Identification of Imidazolylpyrazole Ligands as Potent Urease Inhibitors: Synthesis, Antiurease Activity and In Silico Docking Studies

Abstract

Towards discovery of effective urease inhibitors; we disclose here a hybrid series of imidazole and pyrazole motifs as potent antiurease agents. A para-toluenesulfonic acid (TsOH) catalyzed, facile synthetic approach was employed for the preparation of targeted molecular designs in good yields upto 94 %. The novel scaffolds were characterized by different spectroscopic means (FTIR, NMR, and Mass spectrometry) and elemental analysis helped to identify the purity of these compounds. Afterwards, the derivatives was tested against Jack bean's urease enzyme to explore their inhibiting potencies. All analogues (4 a-4 l) were found active against the studied enzyme in comparison with the standard drug thiourea (IC 50 = 21.26 � 0.12 μM). However, following dibromo substituted derivatives: 4 f, 4 g, 4 h, 4 i, 4 j, 4 k, and 4 l were surfaced out as potent urease inhibitors among the series. The identified lead candidates were meta-nitro substituted 4 k with IC 50 = 0.7 � 0.002 μM and a para-nitro containing compound 4 l with IC 50 = 1.0 � 0.003 μM. As observed in docking calculations, ionic and hydrogen bonding, π-stacking, interaction with nickel ions and other hydrophobic interactions probably stabilized the ligand bindings at the active site of 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.…”

“…was composed of a set of 27 coumarin analogues, of which 85.2% were active compounds. Interestingly, even bulky scaffolds based on imidazole–imidazole and imidazole–indole motifs showed high activity, as observed for cluster 6 (26 molecules) with 65.4% actives, some of which reached the nanomolar range activity , (Figure , M.15. and M.16.).…”

Recent Applications of the Multicomponent Synthesis for Bioactive Pyrazole Derivatives

“…Generally, it causes infections of the gastrointestinal tract, gastric ulcers, kidney stones, hepatic coma, and the risk of developing gastric cancer [ 163 ]. As a contribution to this topic, Chaudhry et al reported a pseudo-four-component reaction of pyrazole-4-carbaldehyde 31 , symmetrical 1,2-diarylethane-1,2-diones 143 , and ammonium acetate catalyzed by p -toluenesulfonic acid in ethanol at ambient temperature, affording a series of imidazolylpyrazole derivatives 165 up to 94% yield in short reaction times (4 h) ( Scheme 28 ) [ 164 ]. This TsOH-catalyzed approach resulted in being a simple and convergent method to prepare products via the formation of four C-N bonds in one-step.…”

“… 3D and 2D Interactions of compounds 165k and 165l with the amino acids of 4GY7. Image adapted from Chaudhry et al [ 164 ]. …”

Synthesis, Biological Evaluation and in Silico Studies of New Pyrazoline Derivatives Bearing Benzo[d]thiazol‐2(3H)‐one Moiety as Potential Urease Inhibitors

“…[11] Pyrazolines, a five-membered nitrogen-containing heterocyclic compounds, are important pharmacophores in drug designing because of their capability of making hydrogen bonds and other non-covalent interactions with different target enzymes or receptors. [12] Pyrazoline derivatives exhibited a wide range of biological activities such as antimicrobial, antifungal, antibacterial, antiinflammatory, anticancer. [13] In addition, they were reported to possess the urease inhibitory activity.…”