Antimalarial activity of new floxacrine-related acridinedione derivatives: studies on blood schizontocidal action of potential candidates againstP. berghei in mice andP. falciparum in vivo and in vitro

Abstract

Deoxyfloxacrine derivatives (1-hydrazone: S 83 0083; 1-imine: S 84 7277) and floxacrine derivatives (10-methoxy-floxacrine: L 84 7667; 1-imine: L 84 7693) selected from a series of newly synthesized 3-aryl-7-chloro-3,4-dihydro-1,9(2H,10H)-acridinediones were evaluated for blood schizontocidal activities in mice infected with asexual stages of various drug-resistant lines of P. berghei and in New World monkeys infected with blood schizonts of different chloroquine-resistant strains of P. falciparum. All compounds tested showed high activity against drug-resistant lines of P. berghei (ED50: 1.0-4.4 mg/kg x 5, per os) and were distinctly superior in their antimalarial potency to floxacrine. Compounds L 84 7667 and L 84 7693 proved to be highly active against the FCBR strain of P. falciparum in vitro (IC50: 0.73-1.78 nmol); they effected temporary clearance of parasitemias due to the Palo Alto strain of P. falciparum in squirrel monkeys at oral doses of 15 mg/kg given daily for 5 consecutive days. Compounds S 83 0083 and S 84 7277, showing moderate in vitro effects (12.9-24.8 nmol), cleared parasitemias of the FCBR strain of P. falciparum in owl monkeys at oral doses of 20 mg/kg (S 84 7277) given daily for 5 or 7 consecutive days (follow-up period, 17 and 30 days, respectively) or at doses of 20 mg/kg (x 4) (S 83 0083) followed by doses of 40 mg/kg (x 3) within a follow-up period of 30 days. These observations suggest that the range of doses required for the cure of established P. falciparum infections is probably too large to cover infections with strains of the least susceptibility and might evoke toxic reactions by the potential candidates tested.

Plasmodium falciparum PfA-M1 aminopeptidase is trafficked via the parasitophorous vacuole and marginally delivered to the food vacuole

“…Parasites (FCBR strain of P. falciparum [12]) were continuously cultured in erythrocytes of blood group A + in heat inactivated human serum as described previously [13]. Cultures were synchronized and trophozoite infected erythrocytes (iRBC), 28-30 hours post infection, were enriched to a parasitaemia of more than 90% by gel flotation [14].…”

Falcipain Inhibition as a Promising Antimalarial Target

“…Based on acridinediones with antimalarial activity [89] and trying to eliminate their toxicity, the carbonyl group was replaced with a sulfur or sulfone isoster. Thus, a series of phenothiazin-4-ones and phenothiazin-4-one-5,5-dioxides were designed and evaluated as falcipain inhibitors by Dominguez et al, [90] (Fig.…”

Acridine and Acridinones: Old and New Structures with Antimalarial Activity

“…Those reasons led to substantial efforts to identify an analogue of floxacrine without those drawbacks [30, 32-34]. A QA-Floxacrine , hybrid, WR 243251, (1 E )-7-chloro-3-(2,4-dichlorophenyl)-1-{[3-(dimethylamino)propyl]imino}-1,3,4,10-tetrahydroacridin-9(2 H )-one (23 , Fig.…”