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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).

SUBMITTER: Kassab RM

PROVIDER: S-EPMC10809241 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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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.

Kassab Refaie M RM Zaki Magdi E A MEA Al-Hussain Sami A SA Abdelmonsef Aboubakr H AH Muhammad Zeinab A ZA

ACS omega 20240109 3

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 ...[more]

PMID: 38284096

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Project description:The discovery of new antimicrobial agents as a means of treating drug-resistant microbial pathogens is of utmost significance to overcome their immense risk to human well-being. The current investigation involves the development, synthesis, and assessment of the antimicrobial efficacy of novel quinoline derivatives incorporating a thiosemicarbazide functionality. To design the target compounds (QST1-QST14), we applied the molecular hybridization approach to link various thiosemicarbazides to the quinoline core with a sulfonyl group. Upon the synthesis and completion of structural characterization via spectroscopic techniques (1H NMR, 13C NMR, 15N NMR, IR, and HRMS), the title molecules were extensively evaluated for their potential antitubercular, antibacterial, and antifungal activities. N-(3-Chlorophenyl)-2-(quinolin-8-ylsulfonyl)hydrazine-1-carbothioamide (QST4), the most effective compound against Mycobacterium tuberculosis H37Rv, was also tested on isoniazid-resistant clinical isolates with katG and inhA promoter mutations. Based on molecular docking studies, QST4 was also likely to demonstrate its antimycobacterial activity through inhibition of the InhA enzyme. Furthermore, three derivatives (QST3, QST4, and QST10) with preferable antimicrobial and drug-like profiles were also shown to be nontoxic against human embryonic kidney (HEK) cells. All compounds were optimized by the density functional theory method using B3LYP with the 6-31+G(d,p) basis set. Structural analysis, natural bond orbital calculations of donor-acceptor interactions, molecular electrostatic potential analysis, and frontier molecular orbital analysis were carried out. Quantum chemical descriptors and charges on the atoms were determined to compare the strengths of the intramolecular hydrogen bonds formed and their stabilities. We determined that the sulfur atom forms a stronger intramolecular hydrogen bond than the nitrogen, oxygen, and fluorine atoms in these sulfonyl thiosemicarbazide derivatives.

Project description:IntroductionStaphylococcus aureus is a prominent cause of postoperative infections, often persisting within host cells, leading to chronic infections. Conventional antibiotics struggle to eliminate intracellular S. aureus due to poor cell penetration. Antimicrobial peptides are a new hope for tackling intracellular bacteria. Accordingly, this study examines the antimicrobial peptide MDP1, derived from melittin, for its efficacy against intracellular S. aureus.MethodsIn this study, the physiochemical properties (Prediction of three-dimensional structure, circular dichroism and helical wheel projection analysis) were investigated. Extracellular antibacterial activity and cytotoxicity of MDP1 were also assessed. The mechanism of interaction of MDP1 with S. aureus was evaluated by molecular dynamic simulation, atomic force and confocal microscopy. Bacterial internalization into an endothelial cell model was confirmed through culture and transmission electron microscopy. The effect of the peptide on intracellular bacteria was investigated by culture and epi-fluorescence microscopy.Results and discussion3D structural prediction proved the conformation of MDP1 as an α-helix peptide. Helical-wheel projection analysis indicated the proper orientation of hydrophobic amino acid residues for membrane interaction. CD spectroscopy of MDP1 showed that MDP1 in SDS 10 and 30 mM adopted 87 and 91% helical conformation. Atomic force and confocal microscopy assessments as well as molecular dynamics studies revealed the peptide-bacterial membrane interaction. MDP1, at the concentration of 0.32 μg mL-1, demonstrated a fold reduction of 21.7 ± 1.8, 1.7 ± 0.2, and 7.3 ± 0.8 in intracellular bacterial load for ATCC, VRSA, and MRSA, respectively. Molecular dynamics results demonstrate a preferential interaction of MDP1 with POPG/POPE membranes, primarily driven by electrostatic forces and hydrogen bonding. In POPC systems, two out of four MDP1 interacted effectively, while all four MDP1 engaged with POPG/POPE membranes. Gathering all data together, MDP1 is efficacious in the reduction of intracellular VRSA and MRSA proved by culture and epi-fluorescent microscopy although further studies should be performed to increase the intracellular activity of MDP1.

Dataset Information

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.

Publications

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

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