Analogues of thiolactomycin: potential drugs with enhanced anti-mycobacterial activity a aDetails for the preparation of the thiolactomycin analogues shown in Table 1 are available as supplementary data in Microbiology Online (http://mic.sgmjournals.org)

Autor: Suzanne J. Senior, James D. Douglas, Caroline B. Morehouse, David E. Minnikin, Benjawan Phetsukiri, Ian B. Campbell, Gurdyal S. Besra
Rok vydání: 2002
Předmět:
Zdroj: Microbiology. 148:3101-3109
ISSN: 1465-2080
1350-0872
DOI: 10.1099/00221287-148-10-3101
Popis: Analogues of the antibiotic thiolactomycin (TLM) have been synthesized and have been shown to have enhanced activity against whole cells of Mycobacterium tuberculosis H37Rv and against mycolic acid biosynthesis in cell extracts of Mycobacterium smegmatis. TLM has a methyl-branched butadienyl side chain attached at position 5 on a ‘thiolactone’ ring, namely 4-hydroxy-3,5-dimethyl-5H-thiophen-2-one. Various combinations of strong bases were explored to create a reactive anion at position 5 on the thiolactone ring which could react with halides to produce 5-substituted derivatives; the best reagent was two equivalents of lithium-bis-(trimethylsilyl)amide in tetrahydrofuran. The analogue with a 5-tetrahydrogeranyl substituent showed the best biological activity with an MIC90 for M. tuberculosis of 29 μM and 92% mycolate inhibition in extracts of M. smegmatis, as compared to 125 μM and 54%, respectively, for TLM; other related C10 and C15 isoprenoid derivatives had similar biological activity. These isoprenoid-based derivatives did not inhibit type II fatty acid synthase from M. smegmatis, but compounds with iso-butyl and iso-butenyl side chains did show some inhibitory activity against this enzyme. These short-chain derivatives did not inhibit mycolate synthesis or have significant antibiotic activity. Treatment of the thiolactone with a weaker base, sodium hydride in tetrahydrofuran, gave 3-alkyl-3,5-dimethyl-thiophene-2,4-dione analogues, which had no effect on fatty acid or mycolate synthesis. However, the geranyl derivative had an MIC99 of 60 μM for M. tuberculosis, one quarter that (240 μM) of TLM, demonstrating its excellent antibiotic potential against an unknown cellular target.
Databáze: OpenAIRE
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