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Structural finding of R/S -3,4-dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonylamino)-2 H -1-benzopyrans as selective pancreatic β-cells K ATP-pβ channel openers

2007; NRC Research Press; Volume: 85; Issue: 12 Linguagem: Inglês

10.1139/v07-127

1480-3291

Sk. Mahasin Alam, Soma Samanta, Amit Kumar Halder, Soumya Basu, Tarun Jha,

Free Radicals and Antioxidants

R/S-3,4-Dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonyl-amino)-2H-1-benzopyrans are pancreatic β-cells potassium (K ATP-pβ ) channel openers with inhibitory effect on insulin secretion. To find the more active and effective benzopyrans as selective potassium (K ATP-pβ ) channel openers towards the pancreatic tissues, quantitative structure–activity relationships (QSAR) study was performed using E-state and R-state indices along with Wang–Ford charges, n-octanol/water partition coefficient, molar refractivity, and indicator parameters. QSAR models were developed by statistical techniques, e.g., multiple linear regression (MLR), principle component regression analysis (PCRA), and partial least squares (PLS) analysis. The generated equations were validated by the leave-one-out cross-validation method. The models show the importance of ETSA indices of atom numbers 16, 17, 18, 19, 21 as well as 22. The positive coefficient of S 16 , S 17 , S 18 , S 19 , S 21 , and S 22 indicate that with the increase of the value of E-state indices, desired activity decreases. RTSA index is also important for the biological activity, and the atom numbers 16, 17, 18, 19, 20 and 22 are involved in van der Waals interactions. RTSA index also possesses negative impact on the inhibition of residual insulin secretion. Wang–Ford charges of some particular atoms are also important for the inhibition. Increase of n-octanol/water partition coefficients of compounds inhibit insulin secretion, and the presence of chlorine atom at m- and p- positions of the phenyl ring B is necessary for the inhibition of residual insulin secretion.Key words: benzopyran derivatives, potassium channel openers, PCRA, PLS, QSAR.