5 research outputs found
Enantioselective Total Synthesis of Cannabinoidsî—¸A Route for Analogue Development
A practical
synthetic approach to Δ<sup>9</sup>-tetrahydrocannabinol
(<b>1</b>) and cannabidiol (<b>2</b>) that provides scalable
access to these natural products and should enable the generation
of novel synthetic analogues is reported
Identification of a Hit Series of Antileishmanial Compounds through the Use of Mixture-Based Libraries
From a screening campaign that included
mixture-based libraries containing more than 6 million compounds,
a lead series of bis-cyclic guanidines was identified as the most
promising. Lead optimization resulted in the identification of potent
(IC<sub>50</sub> < 500 nM) and selective compounds within this
series as well as potent and selective monoguanidines
Synthesis and Activity of a New Series of Antileishmanial Agents
We have determined that tetrahydroindazoles
such as <b>1</b> show potent activity against <i>Leishmania
donovani</i>, the causative agent of leishmaniasis. While the
Hsp90 activity and anticancer properties of <b>1</b> have previously
been explored, we present here our efforts to optimize their activity
against <i>L. donovani</i> via the synthesis of novel analogues
designed to probe the hydrophobic pocket of the protozoan Hsp90 orthologue,
specifically through the auspices of functionalization of an amine
embedded into the scaffold
Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases
Pathogenic free-living amoebae (pFLA) can cause life-threatening
central nervous system (CNS) infections and warrant the investigation
of new chemical agents to combat the rise of infection from these
pathogens. Naegleria fowleri glucokinase
(NfGlck), a key metabolic enzyme involved in generating
glucose-6-phosphate, was previously identified as a potential target
due to its limited sequence similarity with human Glck (HsGlck). Herein, we used our previously demonstrated multifragment
kinetic target-guided synthesis (KTGS) screening strategy to identify
inhibitors against pFLA glucokinases. Unlike the majority of previous
KTGS reports, our current study implements a “shotgun”
approach, where fragments were not biased by predetermined binding
potentials. The study resulted in the identification of 12 inhibitors
against 3 pFLA glucokinase enzymesNfGlck, Balamuthia mandrillaris Glck (BmGlck), and Acanthamoeba castellanii Glck (AcGlck). This work demonstrates the utility
of KTGS to identify small-molecule binders for biological targets
where resolved X-ray crystal structures are not readily accessible
Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases
Pathogenic free-living amoebae (pFLA) can cause life-threatening
central nervous system (CNS) infections and warrant the investigation
of new chemical agents to combat the rise of infection from these
pathogens. Naegleria fowleri glucokinase
(NfGlck), a key metabolic enzyme involved in generating
glucose-6-phosphate, was previously identified as a potential target
due to its limited sequence similarity with human Glck (HsGlck). Herein, we used our previously demonstrated multifragment
kinetic target-guided synthesis (KTGS) screening strategy to identify
inhibitors against pFLA glucokinases. Unlike the majority of previous
KTGS reports, our current study implements a “shotgun”
approach, where fragments were not biased by predetermined binding
potentials. The study resulted in the identification of 12 inhibitors
against 3 pFLA glucokinase enzymesNfGlck, Balamuthia mandrillaris Glck (BmGlck), and Acanthamoeba castellanii Glck (AcGlck). This work demonstrates the utility
of KTGS to identify small-molecule binders for biological targets
where resolved X-ray crystal structures are not readily accessible