Structure-Activity-Selectivity Relations on the Keto-Pyrrolyl-Difluorophenol Aldose Reductase Inhibitory Scaffold

Publication: Pharmakeftiki


In recent years it has been observed worldwide a striking increase of cases of diabetes mellitus, which tend to attain an epidemic prevalence. Aldose reductase (ALR2, AR, AKR1B1, EC belongs to the aldoketoreductase superfamily. It is the first enzyme of the polyol pathway, which converts glucose to sorbitol. The physiological role of ALR2 is detoxifying and regulating, but in cases of diabetes and/or hyperglycemia, glucose is converted rapidly to sorbitol, which tends to concentrate into the cells, damaging them in many tissues. Therefore, ALR2 was proposed responsible for the long term complications of diabetes, such as neuropathy, nephropathy, retinopathy and cataract. Aldehyde reductase (ALR1, AKR1A1, EC belongs also to the ketoreductase superfamily. The major role of ALR1 is also the detoxification of toxic aldehydes. The two enzymes exhibit 65% sequence, as well as structural homology. Thus, simultaneous inhibition of both enzymes could cause unwanted effects, due to deteriorated detoxification. The fifteen compounds of this study (Figure 1) have been previously synthesized in our lab and their inhibitory activity in ALR2 and ALR1 has been tested in vitro. We have tried to correlate statistically pIC 50 ALR2 and selectivity index (IC 50 ALR1 /IC 50 ALR2 , SI) with various calculated physicochemical properties of the molecules, such as lipophilicity, pKa, MR, TPSA, atomic and electronic spatial parameters, as well as the energies of HOMO and LUMO. We have found out, from the best equation, that pIC 50 ALR2 depends on the distance between the carbonyl oxygen and the phenolic oxygen (D 1), the energy of HOMO (E HOMO) and the dihedral angle between the pyrrolyl ring and the aroyl substituent (A): pIC 50 ALR2 =-0.18(±0.07)D 1 +0.014(±0.006)A-39.03(±15.76)E HOMO -5.84(±5.39) n=15, r 2 =0.647, s =0.313, MAE=0.200 We have also found out that the selectivity index (SI) depends on the distance of the aromatic centre of the molecule to the phenolic oxygen (D 2), coupled with lipophilicity (calculated as S+logP): SI=-33.06(±10.42)D 2 +67.00(±18.74)logP-39.94(±73.41) n=14, r 2 =0.583, s=43.467, MAE=32.519
(PDF) Structure-Activity-Selectivity Relations on the Keto-Pyrrolyl-Difluorophenol Aldose Reductase Inhibitory Scaffold.