LIPOPHILIC LIGAND EFFICIENCY DRIVEN BIOISOSTERIC REPLACEMENT IN ALDOSE REDUCTASE INHIBITORS: THE CASE OF PHENYLSULFONYL-PYRROLYL-DIFLUOROPHENOLS: Athens, Greece, IXth Joint Meeting in Medicinal Chemistry

Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase (ALR2) and its inhibitors (ARIs) have been gaining attention over the years. On the other hand, optimizing ligand efficiency metrics based on lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of this property that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates. In the present work, in order to address the high lipophilicities, and consequently poor lipophilic ligand efficiencies (LLEs), of ARIs I and II, their less hydrophobic phenylsulfonyl isosters 1 and 2 were designed. I: (1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl)(phenyl)methanone Smiles: C(=O)(c1cn(-c2cc(F)c(c(F)c2)O)cc1)c3ccccc3 IC50=0.40μM pIC50=6.398 S+logP=4.134 LLE=2.264 LE=0.398 1: 2,6-difluoro-4-(3-(phenylsulfonyl)-1H-pyrrol-1-yl)phenol Smiles: O=S(=O)(c1cn(-c2cc(F)c(c(F)c2)O)cc1)c3ccccc3 IC50=1.27μM pIC50=5.896 S+logP=3.453 LLE=2.443 LE=0.351 II: (1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-2-yl)(phenyl)methanone Smiles: C(=O)(c1n(-c2cc(F)c(c(F)c2)O)ccc1)c3ccccc3 IC50=1.06μM pIC50=5.985 S+logP=4.097 LLE=1.878 LE= 0.373 2: 2,6-difluoro-4-(2-(phenylsulfonyl)-1H-pyrrol-1-yl)phenol Smiles: O=S(=O)(c1n(-c2cc(F)c(c(F)c2)O)ccc1)c3ccccc3 IC50=0.62μM pIC50=6.208 S+logP=3.618 LLE=2.589 LE=0.370 The preparation of compounds 1 and 2 involved a ZnO catalyzed electrophilic aromatic substitution of 2,6-difluoro-4-(1H-pyrrol-1-yl)phenol with phenylsulfonyl chloride, followed by alkaline hydrolytic workup and flash column chromatography. ALR2 inhibitory activities were evaluated on partially purified rat lens enzyme by spectrophotometrically determining NADPH consumption at 340 nm. Lipophilicities (S+logP) were calculated with the freeware MedChem Designer v.3.0.0.28. LLEs were calculated using the equation: LLE=pIC50 – (S+logP), while the ligand efficiencies (LEs) with the equation: LE=(1.37/HA) × pIC50, where HA denotes the number of non-hydrogen (that is, heavy) atoms. The target compounds were isolated in fair yields (1, 32% and 2, 24%), and exhibited low micromolar (1) or submicromolar (2) ALR2 inhibitory activities. Furthermore, from the calculated S+logP values it is expected that these compounds could be almost three times less lipophilic than their benzoyl counterparts. This reduced lipophilicity improves the LLE metric, rendering especially compound 2 as a promising new lead for the development of hydrophilic ARIs. Moreover, the ligand efficiency (LE) metric for compound 2 is calculated to be equal to 0.370, which falls into the proposed acceptable range (i.e. LE>0.3) for drug candidates.