Complex interplay of hydrogen bonding, halogen bonding and π-interactions in methyl 2-(7-chloro-1H-pyrazolo[3,4-b]quinolin-1-yl)acetate: Synthesis, X-ray crystallography, energetic features and anti-urease efficacy.

• Synthesis of pyrazoloquinoline scaffold in excellent yield. • Unraveling the synergistic effects of C-H...O, C-H...N, Cl...O, π...π, Cl...π and CH...π interactions. • Evaluation of energetic features using Hirshfeld analysis and DFT calculations. • Characterization of π-stacking and halogen bonding interactions using QTAIM and NCIPlot methods. • Assessment of urease inhibitory potential using indophenol method. The present study investigates the influence of noncovalent interactions in the design and structural control of crystal packing of pyrazoloquinoline derivative. Compound 3 was prepared in a two-step process in excellent yield. The reaction of 2,7-dichloroquinoline-3-carbaldehyde (1) and hydrazine monohydrate gave access to intermediate 2 which was alkylated regioselectively at the N1 pyrazole nitrogen. The synergistic effects of noncovalent interactions such as H-bonding (C-H...O, C-H...N), halogen bonding (Cl...O) and π-contacts (π...π, Cl...π and CH...π) remained crucial in leading the structural topology of pyrazoloquinoline skeleton. The types of noncovalent interactions was energetically evaluated using Hirshfeld analysis and DFT calculations. The π-stacking and halogen bonding contacts have been studied using QTAIM and NCIPlot techniques. The pharmacological evaluation of compound 3 as anti-urease agent revealed considerably strong potency (IC 50 = 8.51 ± 0.10 µM) when compared with positive control, thiourea. In vitro inhibitory data were confirmed through molecular modeling investigation where several key binding interactions were revealed between pyrazoloquinoline and vital residues inside the binding pocket of urease enzyme. ADME investigation successfully predicted various pharmacokinetic properties satisfying the druggable criteria and presenting the title compound to act as a lead inhibitor of Jack bean urease for further investigations. [Display omitted] QTAIM and NCIPlot for the π-stacked dimer (a) and HB/XB dimer (b) in compound 3. The combination of π-interactions (π...π, Cl...π and CH...π) is evidenced by the NCIplot analysis. The existence of the XB and another one connecting one CH group to the negative belt of the Cl-atom is also confirmed. [ABSTRACT FROM AUTHOR]