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.

Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign

“…These target families include phosphodiesterases 11], histone deacetylases 12], and kinases 13,14,15,16,17].…”

In vitro evaluation of imidazo[4,5 -c ]quinolin-2-ones as gametocytocidal antimalarial agents

“…11,12,13 A recent publication described the optimization of NVP-BEZ235 for anti-trypanosomal activity and reported promising compounds with improved selectivity over human PI3K and mTOR. 14 Given that these agents have safety profiles consistent with clinical use, we reasoned this series merited further study to optimize their antimalarial properties. Described herein is the rational design, synthesis, and establishment of structure-activity relationships that will facilitate the development of imidazo[4,5- c ]quinolin-2-ones as gametocytocidal agents.…”

Acid‐Promoted Cascade Reaction of N‐(4‐Chloroquinolin‐3‐yl)carbamates with Amines: One‐Pot Assembly of Imidazo[4,5‐c]quinolin‐2‐ones

“…[2] AZD0156, a potent and selective ATM kinase inhibitor, has recently been approved for clinical study for advanced solid tumors (Figure 1). [3] We and other groups reported that NVP-BEZ235, NVP-BGT226, and their analogs exhibited potent anti-parasitic activities against Plasmodium falciparum , [4] Trypanosoma cruzi , [5] Trypanosoma brucei , [5b, 6] Leishmania major , and Leishmania donovani . [5b] …”