Abstract
Metalloenzyme inhibitors typically share a common need to possess a metal-binding pharmacophore (MBP) for binding the active site metal ions. However, MBPs can suffer from physicochemical liabilities, impeding the pharmacological properties and drug-likeliness of inhibitors. To circumvent this, problematic features of the MBP can be identified and exchanged with isosteric replacements. Herein, the carboxylic and hydroxyl group of the salicylic acid MBP were replaced and a total of 27 salicylate metal-binding isosteres (MBIs) synthesized. Of these 27 MBIs, at least 12 represent previously unreported compounds, and the metal-binding abilities of >20 of the MBIs have not been previously reported. These salicylate MBIs were examined for their metal-binding features in model complexes, physicochemical properties, and biological activity. It was observed that salicylate MBIs can demonstrate a range of attractive physicochemical properties and bind to the metal in a variety of expected and unexpected binding modes. The biological activity of these novel MBIs was evaluated by measuring inhibition against two Zn2+-dependent metalloenzymes, human glyoxalase 1 (GLO1) and matrix metalloproteinase 3 (MMP-3), as well as a dinuclear Mn2+-dependent metalloenzyme, influenza H1N1 N-terminal endonuclease (PAN). It was observed that salicylate MBIs could maintain or improve enzyme inhibition and selectivity. To probe salicylate MBIs as fragments for fragment-based drug discovery (FBDD), an MBI that showed good inhibitory activity against GLO1 was derivatized and a rudimentary structure–activity relationship was developed. The resulting elaborated fragments showed GLO1 inhibition with low micromolar activity.
Highlights
Metalloenzymes have been found to play important roles in the propagation of various diseases, ranging from microbial infections to cancer, which makes them an important class of targets for drug development.[1]
The biological activity of these novel metal-binding isosteres (MBIs) was evaluated by measuring inhibition against two Zn2+-dependent metalloenzymes, human glyoxalase 1 (GLO1) and matrix metalloproteinase 3 (MMP-3), as well as a dinuclear Mn2+-dependent metalloenzyme, influenza H1N1 N-terminal endonuclease (PAN)
Similar to a previous study on picolinic acid MBIs, the carboxylic acid moiety was substituted by a hydroxamic acid ester, tetrazole, and oxetane.[13]
Summary
Metalloenzymes have been found to play important roles in the propagation of various diseases, ranging from microbial infections to cancer, which makes them an important class of targets for drug development.[1]. In a proof-of-concept study, the carboxylic acid moiety of picolinic acid was exchanged for known carboxylic acid isosteres to obtain a library of metalbinding isosteres (MBIs). These picolinic acid MBIs showed a broad range of physicochemical properties while maintaining similar metal-binding properties and biological activity as the parent MBP. This demonstrated the potential value of the MBI concept to allow for modulation of properties in the development of more drug-like metalloenzyme inhibitors by FBDD.[12,13]. It was shown that salicylate MBI fragments are easy to derivatize, which makes them strong candidates for lead development and rational drug design
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