Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery

Abstract

Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors’ biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

“…Most importantly, our cross-screening campaign of lapatinib-derived analogs has produced multiple active compounds against one or more parasites in a single library [15]. We therefore tested our new analogs against the causative agents for Chagas disease ( Trypanosoma cruzi ), leishmaniasis ( Leishmania major ), and malaria ( Plasmodium falciparum ).…”

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Furthermore, phylogenetic analysis shows an ancestral relationship between multiple human and T. brucei kinases, suggesting that known kinase inhibitors may inhibit several kinases between the two species . Considering the druggability of many kinases, repurposing of human protein kinases has proven to be a strong strategy for the discovery of new antitrypanosomal agents …”

Novel Effects of Lapatinib Revealed in the African Trypanosome by Using Hypothesis-Generating Proteomics and Chemical Biology Strategies

“…Further, we note that the 4-anilinoquinazoline scaffold of lapatinib is present in other marketed drugs (e.g., gefitinib, erlotinib). Considering these facts, we have initiated projects to improve potency of the 4-anilinoquinazole scaffold and its derivatives against trypanosomes with great success (6)(7)(8). The next stage of the drug development process, which is ongoing, involves improvement of pharmacokinetic properties as well as adsorption, distribution, metabolism, and excretion (ADME) in vertebrate animals, for example, increasing central nervous system (CNS) penetrance.…”