2
C.M. Brackett et al. / Tetrahedron xxx (2015) 1e5
Fig. 1. Structures of compound 1 and 2.
accelerated rate of resistance evolution, we wondered whether we
could augment the activity of 1 while decreasing inherent toxicity
through analogue synthesis. In this regard, our group has also
recently developed several 2-AIs based upon compound 2 (Fig. 1)
hexylbenzoyl chloride was reacted with diazomethane, and the
resulting diazoketone was subjected to standard ArndteEistert
conditions (silver benzoate in methanol).15 The homologated ester,
3 underwent diazotransfer reaction, accomplished by reaction
with para-acetamidobenzenesulfonyl azide (p-ABSA) in the pres-
ence of DBU, to yield diazoketone 4.16 Analog diversity was then
introduced via a Ru-catalyzed NeH insertion reaction.17 Conver-
sion of the ester to the N-methoxy-N-methylamide (Weinreb
amide) proceeded without the need for protection of the newly
installed amine. Finally, reduction of the Weinreb amide to the
corresponding aldehyde using diisobutylaluminum hydride
(DIBAL-H), followed by cyclization with cyanamide afforded the
1,5-2AI derivatives 7aee.10
that are capable of reversing
b-lactam resistance in methicillin-
resistant S. aureus (MRSA).10,13,14 In these studies, we were able
to modify adjuvant activity through imprinting either a 1,4- or 1,5-
substitution pattern on the 2-AI ring. Specifically, compound 2 was
able to lower the MIC of oxacillin against MRSA four-fold at 25 mM,
while from the library of 1,5 substituted derivatives of compound
2, a compound emerged that is capable of lowering the MIC of
oxacillin against MRSA up to 512-fold at 5 m
M.10 Inspired by these
results, we set out to determine whether imparting either a 1,4- or
1,5-substitution pattern upon the 2-AI of 1 would deliver com-
pounds with augmented activity and reduced inherent toxicity.
Herein we report the synthesis of both 1,5- and 1,4-substituted
analogues of 1, as well as the evaluation of their biological activ-
ity in terms of colistin resistance suppression. Moreover, we report
a compound capable of lowering the MIC of colistin against re-
sistant strains of both A. baumannii and P. aeruginosa to a greater
degree than compound 1.
Our pilot library of 1,5 2-AIs was evaluated for the ability to
break resistance to colistin against the colistin-resistant strains of A.
baumannii that we employed in our previous study.11 These strains,
obtained from the Walter Reed Army Institute of Research (WRAIR),
have colistin MICs significantly higher (512e1024
Clinical and Laboratory Standards Institute (CLSI) defined threshold
g/mL).18 As is common practice
mg/mL) than the
for resistance for A. baumannii (ꢁ4
m
for evaluating adjuvant activity of our 2-AIs, we first established the
intrinsic antibiotic activity of our library alone. Whereas the parent
compound 1 has an MIC of 100
of our library had MICs of ꢁ200
m
M against all strains, all members
2. Results and discussion
m
M. We then determined the MIC of
colistin against two strains of A. baumannii in the presence of 30
2.1. Synthesis and biological evaluation of 1,5 2-AIs
and 60
stitution pattern essentially eradicated activity against A. bau-
mannii in the context of colistin resensitization. At 30
compounds 7aee only reduced the colistin MIC four-fold, from 512
to 128 g/mL, whereas the parent compound at the same concen-
tration was able to lower the MIC to 4 g/mL.
mM of each compound (Table 1). Surprisingly, the 1,5 sub-
As we had the most success in our previous MRSA studies with
the 1,5-substitution pattern where the introduced appendage was
an aromatic substituent, we chose to initially evaluate a pilot li-
brary of five aryl-1,5-substituted 2-AIs that were synthesized
according to Scheme 1. Briefly, commercially available 4-
m
M
m
m
Scheme 1. Synthesis of 1,5-substituted 2-aminoimidazoles. a) i. CH2N2, rt, 1 h. ii. AcOH, rt, 1 h. b) AgOBz, Et3N, MeOH, rt, 16 h. c) p-ABSA, DBU, MeCN, rt, 16 h. d) [Ru(p-cymene)Cl2]2,
ReNH2, CH2Cl2, rt, 1 h. e) HN(OCH3)CH3, i-PrMgCl, THF, ꢂ40 ꢃC, 8 h. f) i. DIBAL-H, THF ꢂ78 ꢃC, 1 h. ii. EtOH/H2O, pH 4.3, H2NCN, 95 ꢃC, 2 h. iii. MeOH/HCl.