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Abstract With the aim of constructing hydrogen‐bonding networks in synthetic complexes, two new ligands derived fromcis,cis‐1,3,5‐triaminocyclohexane (TACH) have been prepared that feature pendant pyrrole or indole rings as outer‐sphere H‐bond donors. The TACH framework offers a facial arrangement of threeN‐donors, thereby mimicking common coordination motifs in the active sites of nonheme Fe and Cu enzymes. X‐ray structural characterization of a series of CuI‐X complexes (X=F, Cl, Br, NCS) revealed that these neutral ligands (H3LR, R=pyrrole or indole) coordinate in the intended facialN3manner, yielding four‐coordinate complexes with idealizedC3symmetry. The N−H units of the outer‐sphere heterocycles form a hydrogen‐bonding cavity around the axial (pseudo)halide ligand, as verified by crystallographic, spectroscopic, and computational analyses. Treatment of H3Lpyrroleand H3Lindolewith divalent transition metal chlorides (MIICl2, M=Fe, Cu, Zn) causes one heterocycle to deprotonate and coordinate to the M(II) center, giving rise to tetradentate ligands with two remaining outer‐sphere H‐bond donors. Further ligand deprotonation is observed upon reaction with Ni(II) and Cu(II) salts with weakly coordinating counteranions. The reported complexes highlight the versatility of TACH‐based ligands with pendant H‐bond donors, as the resulting scaffolds can support multiple protonation states, coordination geometries, and H‐bonding interactions.
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Synthesis, Biological Evaluation, and Computational Analysis of Biaryl Side‐Chain Analogs of Solithromycin
Abstract There is an urgent need for new antibiotics to mitigate the existential threat posed by antibiotic resistance. Within the ketolide class, solithromycin has emerged as one of the most promising candidates for further development. Crystallographic studies of bacterial ribosomes and ribosomal subunits complexed with solithromycin have shed light on the nature of molecular interactions (π‐stacking and H‐bonding) between from the biaryl side‐chain of the drug and key residues in the 50S ribosomal subunit. We have designed and synthesized a library of solithromycin analogs to study their structure‐activity relationships (SAR) in tandem with new computational studies. The biological activity of each analog was evaluated in terms of ribosomal affinity (Kddetermined by fluorescence polarization), as well as minimum inhibitory concentration assays (MICs). Density functional theory (DFT) studies of a simple binding site model identify key H‐bonding interactions that modulate the potency of solithromycin analogs.
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- Award ID(s):
- 1665407
- PAR ID:
- 10360295
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemMedChem
- Volume:
- 16
- Issue:
- 21
- ISSN:
- 1860-7179
- Format(s):
- Medium: X Size: p. 3368-3373
- Size(s):
- p. 3368-3373
- Sponsoring Org:
- National Science Foundation
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