Abstract
The PPARγ transactivation activity of benzylpyrazole acylsulfonamide derivatives have been quantitatively analyzed in terms of 0D- to 2D-Dragon descriptors. This study has provided a rational approach for the development of titled derivatives as PPARγ agonists. The descriptors identified in CP-MLR analysis for the PPARγ transactivation activity have highlighted the role of atomic properties (mass, electronegativity, van der Waals volumes and polarizability) in terms of weighted 2D autocorrelations and BCUT descriptors and electronic content in terms of Galvez charge indices and maximal electrotopological positive variation (MAXDP). Additionally, Balaban’s U and centric indices (Uindex and BAC, respectively), Lopping centric index (Lop), topological distance between N and O atom and hydrophobicity accounting parameter MLOGP have also shown prevalence to optimize the PPARγ transactivation of titled compounds. PLS analysis has further confirmed the dominance of the CP‐MLR identified descriptors and applicability domain analysis revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data and all of the compounds was within the applicability domain of the proposed model and were evaluated correctly.
Highlights
Elevated plasma glucose in the presence of high endogenous insulin levels is characteristic of type 2 diabetes (T2D)
On analyzing the model applicability domain (AD) in the Williams plot (Figure 3) of the model based on the whole dataset (Table 6), it has appeared that none of the compounds were identified as an obvious outlier for the Peroxisome proliferator-activated receptors (PPARs) transactivation activities if the limit of normal values for the Y outliers was set as 3 units
The PPAR transactivation activity of benzylpyrazole acylsulfonamide derivatives have been quantitatively analyzed in terms of 0D- to 2D-Dragon descriptors
Summary
Elevated plasma glucose in the presence of high endogenous insulin levels is characteristic of type 2 diabetes (T2D). The prevalence of T2DM in developed and developing countries is rising speedily and it is expected that number of diabetics to reach 380 million by 2025 [3.4] In this scenario development of new and safer antidiabetic agents which may lower hemoglobin A1c (HbA1c) levels and improve the lipid profile of patients simultaneously is ardently needed [5,6,7,8]. Introduction of troglitazone, pioglitazone hydrochloride and rosiglitazone maleate (the representatives of thiazolidinediones (TZDs)) as insulin sensitizers and the fact that TZDs are high-affinity PPAR ligands [12] has opened new avenues for extensive research in the area of antidiabetic drug discovery and development [13,14,15]. The aim of present communication is to establish the quantitative relationships between the reported activities and molecular descriptors unfolding the substitutional changes in titled compounds
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