pubs.acs.org/acsmedchemlett
Discovery of Novel Benzoxaborole-Based Potent
Antitrypanosomal Agents
Dazhong Ding,† Yaxue Zhao,† Qingqing Meng,† Dongsheng Xie,† Bakela Nare,‡ Daitao Chen,‡
Cyrus J. Bacchi,§ Nigel Yarlett,§ Yong-Kang Zhang, Vincent Hernandez, Yi Xia,
Yvonne Freund, Maha Abdulla,^ Kean-Hooi Ang,^ Joseline Ratnam,^
James H. McKerrow,^ Robert T. Jacobs,‡ Huchen Zhou,*,† and Jacob J. Plattner
†School of Pharmacy and E-Institute of Chemical Biology, Shanghai Jiao Tong University, Shanghai, 200240, China,
‡SCYNEXIS, Inc., P.O. Box 12878, Research Triangle Park, North Carolina 27709, §Haskins Laboratory, Pace University, New York,
New York 10038, Anacor Pharmaceuticals Inc., 1020 East Meadow Circle, Palo Alto, California 94303, and ^Small Molecule
Discovery Centerand Sandler Center for Basic Research in Parasitic Diseases, Universityof California, San Francisco, California 94158
ABSTRACT We report the discovery of benzoxaborole antitrypanosomal agents
and their structure-activity relationships on central linkage groups and different
substitution patterns in the sulfur-linked series. The compounds showed in vitro
growth inhibition IC50 values as low as 0.02 μg/mL and in vivo efficacy in acute
murine infection models against Tryapnosoma brucei.
KEYWORDS Tryapnosoma brucei, African trypanosomiasis, benzoxaborole
frican sleeping sickness (African trypanosomiasis),
a fatal disease, is caused by the protozoan parasite
Trypanosoma brucei and is transmitted by the bite of
of 1 to provide aldehyde 19, followed by reduction with
NaBH4 and acid-catalyzed cyclization to the benzoxaboroles
20-24. Thioethers were oxidized to their sulfoxide analo-
gues either by heating with NaIO4 at 60 ꢀC for an hour or by
treatment with an equivalent of m-CPBA at -20 ꢀC. Sulfones
were obtained by treatmentof thioethers with NaIO4 at 60 ꢀC
for 12 h or by treatment with 2 equiv of m-CPBA at -60 ꢀC.
Analogously, ether 28 was obtained from 2-bromo-4-fluoro-
benzaldehyde and phenol as depicted in Scheme 2.
Benzoxaboroles with carbonyl and carbinol linkage
groups were synthesized as shown in Scheme 3. Diphenyl
ketone 29 was prepared by Friedel-Crafts reaction and was
subsequently brominated with NBS in the presence of Bz2O2
and converted to hydroxymethyl group by treatment with
sodium acetate followed by basic hydrolysis to give com-
pound 30. After oxidation with PCC, both carbonyl groups
were protected as acetals (32). Introduction of the boronic
acid functionality via lithiation and trapping with triisopropyl
borate afforded boronic acid 33 after hydrolysis of the acetal
groups. Reduction of compound 33 led to the formation of
carbinol 34. Oxidation of compound 34 with PCC resulted in
ketone 35.
A
the tsetse fly.1 Although it affects a large population in Africa,
drug discovery has been largely neglected during the past
half century.2 The currently available treatments for early
stage infection, pentamidine and suramin, and melarsoprol
and eflornithine for late stage infection, have the problems
of high toxicity, high cost, or low efficacy.3 There is an urgent
need to develop new therapies with low toxicity, improved
efficacy, and affordable cost.4,5
We report here the discovery and structure-activity
relationship (SAR) of novel benzoxaborole antitrypanosomal
agents. During an initial screening of a focused library of
antiinfective benzoxaboroles, compound 12 was found to
inhibit in vitro T. brucei growth (IC50 = 0.12 μg/mL). There
was no previous report on benzoxaboroles as effective
antiprotozoals, although they had been studied as antifun-
gal6 and antiinflammatory7 agents. In this study, we ex-
plored the effect of a variety of linkage groups at C(6) and
different substitution patterns in the 6-sulfur linked series on
T. brucei growth inhibition.
The synthesis of benzoxaboroles with thioether, sulfoxide,
and sulfone linkage groups at C(6) is outlined in Scheme 1.
Nucleophilic substitution of 2-bromo-4-fluorobenzaldehyde
by phenylthiol gave thioether 1, where an ice bath was
necessary in some cases to minimize side reactions due to
the substitution of bromide. After the aldehyde was con-
verted to MOM-protected hydroxyl, the oxaborole ring was
installed by halogen-metal exchange with n-butyllithium
followed by in situ trapping with triisopropylborate and
deprotection with HCl to give benzoxaboroles 4-8. An
alternative route utilized a palladium-mediated boronylation
Benzoxaboroles with linkage groups derived from 6-OH
and 6-NH2 were also synthesized (Scheme 4). First, com-
pound 37 was prepared from acetal 36 by treatment with
benzyl alcohol and NaH. Benzoxaborole 39 was obtained
after boronylation and reduction as described above. Hydro-
genation of compound 39 in the presence of Pd/C resulted in
the 6-OH benzoxaborole 40, which was coupled with phenyl
Received Date: January 20, 2010
Accepted Date: March 19, 2010
Published on Web Date: April 06, 2010
r
2010 American Chemical Society
165
DOI: 10.1021/ml100013s ACS Med. Chem. Lett. 2010, 1, 165–169
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