistance reversal. Although a second distal aliphatic nitrogen atom was unnecessary for resistance reversal, the direction of the dipole moment vector was critical.The tricyclic antidepressants imipramine and desipramine possess modest antimalarial activity (8) and are two well-studied compounds known to reverse chloroquine (CQ) resistance in plasmodia in vitro (1,4,5,7,11). One report (8), however, noted that neither drug reversed CQ resistance in vitro, and in one clinical study (15) desipramine did not enhance the efficacy of CQ. Nonetheless, the identification of compounds that reverse CQ resistance is an important goal in malaria chemotherapy.In order to probe the structural specificity of this phenomenon, we compared the abilities of imipramine (referred to as compound 1), desipramine (compound 2), clomipramine (compound 5), and six analogs of these well-known drugs (compounds 3, 4, 6, 7, 8, and 9) (Fig. 1) to reverse CQ resistance. In these experiments, the 50% inhibitory concentration (IC 50 ) of CQ against the W2 clone of Plasmodium falciparum was determined in the presence and absence of 500 ng of test compound/ml (Table 1). A resistance modification index (RMI) was calculated by dividing the IC 50 of CQ in the presence of the tricyclic antidepressant by the IC 50 of CQ alone. The IC 50 s of CQ against the CQ-sensitive D6 and CQ-resistant W2 P. falciparum clones were 2.5 and 49 ng/ml, respectively.The W2 clone was rendered fully sensitive to CQ in the presence of compounds 1 to 6, each of which contained a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two-or three-carbon bridge to the heteroaromatic nitrogen (N-5). Notably, compound 7, a regioisomer of compound 6, had almost no effect on altering the susceptibility of the W2 clone to CQ, suggesting that its methyl group sterically prevents a receptor binding interaction with the proximal piperazine nitrogen atom. The more rigid alkyne-bridged compound 8 and diazepine (compound 9) were somewhat less effective than compounds 1 to 6, but they still increased the CQ sensitivity of the W2 clone 4.9-and 4.1-fold, respectively. Consideration of these data reveals that N-5-aminoalkyl substitution is a minimum but insufficient structural feature associated with resistance reversal. This conclusion is also supported by the complete lack of activity of the N-5-acetamide derivative (data not shown). As illustrated for the data for compounds 6, 7, and 9, we can also infer that a second distal aliphatic nitrogen atom is unnecessary for resistance reversal. These results suggest that there is considerable latitude in the distance and geometry between the two nitrogen atoms in this series of imipramine analogs.To better understand this situation, the structures for compounds 1 to 9 were entered into the molecular modeling software Spartan (Wavefunction, Inc.) and ene...

Design, Synthesis, and Evaluation of 10-N-Substituted Acridones as Novel Chemosensitizers in Plasmodium falciparum

“…Structureactivity profiling and three-dimensional quantitative structureactivity relationship (QSAR) studies by Bhattacharjee and colleagues revealed a pharmacophore with critical features for potent CQ-chemosensitizing activity, which consists of two aromatic hydrophobic groups and a hydrogen bond acceptor site at the side chain, preferably on a nitrogen atom (8,9,25).…”

“…1) (4,6,42,43,46,55) and tricyclic antidepressants (e.g., desipramine) ( Fig. 1) (5,8,10,11,13,40,51,57) among the most effective and best studied (27,59).…”

“…1) (4,6,42,43,46,55) and tricyclic antidepressants (e.g., desipramine) ( Fig. 1) (5,8,10,11,13,40,51,57) among the most effective and best studied (27,59).While the mechanism of chemosensitization is not fully understood, recent studies suggest that mutations in the P. falciparum CQ resistance transporter (PfCRT) protein, particularly amino acid substitutions at position 76, may play key roles in the mode of action of verapamil (14,18,37). Structureactivity profiling and three-dimensional quantitative structureactivity relationship (QSAR) studies by Bhattacharjee and colleagues revealed a pharmacophore with critical features for potent CQ-chemosensitizing activity, which consists of two aromatic hydrophobic groups and a hydrogen bond acceptor site at the side chain, preferably on a nitrogen atom (8, 9, 25).…”

5HT1A Serotonin Receptor Agonists InhibitPlasmodium falciparumby Blocking a MembraneChannel

“…Other antidepressants, such as desipramine and imipramine (23), have modest antimalarial activity alone and have also been found to facilitate the reversal of chloroquine resistance (3,4,18,34). Nevertheless, since desipramine has not had success in clinical trials for the treatment of chloroquineresistant malaria (35), new leads and structure-function relationships need to be explored (2).…”

“…To evaluate mammalian cell cytotoxicity, the MRC-5 human lung fibroblast cell line was cultured in minimal essential medium Rega 3 medium supplemented with 20 mM glutamine, 16.5 mM NaHCO 3 , and 5% fetal calf serum. The test compounds were routinely tested at four concentrations (32,8,2, and 0.5 M) in 384-well microtiter plates. If the IC 50 was higher than 16 M, the compound was classified as nontoxic, if it was between 16 and 1 M, the compound was classified as moderately toxic, and if it was less than 1 M, the compound was classified as highly toxic.…”