Antimalarial N 1, N 3-Dialkyldioxonaphthoimidazoliums: Synthesis, Biological Activity, and Structure-activity Relationships

Abstract

Here we report the nanomolar potencies of N ¹,N ³-dialkyldioxonaphthoimidazoliums against asexual forms of sensitive and resistant Plasmodium falciparum. Activity was dependent on the presence of the fused quinone-imidazolium entity and lipophilicity imparted by the N¹/N³ alkyl residues on the scaffold. Gametocytocidal activity was also detected, with most members active at IC₅₀ < 1 μM. A representative analog with good solubility, limited PAMPA permeability, and microsomal stability demonstrated oral efficacy on a humanized mouse model of P. falciparum.

Figure 1

(A) Stepwise conversion of SJ000030570 to SJ0000541602, and SJ0000561981 and their EC₅₀ values against the asexual and sexual stages of P. falciparum 3D7. Structures of (B) YM155 and (C) analogs 1–4 and their IC₅₀ values (±SD) against asexual stages of drug sensitive NF54 and drug resistant Dd2 P. falciparum. Parasitemia was assessed by the parasite lactate dehydrogenase assay. Positive controls were chloroquine (IC_50NF54 = 8.2 ± 0.4 nM; IC_50Dd2 = 118 ± 3 nM) and artesunate (IC_50NF54 < 5 nM; IC_50Dd2 = 18.8 ± 1.5 nM).

Scheme 1

Reagents and conditions: (a) R¹-amine, EtOH, rt, 18 h; (b) acetic anhydride, conc. H₂SO₄, rt, 1.5 h; (c) R²-amine, toluene, 45 °C, 4 h; (d) 48% HBr (aq), EtOH + EtOAc, 45 °C, 4 h to rt overnight; (e) NH₃ in MeOH, EtOH, 35 °C, 3 h; (f) 48% HBr (aq), 2 M NaOH (2 drops), EtOH, 50 °C, 1 h.

Figure 2

Systemic exposure of 19 over 24 h following administration of a single oral dose (20 mg/kg) to healthy mice over 24 h. Dotted lines embedded within plot are the IC₅₀ (1×, 3×) values of 19 against CQ sensitive 3D7 P. falciparum.

Figure 3

In vivo efficacy of 19 on the humanized P. falciparum (Pf3D7^0067/N9) mouse model. ED₉₀ is the effective dose (mg/kg) required to reduce parasitemia by 90% on day 7 compared to untreated control animals. It was obtained from nonlinear fitting of log parasitemia on day 7 postinfection versus administered oral dose of 19. ED₉₀ was estimated to be 34 mg/kg.