Synthesis, Characterization and in Silico Studies of Some Pyrazolo-Acridine Hybrid Compounds as Antimicrobial Agents

Abstract

Pyrazole and acridine derivatives play an important role in medicinal chemistry due to their different biological activities. In this context, new heterocyclic hybrid compounds (7a-h) containing pyrazole, acridine and benzothiazole scaffolds were synthesized. These compounds were achieved via three-component reaction of pyrazolecarbaldehyde (4) with cyclohexane-1,3-dione (5) and substituted aromatic amines (6a-h) usingp-toluenesulfonic acid (PTSA) as catalyst. The structures of the obtained pyrazolo-acridine hybrids were determined by spectroscopic methods (FT-IR, 1H-NMR, 13C-NMR, and mass spectra) and confirmed by elemental analysis. The antibacterial activity of the synthesized molecules against two Gram-positive and one Gram-negative microorganisms and their antifungal activity against two yeasts was evaluated using four control compounds: Vancomycin, Levofloxacin, Cefepime and Fluconazole. All synthesized pyrazolo-acridine derivatives showed good antibacterial and antifungal activity. The results of the preliminary screening indicate that some synthesized pyrazolo-acridine derivatives gave twofold to quadruple potent antimicrobial activity, compared to standard drugs. The results confirm that the antimicrobial activity is strongly dependent on the substituents linked to aromatic ring. Additionally, molecular docking studies were performed to highlight the modes of interaction between the studied hybrid pyrazolo-acridine derivatives and the 3Q70, 3FV5, 3FYV and 3IL5 receptors. Prediction of ADMET properties has been performed. Finally, molecular dynamics (MD) simulations were also performed to investigate the stability of the molecular docking results. In silico studies show that hybrid pyrazoloacridine derivatives are potential promising candidates when compared to reference compounds.