Reversal of chloroquine resistance of ‘wild’ isolates of Plasmodium falciparum by desipramine

The ability of four 9,10-dihydroethanoanthracene derivatives (BG920, BG932, BG958, and BG996), as well as verapamil and promethazine, to reverse chloroquine resistance was assessed against 24 chloroquine-resistant and 10 chloroquine-susceptible strains of Plasmodium falciparum from different countries. The 9,10-dihydroethanoanthracene derivatives clearly increase chloroquine susceptibility only in chloroquine-resistant isolates

supporting

confidence: 51%

mentioning

confidence: 99%

Dihydroethanoanthracene Derivatives as In Vitro Malarial Chloroquine Resistance Reversal Agents

Millet

Torrentino-Madamet

Alibert

et al. 2004

“…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).…”

mentioning

confidence: 99%

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

Kelly

Smilkstein

Cooper

et al. 2007

A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.Malaria remains a major world health problem and continues to be a leading cause of morbidity and mortality, particularly in developing countries (64). The devastating situation is largely attributed to and aggravated by the emergence and spread of multidrug-resistant (MDR) Plasmodium falciparum, the cause of the most deadly form of malaria (3,28,47,67). Chloroquine (CQ) (Fig. 1) and other quinoline antimalarials, including the naturally occurring quinine (QN) (Fig. 1), were among the most successful chemotherapeutic agents for treatment of malaria for decades, if not centuries. Unfortunately, at present, resistance to CQ exists virtually wherever P. falciparum does, making it essentially useless in nearly all regions where malaria is endemic (3,22,63,67). Although resistance to pregnancysafe QN is far less extensive, reports of QN resistance are steadily increasing (3,32,48,49,53,67).In the 1980s, artemisinin-based drugs were not readily available. The lack of new effective drugs heightened the urgency for quick fixes to restore the usefulness of CQ and to counter the spread of CQ resistance. The discovery of MDR chemosensitizers (or so-called "resistance reversal agents") in the cancer research field stimulated a study by Martin et al., which revealed that the calcium channel blocker verapamil (Fig. 1) also restored CQ sensitivity to MDR P. falciparum parasites (39). Since then, many structurally and functionally diverse compounds have been identified and reported to demonstrate...

“…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.…”

mentioning

confidence: 99%

Structural Analysis of Chloroquine Resistance Reversal by Imipramine Analogs

Bhattacharjee

Kyle

Vennerstrom

2001

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...