Design, synthesis, biochemical evaluation and antimycobacterial action of phosphonate inhibitors of antigen 85C, a crucial enzyme involved in biosynthesis of the mycobacterial cell wall.
Phosphonate inhibitors of antigen 85C were prepared. The inhibitors, comprising a phosphonate moiety, mycolic acid mimetic and a trehalose surrogate, contain substituted benzyl alcohols, N-(omega-hydroxyalky)phthalimide, 2-phenylethanol or 4-(phthalimido)butanol as trehalose mimetics, and an alkyl chain of different lengths mimicking the mycolic acid side chain. The best compounds inhibited the mycolyltransferase activity of antigen 85C with IC(50) in the low micromolar range and inhibited the growth of Mycobacterium avium in culture. The best compounds in the 3-phenoxybenzyl- and omega-(phthalimido)alkoxy series, ethyl 3-phenoxybenzyl butylphosphonate (4a) and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl ethyl heptylphosphonate (5c) displayed IC(50) values of 2.0 and 1.3 microM, respectively, in a mycolyltransferase inhibition assay. In a M. avium growth inhibition assay MIC of 4a and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl ethyl nonylphosphonate (5d) were 248.8 and 84.5 microg/mL, respectively.
Gobec
Stanislav
S
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Plantan
Ivan
I
Mravljak
Janez
J
Svajger
Urban
U
Wilson
Rosalind A
RA
Besra
Gurdyal S
GS
Soares
Sousana L
SL
Appelberg
Rui
R
Kikelj
Danijel
D
D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000942:Antigens, Bacterial / Q000737:chemistry; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002473:Cell Wall / Q000378:metabolism; D015195:Drug Design; D009162:Mycobacterium avium / Q000187:drug effects / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D063065:Organophosphonates; D000217:Acyltransferases; C119774:antigen 85C, Mycobacterium tuberculosis