Bio-oriented synthesis of new sulphadiazine derivatives for urease inhibition and their pharmacokinetic analysis

Abstract

Current research is based on biology-oriented synthesis of sulphadiazine derivatives and determination of their urease inhibitory activity. In this regard, a series of (E)-4-(benzylideneamino)-N-(pyrimidin-2-yl)benzenesulfonamide was synthesized from sulphadiazine and substituted aromatic aldehydes. The structures of synthesized compounds were ascertained by spectroscopic techniques, such as, FTIR, NMR and HRMS analysis, and in-vitro and in-silico investigation were carried out for the inhibition of urease. Ureases are harmful for humans by producing by-products of urea (ammonia and carbon dioxide). The most active compound (3l) against urease exhibited IC50 value of 2.21 ± 0.45 µM which is 10 times more potent than the standard thiourea (20.03 ± 2.06 µM). It is noteworthy that most of our synthesized compounds showed significant to excellent activities against urease enzyme and most of them substituted by halogen or hydroxy groups at ortho and para positions in their structures. Inhibition of enzyme by the synthesized analogues was in descending order as 3l > 3a > 3b > 3q > 3e > 3o > 3s > 3t > 3g > 3k > 3r > 3f > 3m > 3p > 3n > 3j > 3i > 3h. Moreover, molecular docking studies were performed to rationalize the binding interactions of the synthesized motifs with the active pocket of the urease enzyme. The synthesized sulphadiazine derivatives (3a–u) were found to be non-toxic, and presented passive gastrointestinal absorption.

Benzimidazole derivatives: A versatile scaffold for drug development against Helicobacter pylori‐related diseases

“…11 ) had an aldehyde moiety in its structure, which could explain its high anti‐urease activity 41 . In accordance, Hamad et al reported anti‐urease activity for aldehyde‐incorporated Schiff base derivatives of sulphadiazine 42 …”

“…41 In accordance, Hamad et al reported anti-urease activity for aldehyde-incorporated Schiff base derivatives of sulphadiazine. 42 Saify et al synthesized pyridyl-benzimidazole analogues and reported that the modification of different groups of the phenyl ring of phenacyl could affect the anti-urease activity of the derivatives. Compound 12 that showed the highest anti-urease activity compared with thiourea (IC 50 = 19.42 vs. 21.4 μM, respectively) had an NO 2 group at the R 1 position adjacent to a nitrogen on the pyridine ring, modulating the enzyme's molecular interactions (Figure 3).…”

Designing metal chelates of halogenated sulfonamide Schiff bases as potent nonplatinum anticancer drugs using spectroscopic, molecular docking and biological studies

“…The magnitude of the calculated dipole moment (D) gives a good indication of the capability of www.nature.com/scientificreports/ the compound to penetrate the biological cell membrane. Generally, the lower the dipole moment, the higher the penetration strength across the phospholipid bilayer 48 . In addition, based on the other calculated molecular descriptors; softness (S), hardness (η), electrophilicity (ω), and electronegativity (χ), the estimated chemical reactivity of the ligands toward metal ions or any neighboring biological receptors is in the order: SB 5 www.nature.com/scientificreports/ SB 2 > SB 3 > SB 1 , where 4 SB 5 is proposed to have the highest softness character (S = 0.300 eV −1 ) and the smallest E, i.e.…”

“…Effectively short H-bond was observed in most of the docked protein-ligand complexes. As an example, the interaction of SB 1 and SB 4 through O (27) with ARG 115 amino acid and O(9) with ARG 435 amino acid respectively, displayed bond lengths that are less than 3.5 Å 8,48 . Worth mentioning that the negative values of the binding energies (Table 4) indicate spontaneous interaction with the protein.…”

Exploring the Potential of New Benzamide-Acetamide Pharmacophore Containing Sulfonamide as Urease Inhibitors: Structure–Activity Relationship, Kinetics Mechanism, and In Silico Studies

“…The active site-bearing unit contains approximately 840 amino acids, and the catalytic process relies on the presence of Ni 2+ within the active site. 6 Developing efficient and safe urease inhibitors has received significant attention from the pharmacological research community primarily because ureases play a crucial role in various disease conditions. The ongoing production of ammonia contributes to heightened gastric mucosa permeability, resulting in states such as ulcers, inflammation, lymphoma, and adenocarcinoma.…”