Bioorganic & Medicinal Chemistry Letters 19 (2009) 324–327
Bioorganic & Medicinal Chemistry Letters
Aryloxy cyclohexyl imidazoles: A novel class of antileishmanial agents q
Nagarapu Srinivas a, Shraddha Palne b, Nishi b, Suman Gupta b, Kalpana Bhandari a,
*
a Medicinal and Process Chemistry Division, Central Drug Research Institute, M.G. Marg, Lucknow, U.P. 226001, India
b Division of Parasitology, Central Drug Research Institute, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Thirteen novel aryloxy cyclohexane-based mono and bis imidazoles were synthesized and evaluated
in vitro as antileishmanials against Leishmania donovani and cytotoxicity assessed. These compounds
were better than the existing drugs, sodium stibogluconate and pentamidine in respect to IC50 and SI val-
ues. Promising compounds were tested further in vivo. Among all, the bis methylimidazole with 2-fluoro,
4-nitro aryloxy group (9) exhibited significant in vivo inhibition of 77.9%, thus providing new structural
lead for antileishmanials.
Received 27 August 2008
Revised 19 November 2008
Accepted 24 November 2008
Available online 27 November 2008
Keywords:
Leishmania
Azoles
Ó 2008 Elsevier Ltd. All rights reserved.
Imidazoles
Aryloxy cyclohexane
Leishmaniasis is a group of parasitic diseases of global distribu-
tion transmitted by the bite of the infected female phlebotomine
sandfly1 and manifest with visceral, cutaneous, and mucocutane-
ous forms. This disease is currently prevalent in four continents,
being endemic in 88 countries, threatening 350 millions world-
wide.2 Chemotherapy for these parasitic diseases is generally
ineffective mainly due to the emergence of drug-resistant strains,
significant toxicity, variable efficacy, lack of oral bioavailability
and high cost of the therapeutic agents.3,4 The pentavalent antimo-
nials are widely used as primary therapy whereas alternative drugs
include amphotericin B, pentamidine, paromomycin, miltefosine
and azoles,5,6 all suffer from one or more of the above deficiencies.
Drug resistance, high toxicity and high treatment costs necessitate
the need for novel therapeutics.7
Among potential orally active drugs for the treatment of these
complex diseases, sterol biosynthesis inhibitors offer an attractive
possibility, as Leishmania parasites synthesize specific sterols
which seem to be essential for cell proliferation and viability.8,9
Azole antifungal agents, have been used as antileishmanial agents
since 1980s,10–12 inhibit the growth of Leishmania amastigotes in
culture systems by inhibiting the cytochrome P-450-mediated
14a-demethylation of lanosterol, blocking ergosterol synthesis,
and causing accumulation of 14a-methyl sterols.8,10 Metronidazole
and N-substituted azoles (ketoconazole, miconazole, fluconazole
and itraconazole) are well-tolerated drugs13,14 that are potentially
active against Leishmania, but their use in the treatment of cutane-
ous and visceral leishmaniasis has produced conflicting results.15,16
Based on above report, we recently prepared a series of novel
aryloxy benzocycloalkyl azoles and found that they were highly
active in vitro against Leishmania donovani and also exhibited
significant in vivo activity in L. donovani/Hamster model. In view
of above and our continuation of studies on chemotherapy of
Leishmania, we decided to synthesize an expanded series of aryloxy
cycloalkyl azoles, and investigated their biological effects against
the Leishmania parasites and the results are reported in this
communication.
The compounds used in the present study were prepared from
cyclohexanone. The synthetic route for the preparation of
2,6-bisimidazolyl-methyl-1-aryloxycyclohexane (5–9) is outlined
in Scheme 1. Mannich reaction on cyclohexanone with 2 moles
of pyrrolidine gave 2,6-bis-pyrrolidin-1-ylmethyl-cyclohexanone
(2) which on reaction with imidazole in presence of ethanol/water
resulted in the replacement of pyrrolidine moiety with imidazole
(3). The keto intermediate 3 was then transformed to correspond-
ing hydroxy derivative 4 in a single diasteriomeric form, which on
reaction with proper aryl halides furnished the desired 2,6-bis-
imidazolylmethyl-cyclohexyl aryl ethers (5–9) (Scheme 1).
For the synthesis of 1-(2-aryloxy-cyclohexylmethyl)-1H-imida-
zoles 13–17, cyclohexanone was reacted with pyrrolidine under
Mannich conditions in the presence of L
-proline17 to give 2-pyrroli-
din-1-ylmethyl-cyclohexanone (10). Subsequent replacement of
the pyrrolidine with imidazole followed by reduction led to the
cis/trans mixture of 2-imidazol-1-ylmethyl-cyclohexanol 12a/
12b.18 The trans isomer 12b (major product) was condensed with
substituted aryl halides to obtain the corresponding ethers 13–17
(Scheme 1). For SAR studies we also synthesized the directly con-
nected imidazole derivatives viz: 1-aryloxy-2, 6-bisimidazolyl
cyclohexane 21–23 (Scheme 2). Bromination of cyclohexanone19
q
CDRI communication number 7527.
* Corresponding author. Tel.: +91 522 2612411x18; fax: +91 522 2623405.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.094