Antibiotic chloramphenicol (CLM) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino-acid analogues of CLM. The L-histidyl analogue binds to the ribosome with the affinity exceeding that of CLM by 10 fold. Several of the newly synthesized analogues were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CLM. However, the inhibitory properties of the semi-synthetic CLM-analogues did not correlate with their affinity and in general, the amino-acid analogues of CLM were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogues showed that CLM derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.

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2-Benzylbenzimidazole derivatives comprise a small but forensically significant group of synthetic opioids. In humans, the metabolism of some members of this group is extensive, with little or none of the parent compound remaining. The recent detection of the 2-benzylbenzimidazole derivative, etazene (etodesnitazene), in products seized in Russia required the detection of its metabolites in biofluids for forensic toxicology purposes. Using GC-MS and HRAM LC-MS, eight etazene metabolites were found in the urine and serum of rats. These were tentatively identified as products of N-deethylation, O-deethylation, hydroxylation or N-oxidation of benzimidazole moiety and combinations of these processes. The parent substance and its O-deethylated metabolite prevailed in rat serum, while in urine, the level of etazene was low compared to N,O-deethylated and N-deethylated with hydroxylation metabolites. Glucuronidated, sulfonated and glutathionated forms were not found. Taking into account reports on the study of the metabolism of other 2-benzylbenzimidazole derivatives in humans, it may be concluded that the mono-deethylated and mono-hydroxylated metabolites are suitable as target analytes in urine.

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