Hybrids of antibiotics inhibiting protein synthesis. Synthesis and biological activity

Abstract

Four hybrid antibiotics combining structural features of chloramphenicol (1a), sparsomycin (2b), lincomycin (5c), and puromycin (6d)--lincophenicol (1c), chloramlincomycin (5a), sparsolincomycin (5b), and sparsopuromycin (6b)--were synthesized. They were investigated as inhibitors of several partial reactions of procaryotic and eucaryotic protein synthesis as well as potential antimicrobial agents. Lincophenicol (1c) was active as inhibitor of Escherichia coli ribosomal peptidyltransferase-catalyzed puromycin reaction. Both lincophenicol (1c) and sparsophenicol (1b) inhibited the binding of the iodophenol analogue of sparsomycin to E. coli ribosomes. The results are discussed in terms of a retro-inverso hypothesis advanced earlier for interpretation of biological activity of chloramphenicol (1a) and sparsophenicol (1b). Chloramlincomycin (5a) suppressed the growth of Streptococcus pyogenes with MIC 6.25 micrograms/mL.

Chloramphenicol Derivatives as Antibacterial and Anticancer Agents: Historic Problems and Current Solutions

“…Whether the latter finding is related to the low lipophilic character of sparsophenicol or inability of this agent to target the eukaryotic cell was never explored. Another CAM hybrid combining structural features of CAM and lincomycin, named lincophenicol (compound 37 ), was found to share similar activity profiles with CAM in inhibiting the puromycin reaction, poly(Phe) synthesis, and the growth of bacterial cells [ 113 ]. Both compounds 36 and 37 were not further investigated as drugs but rather used as tools for the verification of the retro-inverso hypothesis.…”

Natural Product Hybrids as New Leads for Drug Discovery

“…As already mentioned, one of the main problems in the treatment of infectious diseases caused by bacteria is the development of resistance of these organisms to the available antiinfective agents. Therefore several hybrids 340 – 344 were prepared in which the structural entities of well‐known antibiotics such as chloramphenicol ( 336 ) (from Streptomyces venezuelae ), sparsomycin ( 337 ) (from Streptomyces sparsogenes ), lincomycin ( 338 ) (from Streptomyces lincolnensis ), and puromycin ( 339 ) (from Streptomyces alboniger )115 were combined. The synthesis involved a simple amidation of either the appropriate carboxylic acids or their active esters with suitable amines.…”

Speculative strategies for new antibacterials: all roads should not lead to Rome

“…In the early 1980s, Zemlička and Bhuta 55 reported synthesis of sparsophenicol ( Figure 5), derived from chloramphenicol and sparsomycin (a product of Streptomyces sparsogenes), which strongly inhibited protein synthesis in vitro, but was devoid of antibacterial activity. A decade later, Zemlička et al 56 reported synthesis of chloramlincomycin ( Figure 6), in which the aliphatic arm of chloramphenicol is linked to the pyranoside of clindamycin; and lincophenicol ( Figure 6), in which most of the chloramphenicol molecule is linked to the pyrrolidine of clindamycin. Neither hybrid molecule inhibited polyphenylalanine biosynthesis in an in vitro system prepared from Escherichia coli though, surprisingly, chloramlincomycin had an MIC of 6.25 mg ml À1 vs a strain of Streptococcus pyogenes towards which chloramphenicol had an MIC of 3.13 mg ml À1 .…”