N-Aryl-3,4-dihydroisoquinoline Carbothioamide Analogues as Potential Urease Inhibitors

Abstract

N-Aryl-3,4-dihydroisoquinoline carbothioamide analogues 1-22 were synthesized by a simple one-step reaction protocol and subjected to in vitro urease inhibition studies for the first time. All compounds 1-22 were found active and showed significant to moderate urease inhibitory potential. Specifically, analogues 1, 2, 4, and 7 were identified to be more potent (IC₅₀ = 11.2 ± 0.81-20.4 ± 0.22 μM) than the standard thiourea (IC₅₀ = 21.7 ± 0.34 μM). The structure-activity relationship showed that compounds bearing electron-donating groups showed superior activity. Molecular docking study on the most active derivatives revealed a good protein-ligand interaction profile against the corresponding target with key interactions, including hydrogen bonding, hydrophobic, and π-anion interactions.

Figure 1

Rationale of the present research work.

Scheme 1. Synthesis of N-Aryl-3,4-Dihydroisoquinoline Carbothioamide Analogues 1–22

Figure 2

Structure–activity relationship of compounds 1–5.

Figure 3

Structure–activity relationship of compounds 6–8.

Figure 4

Structure–activity relationship of compounds 9–11.

Figure 5

Structure–activity relationship of compounds 12–19

Figure 6

Structure–activity relationship of compounds 11–13

Figure 7

Binding mode of the synthesized compounds. (A) Surface representation of the enzyme with embedded ligands; (B) Binding mode of compound 2; (C) for compound 4; and (D) for compound 7; and (E) for compound 1. The double sided arrow indicates pi-H bonds.