9 research outputs found
Structure-Property Optimization of a Series of Imidazopyridines for Visceral Leishmaniasis
Leishmaniasis is a collection of diseases caused by more than 20 Leishmania parasite species that manifest as either visceral, cutaneous, or mucocutaneous leishmaniasis. Despite the significant mortality and morbidity associated with leishmaniasis, it remains a neglected tropical disease. Existing treatments have variable efficacy, significant toxicity, rising resistance, and limited oral bioavailability, which necessitates the development of novel and affordable therapeutics. Here, we report on the continued optimization of a series of imidazopyridines for visceral leishmaniasis and a scaffold hop to a series of substituted 2-(pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles with improved absorption, distribution, metabolism, and elimination properties
Carbonyl-Assisted Iridium-Catalyzed C–H Amination Using 2,2,2-Trichloroethoxycarbonyl Azide
The carbonyl-directed, mono C–H amination of arenes
has
been achieved using [Cp*Ir(III)Cl2]2 as the
catalyst and 2,2,2-trichloroethoxycarbonyl (Troc) azide as an aminating
reagent. The amination proceeds smoothly with a variety of arylcarbonyl
compounds, including alkyl and vinyl arylketones, secondary and tertiary
aryl amides, and acetyl indoles. The resulting ortho-TrocNH arylcarbonyl compounds are easily transformed to the corresponding
free arylamines, aryl carbamates, or aryl ureas. Taking advantage
of the electrophilic nature of both Troc and carbonyl groups in ortho-TrocNH arylcarbonyl compounds, the subsequent cyclization
with dinucleophilic reagents has also been demonstrated. This provides
an efficient strategy for the construction of aryl-fused N-heterocycles
Iridium-Catalyzed Aryl C–H Sulfonamidation and Amide Formation Using a Bifunctional Nitrogen Source
A new strategy for the sequential
formation of aryl and amidyl
C–N bonds is reported. Using trichloroethoxysulfonyl azide
as a bifunctional nitrogen source, Ir-catalyzed aryl C–H sulfonamidation
and subsequent desulfonative amide formation proceed effectively without
any need of oxidants or coupling reagents. This protocol is suitable
for readily available benzamides and stable carboxylates including
primary, secondary, and tertiary alkyl, alkenyl, and phenyl carboxylates,
thereby providing a direct and efficient method for the synthesis
of biologically and chemically useful <i>N</i>-arylamides
Oxidative Cascade Reaction of <i>N</i>‑Aryl-3-alkylideneazetidines and Carboxylic Acids: Access to Fused Pyridines
A versatile silver-promoted
oxidative cascade reaction of <i>N</i>-aryl-3-alkylideneazetidines
with carboxylic acids is reported,
providing a very efficient pathway to functionalized fused pyridines.
This method allows introduction of fused pyridine ring systems to
heterocycles, drugs, and natural products. A mechanistic study revealed
that silver salt is essential for the chemo- and regioselective ring
expansion, sequential oxidative nucleophilic additions, and oxidative
aromatization. This approach represents the first example of the strained <i>N</i>-heterocycles undergoing a cascade reaction with a π
bond and a nucleophile together
Stability-indicating assay method for determination of actarit, its process related impurities and degradation products: Insight into stability profile and degradation pathwaysâ
The stability of the drug actarit was studied under different stress conditions like hydrolysis (acid, alkaline and neutral), oxidation, photolysis and thermal degradation as recommended by International Conference on Harmonization (ICH) guidelines. Drug was found to be unstable in acidic, basic and photolytic conditions and produced a common degradation product while oxidative stress condition produced three additional degradation products. Drug was impassive to neutral hydrolysis, dry thermal and accelerated stability conditions. Degradation products were identified, isolated and characterized by different spectroscopic analyses. Drug and the degradation products were synthesized by a new route using green chemistry. The chromatographic separation of the drug and its impurities was achieved in a phenomenex luna C18 column employing a step gradient elution by high performance liquid chromatography coupled to photodiode array and mass spectrometry detectors (HPLCâPDAâMS). A specific and sensitive stability-indicating assay method for the simultaneous determination of the drug actarit, its process related impurities and degradation products was developed and validated. Keywords: Actarit, Forced degradation, Stability-indicating assay metho
Discovery of 2-aminoimidazole and 2-amino imidazolyl-thiazoles as non-xanthine human adenosine A 3 receptor antagonists: SAR and molecular modeling studies
A small-molecule combinatorial library of 24 compounds with 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives was synthesized using a 2-chloro trityl resin. The generated compound library was tested against all the human adenosine receptors subtypes. The 2-aminoimidazole derivatives (6a-6l) showed weak to moderate affinity towards the human adenosine receptors. Further modification to 2-aminoimidazolyl-thiazole derivatives (12a-12l) resulted in an improvement of affinity at adenosine A 1 , A 2A and A 3 receptor subtypes. Compound 12b was the most potent and selective non-xanthine human adenosine A 3 receptor antagonist of this series. A receptor-based modeling study was performed to explore the possible binding mode of these novel 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives into human adenosine A 1 , A 2A and A 3 receptor subtypes
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Improvement of Aqueous Solubility of Lapatinib-Derived Analogues: Identification of a Quinolinimine Lead for Human African Trypanosomiasis Drug Development
Lapatinib, an approved epidermal growth factor receptor inhibitor, was explored as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Previous work culminated in 1 (NEU-1953), which was part of a series typically associated with poor aqueous solubility. In this report, we present various medicinal chemistry strategies that were used to increase the aqueous solubility and improve the physicochemical profile without sacrificing antitrypanosomal potency. To rank trypanocidal hits, a new assay (summarized in a cytocidal effective concentration (CEC50)) was established, as part of the lead selection process. Increasing the sp3 carbon content of 1 resulted in 10e (0.19 μM EC50 against T. brucei and 990 μM aqueous solubility). Further chemical exploration of 10e yielded 22a, a trypanocidal quinolinimine (EC50: 0.013 μM; aqueous solubility: 880 μM; and CEC50: 0.18 μM). Compound 22a reduced parasitemia 109 fold in trypanosome-infected mice; it is an advanced lead for HAT drug development