Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7347
Supporting Information Available: Biological methods, syn-
thetic experimental details, and analytical data of compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
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Figure 1. Preliminary SAR of the compounds synthesized.
egoryId)89.
25 with a pyrazine ring as R1 showed moderate activity and
modest cytotoxicity. Although the activity against L. donoVani
remained the same upon replacing the pyrazine moiety in 25
with an indole ring (compound 26), significant reduction in the
cytotoxicity was observed. Surprisingly, the bulkier 2-phe-
nylquinolin-4-yl derivative 28 showed appreciable activity and
low cytotoxicity. The fact that 29, bearing a 5-phenylisoxazole
group linked to the amide linker, showed good antiparasitic
activity and low toxicity while the 5-methylisoxazole derivative
30 was inactive suggests a possible existence of an extended
hydrophobic pocket in the target binding site.
An unsubstituted phenyl ring as R2 group appears to be more
active than a hydroxyl derivative (23 vs 24), while an OH
substituent seems to be a more favorable substitution than OMe
(26 vs 27). Figure 1 summarizes our preliminary SAR for this
series of compounds. Encouraged by these results in amastigote
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In summary, we report the first synthesis of the natural
product 31 and a number of its analogues. Biological evaluation
of these new chemical entities revealed that they are able to
block the growth of the protozoan parasite L. donoVani, with
several of them being active in the submicromolar range and
with activities comparable to that of miltefosine. The lead
compound 31 is 3-fold more active than miltefosine. While all
of the analogues of 31 studied to date are less active than the
lead structure, many of them do show an improved selectivity
index. Our findings underscore the importance of the N-(2-
benzoxazole-2-ylphenyl)benzamides as an important lead scaf-
fold in the design and synthesis of antileishmanial agents. While
results obtained in mouse peritoneal macrophages were not
satisfactory, further work is being directed toward addressing
the apparent cellular penetration issues.
Acknowledgment. We thank Drs. Andrew Mesecar and
Jimmy Orjala for providing us with information on 31. We
acknowledge support from DOD (W81XWH-07-1-0445).
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