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

Abstract

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...

In Vitro Chemosensitization ofPlasmodium falciparumto Antimalarials by Verapamil and Probenecid

“…The most pronounced effect was observed with DEAQ and QN, with a FIC of Ͻ0.5 (Table 1). No chemosensitization was observed when 3D7 was used.The ability of VPM to chemosensitize parasites to CQ and CQ-related drugs in CQ-resistant strains is well established (20, 27); however, this effect is commonly found to be moderate (mean FICs Ͼ 0.5) (10,12,13,15), in line with our data. The molecular mechanism of this chemosensitization is well understood.…”

Know your enemy: understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics

“…The CQ resistance-reversing compounds identified to date share several structural features, and a number of studies have demonstrated structure-activity relationships for resistance-reverser activity [59][60][61][62]. Bhattacharjee and colleagues [63] developed a 3D pharmacophore model for CQ resistance-reversal using structure-activity profiling.…”

“Recycling” Classical Drugs for Malaria

“…96 Later on, the same researchers synthesized acridone derivatives with N-alkylamine substituents in position 10 (64, Figure 30; IC 50 = 2.6−11.8 and 1.6−10.2 μM against P. falciparum D6 and Dd2 strains, respectively), and they found them to display the desired chemosensitization properties and synergy with CQ against CQ-resistant P. falciparum. 97 Further results demonstrated that linking an ionizable side chain to position 6 of the 10-N-substituted acridones (65, Figure 30; IC 50 = 44.8 and 77.3 nM against P. falciparum D6 and Dd2 strains, respectively) promotes compound's accumulation in the parasite's food vacuole (FV) and interferes with hemozoin formation; moreover, compound 65 showed synergy with quinine, since only one-third of the individual dosage was needed to have the same effect as when given separately. 98 A similar set of acridones, bearing different 10-Nsubstitutions (allyl, 3-methyl-2-buthenyl, and 1,2-propadienyl) and a chlorine or fluorine atom in positions 1, 2, or 6 of the acridone moiety, was also synthesized and evaluated by Fernandez-Calienes et al Though the best compound (66, Figure 31) was a hit, as it exhibited an IC 50 (0.16 μg/mL against P. falciparum GHA strain) below the 0.2 μg/mL threshold to qualify as such and presented a SI of 112.2 (SI = 99 Furthermore, 66 could not inhibit hemozoin formation; instead, it inhibited the bc 1 complex, still not with the same specificity as the aforementioned acridinediones developed in the WRAIR.…”