title: 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.
authors.forename: William
authors.initials: W
authors.lastname: Devine
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Woodring
authors.forename: Uma
authors.initials: U
authors.lastname: Swaminathan
authors.forename: Emanuele
authors.initials: E
authors.lastname: Amata
authors.forename: Gautam
authors.initials: G
authors.lastname: Patel
authors.affiliation: ‡Division of Parasitology, Department of Microbiology, New York University School of Medicine, 341 E. 25th St., New York, New York 10010, United States.
authors.forename: Jessey
authors.initials: J
authors.lastname: Erath
authors.affiliation: §Experimental Therapeutics, Walter Reed Army Institute for Research, 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
authors.forename: Norma E
authors.initials: NE
authors.lastname: Roncal
authors.affiliation: §Experimental Therapeutics, Walter Reed Army Institute for Research, 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Lee
authors.affiliation: §Experimental Therapeutics, Walter Reed Army Institute for Research, 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Leed
authors.affiliation: ‡Division of Parasitology, Department of Microbiology, New York University School of Medicine, 341 E. 25th St., New York, New York 10010, United States.|⊥Anti-Infectives Screening Core, New York University School of Medicine, New York, New York 10010, United States.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: ∥Department of Cellular Biology, University of Georgia, Athens, Georgia 30602, United States.
authors.forename: Kojo
authors.initials: K
authors.lastname: Mensa-Wilmot
authors.affiliation: §Experimental Therapeutics, Walter Reed Army Institute for Research, 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sciotti
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006131:Growth Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D010271:Parasites / Q000187:drug effects* / Q000254:growth & development*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D006131:Growth Inhibitors; D011799:Quinazolines