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.
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.
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.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.