Most of the identified aldose

Most of the identified aldose reductase inhibitors possess undesirable effects like poor pharmacokinetic properties, hypersensitivity and Steven-Johnson Syndrome [1]. However, the main side effect is the lack of selectivity relative to aldehyde reductase (ALR1, EC 1.1.1.2). ALR1 plays the important role of detoxification in liver, in specifically metabolizing toxic aldehydes such as 3-deoxyglucosone, hydroxynonenal and methylglyoxal [11], [12]. The enzyme is also thought to be involved in osmoregulation within the renal tubular cells [13] and in cardiac muscles [14]. ALR1 is closely related to aldose reductase but is not involved in diabetic complications. ALR1 and ALR2 share a high degree of homology (65% identity in their amino Imeglimin sequences) in their primary and secondary structures [15], [16]. These enzymes also show similarities in substrate specificities, tissue distribution, co-factor requirement, pH, molecular weight, kinetic mechanism and reaction equilibrium [12], [17]. Therefore, compounds which do not possess selectivity towards ALR2 are supposed to have inhibitory effect on ALR1 [16]. The in vitro and in vivo inhibitory effects of various naturally derived [18], and synthesized compounds, on ALR2 suggest that ALR2 could be a potential target in controlling diabetic complications [19], [20], [21], [22], [22](a), [22](b). A large number of ALR2 inhibitors (ARIs) have been identified to treat diabetic complications. Currently, two classes of ARIs have been tested under Phase II clinical trials: (i) acetic acid derivatives including alrestatin, tolrestat, zopolrestat and epalrestat; (ii) cyclic imides such as sorbinil [23]. The carboxylic acid inhibitors have shown poor tissue permeability and are not very potent in in vivo models; the cyclic imides, on the other hand, though more efficient in tissue penetration, are known to cause skin reactions and liver toxicity [24], [25]. In conjunction to our previous efforts for the utilization of pharmacophore integration approach to access rhodanine-hybrid compounds for the inhibition of aldehyde/aldose reductase enzymes [26], in the present project we wished to explore some non-carboxylic acid ARIs. We focused our attention in combining the heterocyclic core of epalrestat (thioxothiazolidine), a well-exemplified structure of a retailed drug against aldose reductase, with aryl sulfonate nucleus. This approach allowed us to develop a novel scaffold with increased lipophilicity and favorable chemical modifications at various structural sites, that may lead to improved aldose reductase inhibitory activities, which to the best of our knowledge, have not been reported previously for such a scaffold (Fig. 1). One of the goals of this study was to explore the key determinants on various aromatic rings, as identified in Fig. 1, influencing the inhibition properties. These include: (a) the presence of substituent at ortho-, meta- or para-position of the aromatic ring attached to rhodanine core; (b) different R groups on the aryl ring of sulfonate nucleus; and (c) the attachment of sulfonate moiety itself at ortho- or para-position of aromatic ring sandwiched between rhodanine and sulfonate functionalities. Encouraged by this speculation, we embarked on the synthesis of thioxothiazolidinone-sulfonate hybrid compounds and determined their in vitro inhibition potency against aldehyde and aldose reductase enzymes. The experimental results were supported by the molecular docking investigations where the putative binding modes of the powerful inhibitors inside the active pocket of ALR1 and ALR2 were identified in addition to numerous other key interactions of amino acid residues stabilizing the potent molecules in active sites of target enzymes.
Materials and methods
Results and discussion
Conclusions In summary, the present study successfully demonstrated an efficient design and synthesis of a series of thioxothiazolidinone-sulfonate conjugates (8a–r) featuring a set of systematic and modular structural diversification sites. The synthesized derivatives were evaluated for their inhibitory effects against aldehyde/aldose reductase enzymes. Several compounds exhibited promising inhibition profiles, however, compounds 8e and 8o displayed potent in vitro activity against ALR2 and ALR1, respectively. Molecular docking computations provided a deeper insight into the inhibitory mechanism of compounds where detailed binding pattern investigation of the docking computations revealed that the ligands might be stabilized inside the pocket by establishing copious binding interactions with catalytic residues and through various polar and non-polar interactions in a cooperative way. Moreover, these determinant binding interactions of the ligands with the key residues were effectively expedient for the effective identification of ALR1 and ALR2 inhibitors. On the basis of current studies, it could be rationalized that these compounds can be explored in detail for the hit to lead generation. These compounds can serve as the scaffold for the development of novel, safe and potent inhibitors of ALR1 and ALR2. Selectivity of the ligand 8e, 8g, 8k and 8m for ALR2 over ALR1 opens new avenues to consider these ligands for further development as potent and selective inhibitors of ALR2 to treat diabetes and complications originating due to malfunctioning of ALR2.