Three new series of tricyclic pyridazinones have been synthesized and tested in vitro in order to assess (i) their ability to inhibit aldose reductase enzyme (ALR2) and (ii) their specificity toward the target enzyme with respect to other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, and glutathione reductase. The inhibitory capability of the most effective compounds (IC50 values ranging from 6.44 to 12.6 microM) appears to be associated with a rather significant specificity for ALR2. Molecular mechanics and molecular dynamic calculations performed on the ALR2-inhibitor complex give indications of specific interaction sites responsible for the binding, thus providing information for the design of new inhibitors with improved affinity for the enzyme.

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (K = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition.

Despite recent advances both in the chemistry and molecular pharmacology of antidiabetic drugs, diabetes still remains a life-threatening disease, which tends to spread all over the world. The clinical profile of diabetic subjects is often worsened by the presence of several longterm complications, namely neuropathy, nephropathy, retinopathy, and cataract. Several attempts have been made to prevent or at least to delay them. The most relevant are reported in this review, including the development of compounds acting as aldose reductase inhibitors, antiadvanced glycation end-product drugs, free radical scavengers, vasoactive agents, essential fatty acid supplementation, and neurotropic growth factors.

Thymidylate synthase is an attractive target for antiproliferative drug design because of its key role in the synthesis of DNA. As such, the enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious disease. In practice, TS is highly conserved across species, and it has proven to be difficult to develop inhibitors that are selective for microbial TS enzymes over the human enzyme. Using the structure of TS from Lactobacillus casei in complex with the nonsubstrate analogue phenolphthalein, inhibitors were designed to take advantage of features of the bacterial enzyme that differ from those of the human enzyme. Upon synthesis and testing, these inhibitors were found to be up to 40-fold selective for the bacterial enzyme over the human enzyme. The crystal structures of two of these inhibitors in complex with TS suggested the design of further compounds. Subsequent synthesis and testing showed that these second-round compounds inhibit the bacterial enzyme at sub-micromolar concentrations, while the human enzyme was not inhibited at detectable levels (selectivities of 100-1000-fold or greater). Although these inhibitors share chemical similarities, X-ray crystal structures reveal that the analogues bind to the enzyme in substantially different orientations. Site-directed mutagenesis experiments suggest that the individual inhibitors may adopt multiple configurations in their complexes with TS.Thymidylate synthase (TS) 1 is an attractive target for the design of drugs used against proliferative diseases because of its central role in the production of DNA. TS catalyzes the methylation of 2′-deoxyuridine 5′-monophosphate (dUMP) by N 5 ,N 10 -methylene tetrahydrofolate (CH 2 H 4 folate). This reaction is the terminal step in the only de novo synthetic pathway to thymidylate, which is essential for DNA production. Inhibition of TS stops the production of DNA, disrupting the progression through the cell cycle and eventually leading to "thymineless" cell death (1).Much effort in drug design against TS has focused on inhibitors that resemble the substrate, dUMP, or the cofactor, CH 2 H 4 folate. A mechanism-based inhibitor of TS (2), 5-fluorouridylate, which is administered as the premetabolite, 5-fluorouracil (5-FU), is used in chemotherapy. The TS inhibitor, 10-propargyl-5,8-dideazafolate (CB3717), is a mimic of the cofactor, CH 2 H 4 folate (3). Although CB3717 is a potent inhibitor of TS [K i of 40 nM (4)], it shows liver and kidney toxicity in a small number of patients (5). Recent structure-based drug design efforts against TS (6-11, 41, 42) have resulted in a series of potent compounds such as AG337 and Tomudex that bind in the folate binding site of the enzyme. These new compounds show promise as cancer chemotherapeutics.The amino acid sequence of TS is highly conserved across species, particularly among those residues that form the substrate and cofactor binding pockets (12). These residues also interact closely with inhi...