3 research outputs found
Optimization of 2āAnilino 4āAmino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity
Novel
antimalarial therapeutics that target multiple stages of
the parasite lifecycle are urgently required to tackle the emerging
problem of resistance with current drugs. Here, we describe the optimization
of the 2-anilino quinazoline class as antimalarial agents. The class,
identified from publicly available antimalarial screening data, was
optimized to generate lead compounds that possess potent antimalarial
activity against <i>P. falciparum</i> parasites comparable
to the known antimalarials, chloroquine and mefloquine. During the
optimization process, we defined the functionality necessary for activity
and improved <i>in vitro</i> metabolism and solubility.
The resultant lead compounds possess potent activity against a multidrug
resistant strain of <i>P. falciparum</i> and arrest parasites
at the ring phase of the asexual stage and also gametocytogensis.
Finally, we show that the lead compounds are orally efficacious in
a 4 day murine model of malaria disease burden
Optimization of 2āAnilino 4āAmino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity
Novel
antimalarial therapeutics that target multiple stages of
the parasite lifecycle are urgently required to tackle the emerging
problem of resistance with current drugs. Here, we describe the optimization
of the 2-anilino quinazoline class as antimalarial agents. The class,
identified from publicly available antimalarial screening data, was
optimized to generate lead compounds that possess potent antimalarial
activity against <i>P. falciparum</i> parasites comparable
to the known antimalarials, chloroquine and mefloquine. During the
optimization process, we defined the functionality necessary for activity
and improved <i>in vitro</i> metabolism and solubility.
The resultant lead compounds possess potent activity against a multidrug
resistant strain of <i>P. falciparum</i> and arrest parasites
at the ring phase of the asexual stage and also gametocytogensis.
Finally, we show that the lead compounds are orally efficacious in
a 4 day murine model of malaria disease burden
Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors
A number
of diazepines are known to inhibit bromo- and extra-terminal
domain (BET) proteins. Their BET inhibitory activity derives from
the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine
framework. Herein we describe a straightforward, modular synthesis
of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole
acts as an effective acetyl-lysine mimetic heterocycle. Structure-based
optimization of this series of compounds led to the development of
potent BET bromodomain inhibitors with excellent activity against
leukemic cells, concomitant with a reduction in c-<i>MYC</i> expression. These novel benzodiazepines therefore represent a promising
class of therapeutic BET inhibitors