Bioorganic & Medicinal Chemistry Letters
Evaluation of the Influence of thiosemicarbazone–triazole hybrids
on genes implicated in lipid oxidation and accumulation as potential
anti-obesity agents
a
b
b,
Henok H. Kinfe a, , Yonas H. Belay , Jitcy S. Joseph , Emmanuel Mukwevho
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a Department of Chemistry, University of Johannesburg, PO Box 524, Auckland park 2006, South Africa
b Department of Biochemistry, University of Johannesburg, PO Box 524, Auckland Park 2006, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of thiosemicarbazone–triazole hybrids 1a–h are efficiently synthesised and evaluated for their
influence on the expression of genes, cpt-1, acc-1 and pgc-1, which are essential in lipid metabolism.
The test results show that hybrids 1c and 1g exhibited relatively high influence on the expression of
cpt-1 and pgc-1 and suppression of acc-1 as desired.
Received 31 May 2013
Revised 1 August 2013
Accepted 5 August 2013
Available online 13 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Thiosemicarbazon–triazole hybrid
Obesity
Diabetics
Lipid
Obesity is a serious chronic disease that may lead to type 2 dia-
betes and insulin resistance.1 Impaired lipid metabolism and diet
(e.g., high calorie diet such as fast foods, fizzy drinks, beacon etc)
contribute significantly to lipid accumulation in the body. It is well
established that excess accumulation of lipids/fats in adipose and
intramuscular tissues results in obesity which predisposes individ-
uals to metabolic diseases such as type 2 diabetes.2,3 Lipid metab-
olism occurs mainly in the mitochondria and is controlled by a set
of mitochondrial enzymes responsible for both lipid oxidation and
synthesis. For instance, carnitine palmityol transferase (CPT)-1 en-
zyme encoded by cpt-1 gene controls the rate limiting step in the
mitochondrial lipid oxidation while, on the contrary, mitochon-
drial acetyl-CoA carboxylase (ACC)-1 enzyme encoded by acc-1
gene catalyzes lipid synthesis and accumulation by inhibiting
CPT-1. Literature reports have indicated that down-regulation of
ACC-1 and up-regulation of CPT-1 may result in increased oxida-
tive capacity of the mitochondria by reducing lipid accumulation
and obesity in adipocytes and myocytes.4–21 The essential roles
of ACC-1 and CPT-1 in regulating lipid synthesis and oxidation,
respectively, makes them important targets for the development
of effective therapeutic modalities that can treat or better manage
obesity and type 2 diabetes.
In our pursuit in the identification of novel hybrid compounds,
which comprise two or more drug pharmacophores in one mole-
cule with the intention to exert multi-drug action,22 we are inter-
ested in thiosemicarbazone and triazole hybrids and evaluation of
their biological activities. Thiosemicarbazones having several me-
tal binding sites possess a wide spectrum of biological activity
which includes antiviral,23 anticancer24 and antimalaria25 activities
probably mediated via chelation to intracellular cations. Equally
important are triazoles which can interact with biological targets
through hydrogen bonding and dipole interactions.26 Besides their
wide spectrum of biological activities,27–30 they have also exhib-
ited anti-obesity benefits.31 In this regard, our group has recently
reported the synthesis of novel thiosemicarbazone and triazole hy-
brids 1a–h (Fig. 1) and their antimalarial activity.32 Furthermore,
the anti-obesity activity of triazole derivatives and the bioisoster-
ism of thiosemicarbazones to metformin 2 (Fig. 1), an oral antidia-
betic drug which is believed to inactivate acc-1 inhibiting fatty acid
synthesis and stimulating fatty acid oxidation,33–35 prompted us to
investigate the synergic influence of the hybrids on the gene
expression of cpt-1 and suppression of acc-1. Herein, we report
the synthesis of thiosemicarbazone-triazole hybrids 1a–h and their
effect on the expression and suppression of the essential genes,
cpt-1 and acc-1, respectively.
The hybrids 1a–h were synthesized according to the recently
reported protocol as outlined in Scheme 1.32 The synthesis com-
menced with alkylation of commercially available 4-hydroxybenz-
aldehyde with propargyl bromide in the presence of K2CO3 to give
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Corresponding authors. Tel.: +27 11 559 3918; fax: +27 11 5592819.
Mukwevho).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.