Design, synthesis and glucose uptake activity of some novel glitazones Koyel Kar, Uma Krithika, Mithuna, Prabhuddha Basu, S. Santhosh Kumar, Anu Reji, B.R. Prashantha Kumar ⇑ Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysore, India Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ootacamund 643 001, India 1 article info Article history: Received 23 September 2013 Available online 24 May 2014 Keywords: Thiazolidinediones Glitazones Glucose uptake activity Rat hemi-diaphragm abstract Herein, we report a library consisting of some novel glitazones containing thiazolidinedione and its bio- isosteres, rhodanine and oxadiazolidine ring structures as their basic scaffold for their antidiabetic activ- ity. Twelve novel glitazones with diverse chemical structures were designed and synthesized by adopting appropriate synthetic schemes and analyzed. Later, subjected to in vitro glucose uptake assay in the absence and presence of insulin to confirm their antidiabetic activity using rat hemi-diaphragm. The titled compounds exhibited glucose uptake activity ranging weak to significant activity. Compounds 4, 5, 9, 11, 15, 16, 19 and 20 showed considerable glucose uptake activity apart from rosiglitazone, a stan- dard drug. Compound 16 happens to be the candidate compound from this study to investigate further. The illustration about their design, synthesis, analysis and glucose uptake activity is reported here along with the in vitro and in silico study based structure–activity relationships. Ó 2014 Elsevier Inc. All rights reserved. 1. Introduction Diabetes mellitus is a metabolic disease characterized by hyper- glycemia arises as a consequence of relative or absolute deficiency of insulin secretion or resistance to insulin action or in combina- tion of many factors [1]. Insulin is a hormone necessary for normal carbohydrate, protein and fat metabolism in mammals. Insulin resistance is one of key characteristic features of non-insulin dependent diabetes mellitus (NIDDM) [2]. Patients with NIDDM often suffer from dyslipidemia in the form of high plasma triglyc- erides and low HDL cholesterol levels these factors are considered as major risk factors for coronary heart diseases [3]. The primary therapy for NIDDM is caloric restriction of diet and regulated aer- obic exercises. When lifestyle modifications do not result in nor- malization or near normalization of metabolic abnormalities, pharmacologic therapy is unavoidable [4]. Before 1990, sulfonylu- reas and biguanides were the oral antidiabetic agents available for the treatment of type 2 diabetes to enhance the insulin secretion and action [5,6]. Many drawbacks associated with these drugs restrict their use and creates opportunity to develop some novel insulin sensitizers to reduce insulin resistance [7,8]. Fortunately, since from 1990, there is an explosion with the introduction of new classes of antidiabetic drugs to the market especially glitaz- ones [9]. The pioneering discovery of ciglitazone by the group of scientists at Takeda Co., Japan, for insulin resistance by potentiat- ing insulin action in genetically diabetic and or, obese animals lead to the development of new glitazones or thiazolidine-2,4-diones (TZDs) [10–12]. Among these TZDs, troglitazone was the first approved by USFDA (United States Food and Drug Administration) in late 1990s for the treatment of NIDDM followed by pioglitaz- one and rosiglitazone [13–15]. These agents share a common par- tial chemical structure, TZD, and are commonly called as glitazones. These glitazones correct hyperglycemia by enhancing insulin sensitivity at adipose, hepatic and skeletal muscle tis- sues. Recently, rosiglitazone has been recalled from the market due to its cardiovascular concerns and on the other hand this has created an opportunity to develop some newer glitazones. The major molecular target for these glitazones happens to be the peroxisome proliferator activated receptor-gamma (PPAR-c) which regulates the gene expression mainly in the adipose tissues [16]. PPAR-c and its modulators are well known to play key role in treating NIDDM, gastrointestinal diseases, and genetic disor- ders associated with glucose homeostasis and lipid uptake [17–20]. In the past we have reported the design, synthesis and eval- uation of some novel TZDs [21–23]. In continuation, the present interest on TZDs is mainly due to their structural diver- sity based on structure–activity relationships learnt in the past. http://dx.doi.org/10.1016/j.bioorg.2014.05.006 0045-2068/Ó 2014 Elsevier Inc. All rights reserved. ⇑ Corresponding author at: Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS University, Mysore 570 015, India. Fax: +91 821 2548359. E-mail address: brprashanthkumar@jssuni.edu.in (B.R. Prashantha Kumar). 1 A Constituent Colleges of JSS University, Mysore 570 015, India. Bioorganic Chemistry 56 (2014) 27–33 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg