Evaluation of a class of isatinoids identified from a high-throughput screen of human kinase inhibitors as anti-Sleeping Sickness agents.

Dana M Klug,Conor R Caffrey,Lori Ferrins,Guiomar Pérez-Moreno,Pilar Manzano,Michael P Pollastri,María S Martínez-Martínez,Dolores González-Pacanowska,Miguel Navarro,Francisco Gamarro,Rosario Diaz-Gonzalez,Domingo I Rojas-Barros,Veronica Gomez-Pérez,Gloria Ceballos-Pérez,Luis Miguel Ruiz-Pérez,Raquel García-Hernández

doi:10.1371/journal.pntd.0007129

Abstract

New treatments are needed for neglected tropical diseases (NTDs) such as Human African trypanosomiasis (HAT), Chagas disease, and schistosomiasis. Through a whole organism high-throughput screening campaign, we previously identified 797 human kinase inhibitors that grouped into 59 structural clusters and showed activity against T. brucei, the causative agent of HAT. We herein report the results of further investigation of one of these clusters consisting of substituted isatin derivatives, focusing on establishing structure-activity and -property relationship scope. We also describe their in vitro absorption, distribution, metabolism, and excretion (ADME) properties. For one isatin, NEU-4391, which offered the best activity-property profile, pharmacokinetic parameters were measured in mice.

Highlights

Human African trypanosomiasis (HAT), known as sleeping sickness, is a parasitic disease endemic in 36 African countries
We present the results of medicinal chemistry follow-up work on a group of compounds known as isatins
Along with 19 other indications, HAT is designated as a neglected tropical disease (NTD) by the World Health Organization [1, 2]

Summary

Introduction

Human African trypanosomiasis (HAT), known as sleeping sickness, is a parasitic disease endemic in 36 African countries. Caused by two subspecies of the parasite Trypanosoma brucei The parasite crosses the blood-brain barrier (BBB) into the central nervous system (CNS) and causes a variety of neurological and behavioral changes, including disrupted sleeping patterns [2]. HAT is 100% fatal if left untreated, and the available drugs are associated with safety concerns, susceptibility to resistance, and lack of efficacy against all T. brucei subspecies and stages of the disease [4]. There are two new compounds for HAT in clinical trials: fexinidazole and acoziborole [5, 6]. Given the high failure rate of compounds in clinical trials [7], it is prudent to continue to search for compounds to fill the drug discovery pipeline for HAT

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Conclusion