In an effort to develop a new class of potent aldose reductase inhibitors, a series of 1,3-diarylpyrazole assimilated 3-substituted 4-oxo-2-thioxo-1,3-thiazolidines (9a–n) was designed, and synthesized in good to excellent yields by a pharmacophore integration approach. The structures of the newly synthesized pyrazole–rhodanine derivatives were established by readily available spectroscopic methods (FTIR, ¹H and ¹³C NMR) and mass spectrometry. The hybrid compounds were evaluated as aldehyde and aldose reductase inhibitors. The biological screening results identified several compounds as remarkable inhibitors of ALR1 and ALR2. Among them, compounds 9c and 9k showed excellent activity (and complete selectivity) towards the aldose reductase enzyme with IC₅₀ values of 1.22 ± 0.67, and 2.34 ± 0.78 μM, respectively, as compared to the standard drug (sorbinil; IC₅₀ = 3.10 ± 0.20 μM). The molecular docking analysis of the most potent inhibitor 9c was performed in order to identify the putative binding modes inside the active pocket of the enzymes. These newly discovered aldose reductase inhibitors are believed to represent valuable lead structures to further streamline the generation of candidate compounds to target a number of pathological conditions, most strikingly long-term diabetic complications.

The role played by organic chemistry in the pharmaceutical industry continues to be one of the main drives in the drug discovery process. More than ever, the industry demands from organic chemists the development of small molecules, which could be a rich source of biological potential. In this context, a diverse range of quinoline-4-carboxylic acid derivatives has been synthesized and evaluated as potent inhibitors of alkaline phosphatases. The structural build-up of the synthesized compounds was based on the spectro-analytical data. Most of the tested compounds showed remarkable inhibition of human tissue-nonspecific alkaline phosphatase (h-TNAP), tissue specific human intestinal alkaline phosphatase (h-IAP) and human placental alkaline phosphatase (h-PLAP). Among them, 3j was identified as a potent inhibitor of h-TNAP with an IC₅₀ value of 22 ± 1 nM, whereas, 3e emerged as a lead candidate against h-IAP and h-PLAP with IC₅₀ values of 34 ± 10 and 82 ± 10 nM, respectively. 3a was a potent inhibitor of human germ cell alkaline phosphatase (h-GCAP) with an IC₅₀ value of 150 ± 70 nM. The putative binding sites of the most potent inhibitors were inferred from molecular docking simulations using homology models based on the h-PLAP structure.

All-atom molecular dynamics (MD) simulation combined with Markov state model (MSM) were used to uncover the structural characteristics and misfolding mechanism of the key R3 fragment of tau protein at the atomic level.

Ecto-nucleotidase enzymes catalyze the hydrolysis of extracellular nucleotides to their respective nucleosides. Herein, we place the focus on the elucidation of structural features of the cell surface located ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDase1-3 and 8). The physiological role of these isozymes is crucially important as they control purinergic signaling by modulating the extracellular availability of nucleotides. Since, crystal or NMR structure of the human isozymes are not available – structures have been obtained by homology modeling. Refinement of the homology models with poor stereo-chemical quality is of utmost importance in order to derive reliable structures for subsequent studies. Therefore, the resultant models obtained by homology modelling were refined by running molecular dynamic simulation. Binding mode analysis of standard substrates and of competitive inhibitor was conducted to highlight important regions of the active site involved in hydrolysis of the substrates and possible mechanism of inhibition.

Alkaline phosphatase (AP) isozymes are present in a wide range of species from bacteria to humans with an ability to dephosphorylate and transphosphorylate a wide range of substrates. In humans, four AP isozymes have been identified such as tissue-nonspecific (TNAP), intestinal (IAP), placental (PLAP) and germ cell (GCAP) APs. Modulation of the activity of the different AP isozymes may have therapeutic implications in distinct diseases and cellular processes. To identify potent inhibitors of APs, a diverse range of 4-bromophenylacetic acid derived hydrazone derivatives has been synthesized and characterized by spectro-analytical methods and, in the case of 4i and 4q, by single crystal X-ray diffraction analysis. Among the tested series, several compounds were identified as lead candidates showing IC₅₀ values from micro to nanomolar ranges. Compound 4k displayed exceptional activity with an IC₅₀ value of 10 nM against h-IAP. This inhibitory effect is ∼10 000-fold more potent than the standard drug L-phenylalanine. Compounds 4p, 4g and 4e were potent inhibitors of TNAP, PLAP and GCAP, respectively. Molecular docking studies of the respective potent inhibitors have been carried out to rationalize the important binding modes of the most active inhibitors.