Tractable Quinolone Hydrazides Exhibiting Sub-Micromolar and Broad Spectrum Antitrypanosomal Activities

Abstract

Nagana and Human African Trypanosomiasis (HAT), caused by (sub)species of Trypanosoma, are diseases that impede human and animal health, and economic growth in Africa. The few drugs available have drawbacks including suboptimal efficacy, adverse effects, drug resistance, and difficult routes of administration. New drugs are needed. A series of 20 novel quinolone compounds with affordable synthetic routes was made and evaluated in vitro against Trypanosoma brucei and HEK293 cells. Of the 20 compounds, 12 had sub-micromolar potencies against the parasite (EC₅₀ values=0.051-0.57 μM), and most were non-toxic to HEK293 cells (CC₅₀ values>5 μM). Two of the most potent compounds presented sub-micromolar activities against other trypanosome (sub)species (T. cruzi and T. b. rhodesiense). Although aqueous solubility is poor, both compounds possess good logD values (2-3), and either robust or poor microsomal stability profiles. These varying attributes will be addressed in future reports.

Keywords: Drug; Hydrazide; Nagana; Quinolone; Trypanosomiasis.

Figure 1.

Drugs registered for the treatment of HAT and Nagana.

Figure 2.

Previous identified hit compounds.

Figure 3.

Graphical summary of SAR.

Scheme 1.

Synthetic route to target compounds. Reagents and conditions: (a) Diethyl ethoxymethylenemalonate, ethanol, reflux, 6 h; (b) Diphenylether, 240 C, 45 min; (c) K₂CO₃ (2 equiv), CHCl₃: THF (2: 1), ‘alkyl halide (1.5 equiv), reflux, 24 h; (d) hydrazine, ethanol, reflux, 24–36 h; (v) aldehyde, ethanol, acetic acid, reflux 24–48 h.