Antimalarial Dibenzannulated Medium-Ring Keto Lactams

Abstract

We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5H-dibenzo[b,g]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD_7.4 values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 μg/mL at pH 6.5). The more polar compounds in the series (LogD_7.4 values of <2) had the best metabolic stability (CL_int values of <50 μL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC₅₀ values >30 μM, and there was no correlation between antiplasmodial activity and cytotoxicity. The four most potent compounds had Plasmodium falciparum IC₅₀ values of 4.2 to 9.4 nM and in vitro selectivity indices of 670 to >12,000. They were more than 4 orders-of-magnitude less potent against three other protozoal pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani) but did have relatively high potency against Toxoplasma gondii, with IC₅₀ values ranging from 80 to 200 nM. These keto lactams are converted into their poorly soluble 4(1H)-quinolone transannular condensation products in vitro in culture medium and in vivo in mouse blood. The similar antiplasmodial potencies of three keto lactam-quinolone pairs suggest that the quinolones likely contribute to the antimalarial activity of the lactams.

Keywords: SAR; antimalarial; lactams; medium rings; quinolones.

Figure 1.

Witkop–Winterfeldt oxidation of indole 1 to medium-ring keto lactam 2 and conversion of 2 to 4(1H)-quinolone 3 by Camps transannular condensation.

Figure 2.

Plasma concentrations of 28 in Swiss mice following IV and oral administration. Concentrations were below the limit of quantitation (LLQ) after 60 min following IV dosing. IV vehicle: 5% (v/v) DMSO in 0.9% (w/v) saline containing 20% (w/v) Trappsol; PO vehicle: 7% (v/v) Tween80 and 3% (v/v) ethanol in Milli-Q water.

Scheme 1.. Syntheses of 6–9^a

^aReagents and conditions: (a) O₃, 4–5:1 DCM/MeOH, −78 °C, 5–25 min, then Me₂S, −78 °C to rt, 2 h.

Scheme 2.. Syntheses of 14–16^a

^aReagents and conditions: (a) see Scheme 1 (a).

Scheme 3.. Syntheses of 17, 22–33, and 36^a

^aReagents and conditions: see Scheme 1 (a).

Scheme 4.. Syntheses of 18–21^a

^aReagents and conditions: (a) see Scheme 1 (a); (b) 1 N aq. NaOH, EtOH, 60 °C, 24 h; (c) HOBt, EDCl, DMA, rt, 24 h, then conc. NH₄OH, rt, 5 h; (d) morpholine, HOBt, EDCl, DMA, rt, 24 h.

Scheme 5.. Syntheses of 34, 35, and 37^a

^aReagents and conditions: (a) Boc anhydride, DMAP, DCM, rt, 12 h; (b) see Scheme 1 (a); (c) 1 M HCl, THF, rt, 12 h.

Scheme 6.. Syntheses of 10–13^a

^aReagents and conditions: (a) methanesulfonyl chloride, Et₃N, DCM, rt, 12 h; (b) NaBH₄, 5:1 tert-BuOH/MeOH, reflux, 12 h; (c) hydroxylamine hydrochloride, pyridine, EtOH, rt, 24 h; (d) methoxyamine hydrochloride, pyridine, MeOH, rt, 24 h.