The effect of N-alkyl modification on the antimalarial activity of 3- hydroxypyridin-4-one oral iron chelators

Abstract

The antimalaria effect of iron chelators is attributed to their interaction with a labile iron pool within parasitised erythrocytes, and it was postulated that increased affinity to iron as well as increased lipophilicity may improve antimalarial activity. In the present study we have examined the antimalarial effect of 3- hydroxypyridin-4-ones, a family of bidentate orally effective iron chelators whose lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. A significant dose-related suppression of Plasmodium falciparum cultures was observed with all drugs tested in vitro at concentrations of 5 mumol/L or higher. In contrast, there was a clear segregation of the in vivo effect on P berghei in rats (300 mg/kg/d subcutaneous) into two categories: compounds CP20, 38, and 40 failed to suppress malaria, whereas CP51, 94, and 96 had a strong antimalarial effect, similar or better than deferoxamine. There was a close linear correlation between the suppression of peak parasite counts and the reduction in hepatic nonheme iron induced by the various drugs tested (r = .9837). The most lipophilic compounds were also the most effective in suppressing malaria and in depleting hepatic iron stores. These data indicate that 3-hydroxypyrydin-4-ones are able to suppress malaria in vivo and in vitro. Because lipid solubility is an important determinant of antimalarial action, our study provides useful information regarding the selection of orally effective iron-chelating compounds that may be suitable for clinical application as antimalarial agents.

Assessment of the effect of the oral iron chelator deferiprone on asymptomatic Plasmodium falciparum parasitemia in humans.

“…For example, deferiprone levels of 5-15 mol/L produced only 38-52% inhibition of parasite growth in vitro. 11,12 Thus, the findings serve to emphasize that sustained exposure to effective concentrations of an iron-chelating agent is required for an anti-plasmodial effect.…”

“…Our pharmacokinetic study indicated that the subjects achieved a mean peak plasma deferiprone level of 108.9 mol/L after a dose of 25 mg/kg, which is within the range of concentrations that result in 85-100% inhibition of parasite growth in vitro. [11][12][13] While the peak deferiprone levels were in the range expected for effective anti-plasmodial activity, the drug was administered every 6-8 hr during the study and the t 1/2 was only 92 min. Considering the findings of other investigators, 11,12 these pharmacokinetic results suggest that plasma concentrations of deferiprone with effective anti-malarial activity were maintained only for intermittent brief periods during the therapy.…”

“…Continuous exposure to deferiprone concentrations in the range of 5-100 mol/L has resulted in 52-100% inhibition of the growth of P. falciparum cultured in erythrocytes in vitro. [11][12][13] While these studies suggest that the administration of deferiprone to humans at doses currently used in trials in patients with iron overload might produce an anti-malarial ef-fect, the results of the single reported study of deferiprone treatment of malaria in animals proved to be negative. A deferiprone dose of 300 mg/kg/day in three divided doses administered intraperitoneally for 13 days did not suppress P. berghei infection in six female Wistar rats.…”

New 4(1H)-Pyridinone Derivatives as Analgesic Agents

“…The narcotic analgesics are potent but have several undesirable actions and their use leads to dependence. It is well known that 4(1H)-pyridinone derivatives have shown various pharmacological effects such as antibacterial [1,2], antifungal [3], antimalarial [4,5], cardiotonic agents [6], antihypertensive [7], antineoplastic [8][9][10][11], anti-inflammatory [12], analgesic effects [13][14][15][16], and favourable effect in Parkinson's disease [17,18]. Especially 1,2-dimethyl and 1,2-diethyl-3hydroxy-4(1H)-pyridinone derivatives have shown chelating effect [19][20][21][22][23].…”

The discovery, synthesis and antimalarial evaluation of natural product-based polyamine alkaloids

“…[25][26][27][28][29] Importantly, the antimalarial activity of iron chelating agents has been established both in vitro and in vivo. [28][29][30][31] In addition, compound 1 has been shown to exhibit significant protective effects against DNA damage by hydroxyl radicals generated from the Fenton reaction via iron chelation, as well as free radical-scavenging activity. 23 Encouraged by the antimalarial data of 1, we subsequently performed substructure searching on an in-house natural product library using the spermidine fragment in an attempt to identify additional polyamine alkaloids for antiplasmodial evaluation.…”