A practical access
to four new halogen-substituted pyrrole building
blocks was realized in two to five synthetic steps from commercially
available starting materials. The target compounds were prepared on
a 50 mg to 1 g scale, and their conversion to nanomolar inhibitors
of bacterial DNA gyrase B was demonstrated for three of the prepared
building blocks to showcase the usefulness of such chemical motifs
in medicinal chemistry.
Fluorinated alcohols as solvents strongly influence and direct chemical reaction through donation of strong hydrogen bonds while being weak acceptors. We used 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the activating solvent for a nitric acid and FeCl 3 -catalyzed aerobic oxidation of secondary alcohols to ketones. Reaction proceeded selectively with excellent yields with no reaction on the primary alcohol group. Oxidation of benzyl alcohols proceeds selectively to aldehydes with only HNO 3 as the catalyst, while reaction on tertiary alcohols proceeds through dehydration and dimerization. A mechanistic study showed in situ formation of NOCl that converts alcohol into alkyl nitrite, which in the presence of Fe 3+ ions and fluorinated alcohol decomposes into ketone. The study indicates that iron(III) acts also as the single-electron transfer catalyst in regeneration of NOCl reactive species.
Benzyl alcohols were oxidized with oxygen to aldehydes in excellent yields with high selectivities at room temperature. Dual catalysis was operative with HNO3 as the oxidant and precursor of the nitrogen oxides and with the use of 1,1,1,3,3,3‐hexafluoro‐2‐propanol as a template catalyst and solvent. Fluorinated alcohols also increased the selectivity by inhibiting further oxidation to benzoic acids. Activation of nitric acid catalyzed aerobic oxidation by the fluorinated solvent made the use of 2,2,6,6‐tetramethylpiperidin‐1‐oxyl (TEMPO) or a metal catalyst superfluous.
(1) Background: The voltage-gated potassium channel KV10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling and medicinal chemistry approaches to prepare a novel structural class of KV10.1 inhibitors. Whole-cell patch clamp experiments were used to investigate potency, selectivity, kinetics and mode of inhibition. Anticancer activity was determined using 2D and 3D cell-based models. (3) Results: The virtual screening hit compound ZVS-08 discovered by 3D pharmacophore modelling exhibited an IC50 value of 3.70 µM against KV10.1 and inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structural optimization resulted in the most potent KV10.1 inhibitor of the series with an IC50 value of 740 nM, which was potent on the MCF-7 cell line expressing high KV10.1 levels and low hERG levels, induced significant apoptosis in tumour spheroids of Colo-357 cells and was not mutagenic. (4) Conclusions: Computational ligand-based drug design methods can be successful in the discovery of new potent KV10.1 inhibitors. The main problem in the field of KV10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods.
We have developed compounds with a promising activity
against Acinetobacter baumannii and Pseudomonas
aeruginosa, which are both on the WHO priority list
of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold
improved aqueous solubility, a 10-fold improved inhibition of topoisomerase
IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of
human topoisomerase IIα, and no cross-resistance to novobiocin.
Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed
their binding to the ATP-binding pocket of the GyrB subunit. In further
optimization steps, solubility, plasma free fraction, and other ADME
properties of 27 were improved by fine-tuning of lipophilicity.
In particular, analogs of 27 with retained anti-Gram-negative
activity and improved plasma free fraction were identified. The series
was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial
toxicity, and possessed no ion channel liabilities.
An efficient method for the synthesis of aiodoketones from allylic alcohols and elemental iodine is reported. We show in this paper that the isomerization of allylic alcohols catalyzed by iridium(III) complexes can be combined with an aerobic oxidative iodination protocol, resulting in a straightforward method for the synthesis of a wide range of a-iodoketones as single constitutional isomers and in high yields under mild reaction conditions.
A new series of dual low nanomolar benzothiazole inhibitors
of
bacterial DNA gyrase and topoisomerase IV were developed. The resulting
compounds show excellent broad-spectrum antibacterial activities against
Gram-positive
Enterococcus faecalis
,
Enterococcus faecium
and multidrug
resistant (MDR)
Staphylococcus aureus
strains [best compound minimal inhibitory concentrations (MICs):
range, <0.03125–0.25 μg/mL] and against the Gram-negatives
Acinetobacter baumannii
and
Klebsiella
pneumoniae
(best compound MICs: range, 1–4
μg/mL). Lead compound
7a
was identified with favorable
solubility and plasma protein binding, good metabolic stability, selectivity
for bacterial topoisomerases, and no toxicity issues. The crystal
structure of
7a
in complex with
Pseudomonas
aeruginosa
GyrB24 revealed its binding mode at the
ATP-binding site. Expanded profiling of
7a
and
7h
showed potent antibacterial activity against over 100 MDR
and non-MDR strains of
A. baumannii
and several other Gram-positive and Gram-negative strains. Ultimately,
in vivo efficacy of
7a
in a mouse model of vancomycin-intermediate
S. aureus
thigh infection was also demonstrated.
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