• 2018-07
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  • Similarly synthetic analogs of Alogliptin by replacing


    Similarly synthetic analogs of Alogliptin by replacing the cyanobenzyl group with the butynyl group have been synthesized and tested as selective DPP-4 inhibitors [7], [8]. Additionally, quinazolines [9], [10], pyridopyrimidinediones [11], pyrazolopyrimidinones [12] and pyrimidines [13] as DPP-IV inhibitors are of particular interest for diabetics. Furthermore, various quinazoline and thiazoline analogs have been proved to be effective antidiabetic agents (Fig. 2) [14], [15], [16]. From the literature it has been found that quinazoline and thiazoline analogs (Fig. 3) also have antioxidant activity [17], [18], [19]. Quinazoline clubbed thiazolines have also been proved to show antioxidant and antidiabetic activity (Fig. 2, Fig. 3) [20], [14]. In view of these results, we have observed that substituted quinazolines are worthy of further studies and aiming at finding new structures, which could be a lead in the field of diabetics, therefore we have planned to synthesize new molecules, quinazolines endowed with thiazoline nuclei, in an attempt to significantly improve the antidiabetic activity. Therefore, several Apocynin australia were design, synthesize and screened for their DPP-4 inhibition activity, in vivo antidiabetic activity and also evaluated for their DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity. Further, molecular docking studies were also carried out to identify their possible binding mode within the catalytic domain of DPP-4 enzyme.
    Experimental protocol
    Results and discussion
    Conclusion We have designed and successfully synthesized a series of quinazoline based hybrids compounds containing thiazoline moiety and other heterocyclic moieties. The synthesized compounds were screened for their in vitro DPP-4 inhibitory activity and free radical scavenging effect. The selected compounds were showed good to remarkable DPP-4 inhibitory activity and free radical scavenging effect. Among these, the compound 7g satisfied threshold inhibition criteria and emerged as lead compound with remarkable DPP-4 inhibitory activity with an IC50 of 0.76 nM. Compound 7g exerted most significant in vivo hypoglycemic activity followed by compound 7b, 7h and 8g respectively. Compound 8g was exerted good antioxidant activity by the free radical scavenging activity measurement performed by the 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) assay method. Furthermore, molecular docking study was performed using Maestro 9.0 program (Schrodinger Inc. USA) to provide the binding mode of the compound 7g into the binding sites of DPP-4 enzyme. Molecular docking suggested that binding of 7g with DPP-4 active site is responsible for its high inhibitory activity. In sight of these points, compound 7g could be a subject of further investigations for searching potential new in vivo hypoglycemic agents.
    Conflict of interests
    Acknowledgments We are thankful to Faculty of Pharmacy, Jamia Hamdard (Hamdard University) for providing animals, Laboratory facility and experiment kits for in-vitro anti-diabetic study. Thanks also due to University Grant Commission, New Delhi, Government of India, for financial assistance in terms of Major Research Project [file No. 41-731/2012-SR (SR)].