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 MIC(90) for M.
tuberculosis of 29 micro M and 92% mycolate inhibition in extracts of M. smegmatis, as compared to 125 micro M and 54%, respectively, for TLM; other related C(10) and C(15)
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 MIC(99) of 60 micro M for M.
tuberculosis, one quarter that (240 micro M) of TLM, demonstrating its excellent
antibiotic potential against an unknown cellular target.