Journal of Antimicrobial Chemotherapy, Vol 42, 811-815, Copyright © 1998 by The British Society for Antimicrobial Chemotherapy
WJ Suling, RC Reynolds, EW Barrow, LN Wilson, JR Piper and WW Barrow
Twelve lipophilic 2,4-diamino-5-methyl-5-deazapteridine derivatives and
trimethoprim were evaluated for activity against Mycobacterium tuberculosis
and Mycobacterium avium in vitro. Six of the compounds had MICs of < or
=12.8 mg/L and < or =1.28 mg/L against M. tuberculosis and M. avium,
respectively; trimethoprim MICs were >128 mg/L and >12.8 but < or
=128 mg/L, respectively. Two compounds, with either a 2-methyl-5- methoxy
phenyl or 2-methoxy-5-trifluoromethyl phenyl linked at the 6- position of
the deazapteridine moiety by a CH2NH bridge, had MICs of < or =0.13 mg/L
against M. avium; the two compounds also had apparent I50 values for
dihydrofolate reductase of 2 and 8 nM, respectively, compared with an I50
of 400 nM with trimethoprim. Four of the compounds were selectively toxic
to mycobacteria as compared with Vero cells. These results demonstrated
that lipophilic antifolates can be synthesized which are more active
against mycobacteria than trimethoprim and which possess selective
toxicity.
Susceptibilities of Mycobacterium tuberculosis and Mycobacterium avium complex to lipophilic deazapteridine derivatives, inhibitors of dihydrofolate reductase [In Process Citation]
Southern Research Institute, Birmingham, AL 35205, USA. suling@sri.org
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