Multiparameter ranking of carbazoles for anti-trypanosome lead discovery

TL;DR

Researchers developed a new scoring system to rank carbazole compounds for their potential to treat human African trypanosomiasis, a neglected disease.

Contribution

A multiparametric score called CHLE was introduced to evaluate and rank curaxins for anti-trypanosome lead discovery.

Findings

CBL0137 showed efficacy in mice due to high AUC0–6h:DTC90 ratio, transferrin endocytosis block, and protein synthesis inhibition.

Hydroxylation of carbazole in CBL0137 prevented transferrin endocytosis inhibition.

CHLE scores predicted curaxin performance in mice and could be adapted for other drug scaffolds.

Abstract

The criteria for the progression of hits in the discovery of leads for human African trypanosomiasis (HAT), a neglected disease caused by the microbial eukaryote Trypanosoma brucei, are not standardized. Hits are advanced upon meeting thresholds for drug-like molecules. Following those principles, pharmacokinetics (Cmax and AUC0–6h) and anti-trypanosome characteristics predicted the arrest of T. brucei proliferation in mice by three curaxins. Unexpectedly, while CBL0137 cured HAT in a mouse model, CBL0174 and CBL0187—structural analogs of CBL0137 with similar drug-like properties—failed to control T. brucei division. We here propose an alternative strategy that integrates physicochemical, metabolic, pharmacokinetic, pharmacodynamic, tissue distribution, and trypanocidality parameters into calculating a score for ranking compounds in hit-to-lead campaigns. Data from our studies of curaxins support the feasibility of this goal. Serum dropped the anti-trypanosome potency of CBL0174 and CBL0187 considerably. Delayed trypanocidal concentrations (DTC25 and DTC90) were used to study modes of curaxin actions in trypanosomes. Efficacy of CBL0137 in mice correlated with (i) a high AUC0–6h: DTC90 ratio, (ii) blocking of transferrin endocytosis, and (iii) the inhibition of protein synthesis. Hydroxylation of the carbazole prevented CBL0137 from inhibiting endocytosis of transferrin. The multiparametric score “Curaxin HAT lead efficacy (CHLE)” score was calculated using pharmacokinetic, physicochemical, metabolic, brain exposure, and pharmacodynamic data; CBL0137 was the highest scoring hit. Complementing these observations and predictive of performance of curaxins in mice, CBL0137, but not CBL0174 or CBL0187, was trypanocidal after the exposure of trypanosomes to AUC0–6h amounts of the hits for 6 hours in vitro. We discuss a role for CHLE scores in ranking curaxins for anti-HAT lead discovery. The principles used to develop CHLE scores may be used to calculate new ones for other scaffolds during the discovery of leads for HAT or other infectious diseases.

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