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  • br Conclusion From the series of synthesized N

    2019-09-09


    Conclusion From the series of synthesized N-methylated and N-benzylated pyrimidinediones, it may be concluded that the presence of electron rich species with pyrimidinediones is vital for enhancing binding with target, although, incorporation of steric bulky group must be taken into consideration, which may alter DPP-4 inhibitory activity. The presence of electron withdrawing group has lowered DPP-4 inhibitory activity (like Cl in Compound 3b). Inclusion of bicyclic or tricyclic moieties may favour a strong π-π stacking interaction. N-methylated pyrimidinediones can further be optimized to N-ethylated, N-propylated and so on, that could be an interesting derivatisation to explore further. Presence of CF3 has been contrary with respect to CN and appears to be a key factor in pharmacological activity of N-benzylated compounds. Through comparative molecular docking studies of synthesized potent Compounds (3a, 3c 3d, 3e, 5c and 5d) with some natural DPP-4 inhibitors (Diprotin A, Flavone, Quercetin, Resveratrol), it has led to a conclusion that there are some important amino PX 866 kinase interactions in DPP-4 subunit through Tyr 666, Tyr 662, Arg 125, Glu 206 etc, which are identical in both synthesized compounds as well as natural DPP-4 inhibitor This kind of similarity rationalizes that synthesized compounds possesses important key features like 3D-conformation, physicochemical property like natural DPP-4 inhibitors, which directly corresponds to DPP-4 inhibitory activity against diabetes.
    Conflict of interest
    Acknowledgements
    Introduction Glucocorticoids (GCs) are the most effective anti-inflammatory and immunosuppressive agents for the treatment of severe inflammatory diseases such as asthma and rheumatoid arthritis (Schäcke et al., 2002). Several reports have shown that excess endogenous and exogenous GC exposure has been associated with the development of glucose deregulation such as glucose intolerance, insulin resistance (IR), hyperglycemia and eventually diabetes mellitus in both (Hoes et al., 2011; Di Dalmazi et al., 2012; Rafacho et al., 2014; Pasieka and Rafacho, 2016). Routine administration of exogenous GC is pertinent during late gestation, particularly in women who are at risk of delivering a preterm infant, aiming at ensuring proper neonatal outcome and survival (Kamath-Rayne et al., 2012). Unfortunately, despite its beneficial roles in foetal survival, various studies have reported programmed metabolic disorders such as IR, atherogenic dyslipidemia, increased body weight and type 2 diabetes in mothers (Holness and Sugden, 2001; Gomes et al., 2014) and later life of offsprings that were exposed to prenatal GC exposure (O’Regan et al., 2004). Dipeptidyl peptidase IV (DPP-4) is also a newly identified adipokine that is located on the surface of various cells and exists in plasma and body fluids (Lambeir et al., 2003). Initially, it was believed that DPP-4 only play a predominant role in glucose metabolism by degrading incretins; glucagon like peptide-1 (GLP-1), glucose-dependent insulinotrophic peptide (GIP) (Zhong et al., 2013). Recent reports have also documented its role in pathogenesis of inflammation and cardiometabolic disorder (CMD) (Wronkowitz et al., 2014; Zhong et al., 2015). Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase that is involved in the storage of glucose into glycogen. Increased GSK3 activity is an early event in the development of IR where glycogen synthesis is impaired in type 2 diabetes (Eldar-Finkelman et al., 1999; Nikoulina et al., 2000) and inhibition of GSK3 in Zucker diabetic fatty rats leads to an improvement in both insulin action and glucose uptake (Cline et al., 2002). Furthermore, GCs has also been reported to cause impaired insulin action through GSK-3-dependent (Ruzzin et al., 2005) and independent (Vaughan et al., 2015) pathways. Plasma endoglin levels have been positively correlated with basal glycemia in patients with diabetes and hypertension, and with glycated haemoglobin in all patients with diabetes (Blázquez-Medela et al., 2010). Endoglin, also known as CD105, is one of the key proteins that is synthesized and released by the placenta. It is highly expressed on the vascular endothelium and syncytiotrophoblast and is known to play a role in angiogenesis and in the regulation of the vascular tone through its interaction with endothelial nitric oxide synthase (eNOS) (Robinson and Johnson et al., 2007; Smith and Wear, 2009).