title: Establishment of a structure-activity relationship of 1H-imidazo[4,5-c]quinoline-based kinase inhibitor NVP-BEZ235 as a lead for African sleeping sickness.
abstract: Compound NVP-BEZ235 (1) is a potent inhibitor of human phospoinositide-3-kinases and mammalian target of rapamycin (mTOR) that also showed high inhibitory potency against Trypanosoma brucei cultures. With an eye toward using 1 as a starting point for anti-trypanosomal drug discovery, we report efforts to reduce host cell toxicity, to improve the physicochemical properties, and to improve the selectivity profile over human kinases. In this work, we have developed structure-activity relationships for analogues of 1 and have prepared analogues of 1 with improved solubility properties and good predicted central nervous system exposure. In this way, we have identified 4e, 9, 16e, and 16g as the most promising leads to date. We also report cell phenotype and phospholipidomic studies that suggest that these compounds exert their anti-trypanosomal effects, at least in part, by inhibition of lipid kinases.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: João D
authors.initials: JD
authors.lastname: Seixas
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Luengo-Arratta
authors.forename: Rosario
authors.initials: R
authors.lastname: Diaz
authors.forename: Manuel
authors.initials: M
authors.lastname: Saldivia
authors.forename: Domingo I
authors.initials: DI
authors.lastname: Rojas-Barros
authors.forename: Pilar
authors.initials: P
authors.lastname: Manzano
authors.forename: Silvia
authors.initials: S
authors.lastname: Gonzalez
authors.forename: Manuela
authors.initials: M
authors.lastname: Berlanga
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.forename: Miguel
authors.initials: M
authors.lastname: Navarro
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
mesh_terms: D003603:Cytotoxins / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D062105:Molecular Docking Simulation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010743:Phospholipids / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D012995:Solubility; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D003603:Cytotoxins; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010743:Phospholipids; D011804:Quinolines; D014344:Trypanocidal Agents; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib