Two Novel Regioisomeric Series of Bis-pyrazolines: Synthesis, In Silico Study, DFT Calculations, and Comparative Antibacterial Potency Profile against Drug-Resistant Bacteria; MSSA, MRSA, and VRSA

Abstract

Aims: Design and synthesis of antimicrobial prototypes that are capable of eradicating bacterial biofilm formation that is responsible for many health challenges particularly with antibiotic-resistant bacterial species. Materials and Methods: The utility of 1,3-diarylenones, aka chalcones, 3a-i and 8a-j as building blocks to construct the corresponding bis-pyrazoline derivatives 5aa-bh and 9ad-bj. Screening the antibacterial behavior of the novel bis-pyrazoline derivatives against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and vancomycin-resistant S. aureus (VRSA) bacterial strains was investigated. Results: Chalcones were used as building scaffolds to construct two series of di- and trisubstituted bis-pyrazoline derivatives. Numerous novel bis-compounds displayed decent bacterial biofilm suppression. Conclusions: Two regioisomeric series of bis-chalcones were designed and constructed, and their structural diversity was manipulated to access the intrinsically bioactive, pyrazoline ring. The newly synthesized bis-pyrazoline derivatives presented decent antibacterial behavior against multiple drug-resistant bacterial strands (MSSA, MRSA, and VRSA).

Figure 1

Some pyrazoline-based drugs.

Scheme 1. Synthesis of Bis-chalcone Derivatives 3a–i

Scheme 2. Synthesis of Bis-pyrazoline Derivatives 5aa-bh

Scheme 3. Synthesis of Bis-chalcone Derivatives 8a–j

Scheme 4. Synthesis of Bis-pyrazoline Derivatives 9ad-bj

Figure 2

MIC values of some bis-pyrazolidine and bis-pyridene derivatives vs. MSSA, MRSA, and VRSA.

Figure 3

Biofilm eradication activities of compounds 9ad (green), 9ag (blue), and 9ah (red) against MSSA, MRSA, and VRSA bacterial strains. The tick labels on the x-axis indicate the concentration of the compound in units of MIC (i.e., 1 = 1 MIC, 2 = 2 MIC, etc.).

Figure 4

Cytotoxicity test of compounds 9ad (black), 9ag (red), and 9ah (blue) on normal human lung fibroblast cells. The obtained CC₅₀ values are 693.54 ± 31.8, 495.63 ± 27.6, and 351.79 ± 19.1 μM for compounds 9ad, 9ag, and 9ah, respectively.

Figure 5

2D and 3D representation of intermolecular interactions between the best docked compounds and MRSA enzyme.

Figure 6

Spatial electrostatic potential (ESP) map of compound 9ah. Red and blue zones represented high and low electronegative sides, respectively.