Inhibition of Urease, a Ni‐Enzyme: The Reactivity of a Key Thiol With Mono‐ and Di‐Substituted Catechols Elucidated by Kinetic, Structural, and Theoretical Studies

Abstract

The inhibition of urease from Sporosarcina pasteurii (SPU) and Canavalia ensiformis (jack bean, JBU) by a class of six aromatic poly‐hydroxylated molecules, namely mono‐ and dimethyl‐substituted catechols, was investigated on the basis of the inhibitory efficiency of the catechol scaffold. The aim was to probe the key step of a mechanism proposed for the inhibition of SPU by catechol, namely the sulfanyl radical attack on the aromatic ring, as well as to obtain critical information on the effect of substituents of the catechol aromatic ring on the inhibition efficacy of its derivatives. The crystal structures of all six SPU‐inhibitors complexes, determined at high resolution, as well as kinetic data obtained on JBU and theoretical studies of the reaction mechanism using quantum mechanical calculations, revealed the occurrence of an irreversible inactivation of urease by means of a radical‐based autocatalytic multistep mechanism, and indicate that, among all tested catechols, the mono‐substituted 3‐methyl‐catechol is the most efficient inhibitor for urease.

Exploring the Chemical Space of Urease Inhibitors to Extract Meaningful Trends and Drivers of Activity

“…All safe-bet compounds originated from 14 clusters (2,6,8,18,19,25,26,30,32,33,35,39,42,48) and all dead-end compounds originated from 19 clusters (1,2,10,14,17,18,19,24,25,26,27,32,36,40,41,43,44,45,47), which means that, in alignment with previous observations, this also underscores the complexity and diversity of the structure-activity landscape of urease inhibitors.…”

“…This cluster contained compounds bearing catechol and pyrogallol and methoxy groups. This class of compounds is characterized by their potential to covalently bind with the cysteine on the mobile flap helix, and thus their specificity and potency may be lower. − Finally, cluster 18 (87 compounds, Figure , M.23.) showed 19.5% active molecules.…”

“…Interestingly, each of these rules covered a diverse set of compounds, which is another evidence of the nuance in the molecular determinants of activity, which goes beyond selecting a given family or scaffold to produce active compounds. Rule 1 (the largest inactives rule) covers compounds from nine clusters (7,11,15,16,18,20,23,40,47) and rule 5 (the largest actives rule) covers compounds from 10 clusters (0, 2, 7, 8, 12, 17, 24,42,48,49). This means that the molecules defined by each anchor are structurally diverse but still have a similar Activity Cliffs, Substructural "Dead Ends", and "Safe Bets" in Urease Inhibitors.…”

Novel flurbiprofen clubbed oxadiazole derivatives as potential urease inhibitors and their molecular docking study

“…All the compounds showed varying degrees of inhibition activity. Fourteen compounds 20,26,30,24,21,16,28,31,32,7,19,13,10, and 6 were found as the supreme powerful urease inhibitors having IC 50 values of 12 ± 0.9 to 20 ± 0.5 mM, better than the standard thiourea (IC 50 = 22 ± 2.2 mM). On the other hand, nine compounds exhibited signicant activity, while ve compounds showed moderate to less urease inhibitory activity.…”

“…To carry out the molecular docking study low-resolution 3D structure of the urease enzyme [PDB code: 6ZO1] was retrieved from the PDB database. 28 The water was removed from the crystal structure and hydrogen was added to the structure. Based on the Amber99 force eld charges were assigned to all atoms.…”