## 3 Results and Discussion
### Docking Study  
Molecular docking studies have the potential to identify novel drug-like molecules that display high binding affinity for the target protein, and they can facilitate the understanding of biological activity data with the purpose of designing new compounds with improved activity. Hence, we extended our study to explore the conformational space and binding orientation of the synthesized pyrimidine derivatives. The binding conformations of these compounds were explored by MOE-Dock module implemented in the MOE program [53]. The optimized conformers obtained from the Gaussian program were docked to the active site of urease. The docking results indicated that all the conformers were well accommodated inside the active site and were stabilized by various hydrophilic, hydrophobic and van der Waals interactions. The residues involved in these interactions were Arg439, Ala440, His492, Asp494, His593, His594, Asp633 Ala636 and Met637. Compound **3h** (IC\({}_{50}\) = 6 \(\pm\) 0.3 \(\upmu\)M) showed strong inhibitory potential against urease as compared to **3b** (inactive) due to methyl substitution at the _para_ position of the pyridine ring. Compound **3h** showed good interactions with the residues of the active site by coordinating with the bi-nickel center, via its carbonyl group at the pyrimidine ring and anchoring itself in a way that permitted strong interaction of the carbonyl group with the two nickel ions. Additionally, the two carbonyl groups on the pyrimidine ring acted as hydrogen bond acceptors and mediated hydrogen bond interaction with His492 (2.3 A) and Arg439 (2.04 A) of the binding pocket (Figure 2b). Figure 2: Depiction of the docking results of low energy conformer: (**a**) **3a, (b) 3h, (c) 3d, (d) 3j, (e) 3m, (f) 3f, (g) 3p, and (h) 5. The key residues are presented as sticks models and nickel atoms are shown as green circles. Compound **3a** (IC\({}_{50}\) = 9 \(\pm\) 2 \(\upmu\)M), another active compound of the series, established various potential interactions with the active site of urease, as well as with nickel ions. The oxygen atom of the morpholine ring was involved in the chelation process with the nickel center in the catalytic site. This compound was further stabilized by two typical hydrogen bonds with His492 (2.8 A) and Arg609 (3.0 A). Apart from hydrogen bond interactions, a tetramine of the compound participated in the salt bridge interaction with the negatively charged Asp494 residue (Figure 2a). Compounds **3d** and **3l** (IC\({}_{50}\) = 8 \(\pm\) 0.3 \(\upmu\)M) had almost similar structures, biological activities and patterns of binding interactions with the active site residues. The only difference was the interaction with metal ions. The lone pair of electrons for sulfur (C = S) of **3l** mediated strong interaction with the two nickel ions and hydrogen bond interaction with Arg609 (2.4 A) and Met637 (2.8 A), while in case of **3d**, the carbonyl group on the pyrimidine ring was involved in the interaction with the nickel ions as depicted in Figure 2c. Compounds **3j** (IC\({}_{50}\) =10 \(\pm\) 0.9 \(\upmu\)M) and **3k** (IC\({}_{50}\) =11 \(\pm\) 1 \(\upmu\)M), which showed good biological activity, presented similar types of interactions. The additional effectiveness of **3j** compared to **3k** was due to the absence of a methyl group at the _meta_ position of the benzene ring, which allowed the compound to establish close contacts with the active site residues (Figure 2d). The ring nitrogen of the pyridine is involved in two productive hydrogen bond interaction with His492 and Met637 at 2.54 and 3.4 A, respectively. Moreover, the C = O of pyrimidine rind mediated a potential hydrogen bond interaction with the NH of His593 at 2.59 A, while the compound was further stabilized through hydrophobic interactions with Ala440, Cme592, and His594. The compounds with electron-withdrawing substitution, especially halogens, showed noteworthy inhibitory potential.