title: Spirocyclic chromanes exhibit antiplasmodial activities and inhibit all intraerythrocytic life cycle stages.
abstract: We screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile. We have performed a limited structure-activity-relationship study with commercially available chromanes preserving the spirocyclic motif. Our evaluation of stage specificities of UCF 201 indicated that the compound is early-acting in blocking parasite development at ring, trophozoite and schizont stages of development as well as merozoite invasion. SPC is an attractive lead candidate scaffold because of its ability to act on all stages of parasite's aexual life cycle unlike current antimalarials.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
authors.forename: Bracken F
authors.initials: BF
authors.lastname: Roberts
authors.affiliation: Department of Chemistry and Chemical Biology and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Iredia D
authors.initials: ID
authors.lastname: Iyamu
authors.affiliation: Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Sukjun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Lee
authors.affiliation: Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Ayong
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, FL, USA.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.affiliation: Department of Chemistry, University of Central Florida, Orlando, FL, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Chemistry and Chemical Biology and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Manetsch
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA. Electronic address: dchak@ucf.edu.
authors.forename: Debopam
authors.initials: D
authors.lastname: Chakrabarti
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000469:parasitology*; D008018:Life Cycle Stages / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D052940:Merozoites / Q000187:drug effects / Q000254:growth & development; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D052939:Schizonts / Q000187:drug effects / Q000254:growth & development; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D053058:Trophozoites / Q000187:drug effects / Q000254:growth & development
chemical_list: D000962:Antimalarials; D001572:Benzofurans; D013141:Spiro Compounds; C000612065:UCF 201
keywords: Antimalarials; Antiplasmodials; Natural-product-like compounds; Novel mechanism of action; Spirocyclic chromane