Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure−activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo.
Diarylureas are widely
used in self-assembly and supramolecular
chemistry owing to their outstanding characteristics as both H-bond
donors and acceptors. Unfortunately, this bonding property is rarely
applied in the development of urea-containing drugs. Herein, seven
related dimethyl sulfoxide (DMSO) complexes were screened from 12
substrates involving sorafenib and regorafenib, mainly considering
the substitution effect following a robust procedure. All complexes
were structurally confirmed by spectroscopic means and thermal analysis.
Specially, five cocrystals with three deuterated, named sorafenib·DMSO,
donafenib·DMSO, deuregorafenib·DMSO, 6·DMSO,
and 7·DMSO were obtained. The crystal structures
revealed that all host molecules consistently bonded with DMSO in
intermolecular interaction in a 1:1 stoichiometry. However, further
comparison with documented DMSO complexes and parent motifs presented
some arrangement diversities especially for 6·DMSO
which offered a counter-example to previous rules. Major changes in
the orientation of meta-substituents and the packing stability for
sorafenib·DMSO and deuregorafenib·DMSO were rationalized
by theory analysis and computational energy calculation. Cumulative
data implied that the planarization of two aryl planes in diarylureas
may play a crucial role in cocrystallization. Also, a polymorph study
bridged the transformation between these ureas and their DMSO complexes.
A novel scalable four-step process has been developed to improve the synthesis of obeticholic acid (OCA). The key step of this process was the isolation of the amide intermediate, which underwent hydrogenation, basic epimerization, ketone reduction, and amide hydrolysis in a one-pot procedure. The use of efficient single recrystallization for the final purification in this process made the corresponding work-up procedure more concise and environmentally friendly. A kilogram-scale production of OCA following this process could achieve over 70% yield with all impurities controlled below 0.10%.
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