Analogues of the Antibiotic Chloramphenicol. Synthesis, Docking, and Biological Properties of Products of N- and O-Acetylation of (1S,2S)-2-Amino-1-(4-nitrophenyl)propane-1,3-diol (D-(–)threoamine)

Objective: The objective of this study, taking into account the available data on the biological activity of various chloramphenicol analogues, is to search for new effective compounds with antibacterial and fungicidal properties among N- and O-acyl derivatives of CAM, as well as to conduct a docking study on four different targets to clarify the possible further direction of research on the synthesis of biologically active chloramphenicol analogues. Methods: Antibacterial and antifungal activity were determined by the agar diffusion method. Taking into account the relevance of the search for new effective antiviral, antitumor and neurotropic drugs, a docking study of the synthesized compounds (ligands) was carried out in relation to the complex of RNA-dependent RNA polymerase (RdRp) with the NSP7 and NSP8 proteins of the SARS-CoV-2 virus, the kinase domain of the human epidermal growth factor receptor (EGFR), doubly phosphorylated human mitogen-activated protein kinase 14 (MAPK14) in a complex with the activator of the transcription factor (ATF2) and human monoamine oxidase B in a complex with 2-(2-benzofuranyl)-2 imidazoline (2-BFI). Results and Discussion: The results of the docking analysis of the studied compounds showed that the most active compound, 3-hydroxy-3-(4-nitrophenyl)-2-{[(2-phenylquinolin-4-yl)carbonyl]amino}propyl 2-phenylquinoline-4-carboxylate, strongly interacts with the SARS-CoV-2 RNA-dependent RNA polymerase has a binding energy ΔG0 = –10.435 kcal/mol. The interaction energy for the human EGFR kinase domain ΔG0 = –12.633 kcal/mol, while for the phosphorylated human MAPK14, it is –13.436 kcal/mol. A number of the studied compounds exhibited high antimicrobial activity against Staphylococcus aureus and Bacillus subtilis, but significantly less against a strain of Escherichia coli. The most active benzofuran-based derivative demonstrated relatively high activity against S. aureus, B. subtilis, and Candida albicans, comparable to the control compounds. Conclusions: The study demonstrates the feasibility of using structural analogs. Biological studies have identified antibiotic analogs that exhibit relatively high activity against S. aureus, B. subtilis, and C. albicans. Based on docking analysis data, new chloramphenicol analogs can be predicted to exhibit antiprotein kinase activity against the human epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK). The antibacterial and antifungal properties of the synthesized chloramphenicol analogues create the preconditions for the development of new effective drugs for the treatment of bacterial and fungal infections, and the results of docking analysis also indicate the possibility of creating antitumor drugs.